COMPOUNDS AND METHODS FOR TREATING CORONA VIRUSES

Abstract

This invention provides compounds for the inhibition of papain-like proteases (PLpros) for the inhibition of viruses, including compounds of formula (I), and pharmaceutically acceptable salts thereof.

##STR00001##

Claims

1. A compound of formula (I), ##STR02161## or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of naphthyl, anthracenyl, 8-12 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-12 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R.sup.1; each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O; each R.sup.x is independently C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; m is 0, 1, or 2; is a single bond or double bond; n is 1 or 2; each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy optionally substituted with phenyl, OC.sub.1-6 alkylene-C.sub.1-6 alkoxy, C(O)OR.sup.i, S(O).sub.t, C.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.eR.sup.f, C(O)NR.sup.gR.sup.h, O-phenyl, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; wherein t is 0, 1, or 2; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), and NR.sup.eR.sup.f), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-(5-6 membered heteroaryl), C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f; or R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, C(O)NCH.sub.3OCH.sub.3, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, phenyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.0-6 alkylene-C.sub.1-6 alkoxy; each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy; each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C(O) C.sub.1-6alkyl, and C(O)OC.sub.1-6alkyl; and each R.sup.g, R.sup.h, and R.sup.i are independently, for each occurrence, H or C.sub.1-6 alkyl.

2. A compound of formula (I), ##STR02162## or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of naphthyl, anthracenyl, phenanthrenyl, 8-14 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-14 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R.sup.1, wherein when ring A is 8-12 membered bicyclic heterocyclyl or 8-12 membered partially unsaturated bicyclic carbocyclyl, R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O; each R is independently D, C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; m is 0, 1, 2, 3, or 4; is a single bond or double bond; n is 1 or 2; each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, OC.sub.1-6 alkylene-C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, C(O)OR.sup.i, S(O).sub.tC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, OS(O).sub.tC.sub.1-6haloalkyl, NR.sup.jR.sup.k, C(O)NR.sup.gR.sup.h, O-phenyl, B(OR.sup.m).sub.2, and hydroxy, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, C.sub.1-6 alkyl, C.sub.1-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), C.sub.1-6alkylene substituted with hydroxy, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C(O)-3-6 membered heterocyclyl, hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C(O)C.sub.1-6 alkyl; wherein t is 0, 1, or 2; R.sup.1a is selected from the group consisting of oxo, halo, C.sub.1-6haloalkyl, and C.sub.1-6alkoxy; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.7 is selected from H and C.sub.1-6 alkyl; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; R.sup.3 is selected from the group consisting of C.sub.1-20 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-(5-6 membered heteroaryl), C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AAR.sup.BB, wherein the C.sub.1-20 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, halo, hydroxy, and NR.sup.eR.sup.f; or R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, C(O)NCH.sub.3OCH.sub.3, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, wherein the aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl is not an imidazole; R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, (C.sub.0-20 alkylene)-(3-10 membered heterocyclyl), and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene, 3-10 membered heterocyclyl, and C.sub.3-6 cycloalkyl are each optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy and C.sub.1-6 alkoxy; each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy; each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C(O) C.sub.1-6alkyl, C(O)OC.sub.1-6alkyl, and S(O).sub.2C.sub.1-6alkyl; each R.sup.g, R.sup.h, and R.sup.i are independently, for each occurrence, H or C.sub.1-6 alkyl; and each R.sup.j and R.sup.k are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl optionally substituted with phenyl, C.sub.1-6 haloalkyl, C(O) C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, and C(O)OC.sub.1-6alkyl; each R.sup.3a is independently selected from the group consisting of D, C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-10 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, phenyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.0-6 alkylene-C.sub.1-6 alkoxy; and each R.sup.m is independently selected from hydrogen and C.sub.1-6alkyl or two (OR.sup.m) groups can be taken together with the boron atom to which they are attached to form pinacol ester; with the proviso that, when ring A is naphthyl, R.sup.4 is selected from the group consisting of hydrogen, F, Cl, C.sub.1-6 alkyl, and NR.sup.eR.sup.f; R.sup.5 is hydrogen; R.sup.6 is hydrogen or halo; X is CH.sub.2; and n is 1; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.1-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.XX), 3 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.XX, 4 membered heterocyclyl substituted with one or more (e.g., one, two, three, or four) R.sup.XX, 5 membered partially unsaturated heterocyclyl, 5 membered saturated heterocyclyl that has the point of attachment (to the phenyl) on the carbon atom of the heterocyclyl, 5 membered saturated heterocyclyl substituted with at least 2 (e.g., 2, 3, or 4) of R.sup.XX, 6-membered heterocyclyl with at least 2 (e.g., 2, 3, or 4) of R.sup.XX substituted on the carbon atoms of the heterocyclyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)O-C.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AAR.sup.BB, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; each R.sup.XX is independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene)-OH, C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, and R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy, and at least one of R.sup.AA and R.sup.BB is not hydrogen; or R.sup.AA is hydrogen and R.sup.BB is C.sub.1-6 alkylene-NR.sup.cR.sup.d.

3. The compound of claim 1 or 2, wherein the compound is a compound of formula (Ia): ##STR02163## or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 or 2.

4. The compound any one of claims 1-3, wherein the compound is a compound of formula (Ib): ##STR02164## or a pharmaceutically acceptable salt thereof, wherein: each of G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 is independently selected from CH and N; s is 0, 1, 2, or 3; wherein X, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined in claim 1 or 2.

5. The compound of any one of claims 1-4, wherein the compound is a compound of formula (Ic): ##STR02165## or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 4.

6. The compound of any one of claims 1-5, wherein the compound is a compound of formula (Id): ##STR02166## or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 4.

7. The compound of any one of claims 4-6, wherein G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH.

8. The compound of any one of claims 4-6, wherein G.sup.1 is N, and G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH; or G.sup.2 is N, and G.sup.1, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH.

9. The compound of any one of claims 4-6, wherein G.sup.3 is N, and G.sup.1, G.sup.2, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH; or G.sup.4 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.5, G.sup.6, and G.sup.7 are CH.

10. The compound of any one of claims 4-6, wherein G.sup.5 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.6, and G.sup.7 are CH; or G.sup.6 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, and G.sup.7 are CH.

11. The compound of any one of claims 4-6, wherein G.sup.7 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, and G.sup.6 are CH.

12. The compound of any one of claims 4-6, wherein s is 0.

13. The compound of any one of claims 4-6, wherein s is 1.

14. The compound of any one of claims 4-6, wherein s is 2.

15. The compound of any one of claims 1-3, wherein Ring A is naphthyl.

16. The compound of claim 15, wherein Ring A is selected from ##STR02167##

17. The compound of claim 2, wherein Ring A is anthracenyl.

18. The compound claim 2, wherein Ring A is phenanthrenyl.

19. The compound of any one of any one of claims 1-3, wherein Ring A is 8-14 membered bicyclic or tricyclic heteroaryl.

20. The compound of any one of claims 1-3 and 19, wherein Ring A is 10-membered bicyclic heteroaryl.

21. The compound of any one of claims 1-3, 19, and 20, wherein Ring A is quinolinyl.

22. The compound of claim 21, wherein Ring A is selected from the group consisting of ##STR02168##

23. The compound of claim 22, wherein Ring A is ##STR02169##

24. The compound of any one of claims 1-3, 19, and 20, wherein Ring A is isoquinolinyl, ##STR02170##

25. The compound of claim 24, wherein Ring A is selected from the group consisting of ##STR02171##

26. The compound of claim 2, wherein the compound is a compound of formula (Ie): ##STR02172## or a pharmaceutically acceptable salt thereof, wherein: ##STR02173## represents cyclopropylene or oxetan-3-ylene (i.e., ##STR02174## R.sup.1aa is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl; R.sup.1bb is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; E is selected from the group consisting of O, N(H), and N(C.sub.1-6 alkyl)-; R.sup.CC is H or C.sub.1-6 alkyl; R.sup.DD is H or C.sub.1-6 alkyl; R.sup.c is H or C.sub.1-6 alkyl; or R.sup.CC is H, and R.sup.DD and R.sup.c can be taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle; and R.sup.d is H or C.sub.1-6 alkyl.

27. The compound of claim 26, wherein ##STR02175## is cyclopropylene (i.e., ##STR02176##

28. The compound of claim 26, wherein ##STR02177## represents oxetan-3-ylene (i.e., ##STR02178##

29. The compound of any one of claims 26-28, wherein R.sup.1aa is C.sub.1-6 alkoxy.

30. The compound of any one of claims 26-28, wherein R.sup.1aa is C.sub.2-6 alkenyl.

31. The compound of any one of claim 26-30, wherein R.sup.1bb is H.

32. The compound of any one of claim 26-30, wherein R.sup.1bb is C.sub.1-6 alkyl.

33. The compound of any one of claims 26-32, wherein R.sup.2 is C.sub.1-6 alkyl.

34. The compound of any one of claims 26-33, wherein E is O.

35. The compound of any one of claims 26-33, wherein E is N(H).

36. The compound of any one of claims 26-33, wherein E is N(C.sub.1-6 alkyl)-.

37. The compound of any one of claims 26-36, wherein R.sup.CC is H, and R.sup.DD and R.sup.c are taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle.

38. The compound of any one of claims 26-37, wherein R.sup.d is H.

39. The compound of any one of claims 26-37, wherein R.sup.d is C.sub.1-6 alkyl.

40. The compound of any one of claims 1-4 and 7-25, wherein X is CH.sub.2.

41. The compound of any one of claims 1, 2, or 7-25, wherein X is CH.

42. The compound of any one of claims 1-4 or 7-25, wherein X is NH.

43. The compound of any one of claims 1-4 and 7-25, wherein X is O.

44. The compound of any one of claims 1-4 and 7-25, wherein n is 2 and one of X is O and the other X is CH.sub.2.

45. The compound of any one of claims 1, 2, 7-25, and 40-44 wherein m is 0.

46. The compound of any one of claims 1, 2, 7-25, and 40-44, wherein m is 1.

47. The compound of any one of claims 1, 2, 7-25, and 40-44, wherein m is 2.

48. The compound of any one of claims 2, 7-25, and 40-44, wherein m is 3.

49. The compound of any one of claims 2, 7-25, and 40-44, wherein m is 4.

50. The compound of any one of claims 1, 2, 7-25, and 40-47, wherein is a single bond.

51. The compound of any one of claims 1, 2, 7-25, and 40-47, wherein is a double bond.

52. The compound of any one of claims 1-4, 7-25, 40-43, and 45-51, wherein n is 1.

53. The compound of any one of claims 1-4, 7-25, 40-43, and 45-51, wherein n is 2.

54. The compound of any one of the claims 1, 3-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, S(O)C.sub.1-6alkyl, NR.sup.eR.sup.f, and hydroxy.

55. The compound of any one of the claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, halo, CN, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl; optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, S(O).sub.tC.sub.1-6alkyl, C(O)C.sub.1-6 alkyl, OS(O).sub.tC.sub.1-6haloalkyl, NR.sup.jR.sup.k and hydroxy.

56. The compound of any one of claims 1, 3-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, and C.sub.1-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

57. The compound of any one of claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, and C.sub.1-6 alkyl, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

58. The compound of any one of claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, NR.sup.jR.sup.k, wherein the 5-9 membered heteroaryl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, C.sub.1-6 alkyl, C.sub.1-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), C.sub.1-6alkylene substituted with hydroxy, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C(O)-3-6 membered heterocyclyl, hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C(O)C.sub.1-6 alkyl.

59. The compound of any one of claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, and NR.sup.jR.sup.k.

60. The compound of any one of claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, and 4- or 5-membered heterocyclyl.

61. The compound of any one of claims 2-6, 13, 14, 19, 20, and 40-53, wherein each R.sup.1 is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl.

62. The compound of any one of claims 1-5, 7-25, and 40-61, wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl.

63. The compound of any one of claims 2-5, 7-25, and 40-61, wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl.

64. The compound of any one of claims 2-5, 7-25, and 40-61, wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.

65. The compound of claim 64, wherein R.sup.2 is halo.

66. The compound of claim 64, wherein R.sup.2 is C.sub.1-6 alkyl.

67. The compound of claim 64, wherein R.sup.2 is C.sub.1-6 haloalkyl.

68. The compound of any one of claims 1, 3-25 and 40-67, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), and NR.sup.eR.sup.f), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-(O-3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl benzyl, and C(O)OC.sub.1-6 alkyl), and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

69. The compound of any one of claims 2-25 and 40-67, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-(O-3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl benzyl, and C(O)OC.sub.1-6 alkyl), and NR.sup.AAR.sup.BB, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

70. The compound of any one of claims 1, 3-25 and 40-67, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

71. The compound of any one of claims 1, 3-25 and 40-67, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

72. The compound of any one of claims 2-25 and 40-67, wherein R.sup.3 is NR.sup.AAR.sup.BB or C.sub.1-20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

73. The compound of any one of claims 2-25 and 40-67 wherein R.sub.3 is C.sub.1-20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

74. The compound of claim 1 or 68, wherein R.sup.A and R.sup.B are each independently H or C.sub.1-6 alkyl.

75. The compound of any one of claims 2-25 and 40-67, wherein R.sup.3 is NR.sup.AAR.sup.BB.

76. The compound of any one of claims 2, 69, and 75, wherein R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, and (C.sub.0-20 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, and C.sub.1-6 alkoxy.

77. The compound of any one of claims 2, 69, and 75, wherein R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, and (C.sub.1-20 alkylene)-(3-5 membered heterocyclyl), wherein the 3-5 membered heterocyclyl is optionally substituted with C.sub.1-6 alkyl.

78. The compound of any one of claim 2, 68-71, 76, or 77, wherein each R.sup.e and R.sup.d are independently, H or C.sub.1-6 alkyl.

79. The compound of any one of claims 1-25 and 40-67, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

80. The compound of any one of claims 1-25 and 40-67, wherein R.sup.3 is (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl).

81. The compound of any one of claims 2-25 and 40-67, wherein R.sup.3 is (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl).

82. The compound of any one of claims 1-5, 7-25, and 40-81, wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, and halo.

83. The compound of any one of claims 2-5, 7-25, and 40-81, wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, and halo.

84. The compound of any one of claims 2-5, 7-25, and 40-81, wherein R.sup.4 is selected from the group consisting of H, hydroxy, NR.sup.eR.sup.f, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl.

85. The compound of any one of claims 2-5, 7-25, and 40-81, wherein R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl.

86. The compound of any one of claims 1-5, 7-25, and 40-81, wherein R.sup.4 is H.

87. The compound of any one of claims 1, 3-25, and 40-67, wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

88. The compound of any one of claims 1-25 and 40-87, wherein R.sub.5 is H or C.sub.1-6 alkyl.

89. The compound of claim 88, wherein R.sup.5 is H.

90. The compound of claim 88, wherein R.sup.5 is C.sub.1-6 alkyl.

91. The compound of any one of claim 1-25 or 40-90, wherein R.sup.6 is H or C.sub.1-6 alkyl.

92. The compound of claim 91, wherein R.sup.6 is H.

93. The compound of claim 91, wherein R.sup.6 is C.sub.1-6 alkyl.

94. The compound of any one of claims 1-25, 40-73, 79, 82-86, and 88-93, wherein each R.sup.3a is independently selected from the group consisting of NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

95. The compound of any one of claims 2-25, 40-73, 79, 82-86, and 88-93, wherein each R.sup.3a is independently selected from the group consisting of D, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-10 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

96. The compound of any one of claims 1-25, 40-73, 79, 82-86, and 88-93, wherein each R.sup.3a is NR.sup.AR.sup.B.

97. The compound of any one of claims 1-25, 40-73, 79, 82-86, and 88-93, wherein each R.sup.3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C3.7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

98. The compound of any one of claims 2-25, 40-73, 79, 82-86, and 88-93, wherein each R.sup.3a is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, C(O)OC.sub.1-6 alkyl, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

99. The compound of any one of claims 1, 2, and 94-96, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sub.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy.

100. The compound of any one of claims 1, 2, and 99, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkylene-NR.sup.cR.sup.d.

101. The compound of any one of claims 1, 2, and 99, wherein each R.sup.A and R.sup.B are independently, for each occurrence, H or C.sub.1-6 alkyl.

102. The compound of any one of claims 2, 94, 95, 99, and 100, wherein each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl.

103. The compound of claims 2, 94, 95, 99, and 100, wherein each R.sup.c and R.sup.d are independently, for each occurrence, H or C.sub.1-6 alkyl.

104. The compound of claim 103, wherein each R.sup.c and R.sup.d are H.

105. The compound of any one of claims 1-25 and 40-104, wherein each R.sup.e and R.sup.f are H.

106. The compound of any one of claims 1-6, 13, 14, 19, 20, 40-53, and 62-105, wherein each of R.sup.g and R.sup.h are H.

107. The compound of any one of claims 1-6, 13, 14, 19, 20, 40-53, and 62-106, wherein Riis H.

108. The compound of any one of claims 1, 2, 7-25, and 40-107, wherein R.sup.x is C.sub.1-6 alkyl.

109. The compound of any one of claims 1, 2, 7-25, and 40-107, wherein R.sup.x is halo.

110. The compound of any one of claims 2, 7-25, and 40-107, wherein R is D.

111. A compound of formula (I-1), ##STR02179## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.1 is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; n is 0, 1, or 2; each of R.sup.2, R.sup.3, R.sup.4, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; and R.sup.5 is C.sub.1-6 alkylene-C(O)NH.sub.2, wherein each hydrogen of NH.sub.2 is optionally substituted.

112. The compound of claim 111, wherein n is 0.

113. The compound of claim 111 or 112, wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.6 are hydrogen.

114. The compound of any one of claims 111-113, wherein R.sup.5 is C.sub.1-6 alkylene-C(O)NHNHC(O)C.sub.2-6alkenylene-C(O)OC.sub.1-6 alkyl.

115. The compound of any one of claims 111-114, wherein R.sup.5 is C.sub.2 alkylene-C(O)NHNHC(O)-Czalkenylene-C(O)OCH.sub.3.

116. A compound of formula (II), ##STR02180## or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; each X is independently selected from the group consisting of CH.sup.2, CH, NH, and O; each R.sup.x is independently C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; m is 0, 1, or 2; is a single bond or double bond; n is 1 or 2; each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, O(C.sub.0-6 alkylene)-phenyl, SC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.eR.sup.f, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl optionally substituted with 3-7 membered heterocyclyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f, or R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy, each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy; each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and each R.sup.e and R.sup.f are independently, for each occurrence, H or C.sub.1-6 alkyl.

117. A compound of formula (II), ##STR02181## or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; each X is independently selected from the group consisting of CH.sub.2, CH, NH, and O; each R is independently C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; m is 0, 1, or 2; is a single bond or double bond; n is 1 or 2; each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, O(C.sub.0-6 alkylene)-phenyl, SC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.eR.sup.f, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl optionally substituted with 3-7 membered heterocyclyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.2-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein R.sup.3 is not N(H)C(O)CH.sub.3 or NH.sub.2; R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f, or R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy, each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo or C(O)OC.sub.1-6 alkyl, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy; each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and each R.sup.e and R.sup.f are independently, for each occurrence, H or C.sub.1-6 alkyl.

118. The compound of claim 116 or 117, wherein the compound is a compound of formula (IIa): ##STR02182## or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claims 116 or 117.

119. The compound of any one of claim 116-118, wherein the compound is a compound of formula (IIb): ##STR02183## or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; and R.sup.1-R.sup.6 are as defined in claim 119.

120. The compound of any one of claim 116-119, wherein the compound is a compound of formula (IIc): ##STR02184## or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 119.

121. The compound of any one of claims 116-118, wherein X is CH.sub.2.

122. The compound of claim 116-118, wherein X is NH.

123. The compound of claim 116-118, wherein X is O.

124. The compound of any one of claims 116, 117, and 121-123, wherein m is 0.

125. The compound of any one of claims 116, 117, and 121-123, wherein m is 1.

126. The compound of any one of claims 116, 117, and 121-123, wherein m is 2.

127. The compound of any one of claims 116, 117 and 121-126, wherein is a single bond.

128. The compound of any one of claims 116, 117 and 121-126, wherein is a double bond.

129. The compound of any one of claims 116-118 and 121-128, wherein n is 1.

130. The compound of any one of claims 116-118 and 121-128, wherein n is 2.

131. The compound of any one of claims 116-130, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, SC.sub.1-6alkyl, NR.sup.eR.sup.f, and hydroxy.

132. The compound of any one of claims 116-130, wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

133. The compound of any one of claim 116-119 or 121-132, wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl.

134. The compound of any one of claims 116, 117, and 133, wherein R.sup.2 is halo.

135. The compound of any one of claims 116, 117, and 133, wherein R.sup.2 is C.sub.1-6 alkyl.

136. The compound of any one of claims 116 and 118-135, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

137. The compound of any one of claims 117-135, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.2-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein R.sup.3 is not-N(H)C(O)CH.sub.3 or NH.sub.2.

138. The compound of any one of claims 116 and 118-135, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-(3-8 membered heterocycly) optionally substituted with C(O)OC.sub.1-6 alkyl, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

139. The compound of any one of claims 116-135, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

140. The compound of any one of claims 116, 117, and 139, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

141. The compound of any one of claims 116, 117, and 139, wherein R.sup.3 is 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

142. The compound of any one of 116-119 or 121-141, wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, and halo.

143. The compound of any one of claims 116, 117, and 142, wherein R.sup.4 is H.

144. The compound of any one of claims 116-119 and 121-135, wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

145. The compound of any one of claims 116-119 and 121-144, wherein R.sup.5 is H or C.sub.1-6 alkyl.

146. The compound of claim 145, wherein R.sup.5 is H.

147. The compound of claim 145, wherein R.sup.5 is C.sub.1-6 alkyl.

148. The compound of any one of claim 116-119 or 121-147, wherein R.sup.6 is H or C.sub.1-6 alkyl.

149. The compound of claim 148, wherein R.sup.6 is H.

150. The compound of claim 148, wherein R.sup.6 is C.sub.1-6 alkyl.

151. The compound of any one of claims 116-140, 142, 143, and 145-150, wherein each R.sup.3a is independently selected from the group consisting of NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

152. The compound of any one of claims 116, 117, and 151, wherein each R.sup.3a is NR.sup.AR.sup.B.

153. The compound of any one of claims 116, 117, and 151, wherein each R.sup.3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

154. The compound of any one of claims 116-153, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C36 cycloalkyl are each optionally substituted with hydroxy.

155. The compound of any one of claims 117-153, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo or C(O)OC.sub.1-6 alkyl, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy.

156. The compound of claim 154 or 155, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkylene-NR.sup.cR.sup.d.

157. The compound of claim 154 or 155, wherein each R.sup.A and R.sup.B are independently, for each occurrence, H or C.sub.1-6 alkyl.

158. The compound of any one of claims 116-157, wherein each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl.

159. The compound of claim 158, wherein each R.sup.c and R.sup.d are independently, for each occurrence, H or C.sub.1-6 alkyl.

160. The compound of claim 158, wherein each R.sup.c and R.sup.d are H.

161. The compound of any one of claims 116-160, wherein each R.sup.e and R.sup.f are H.

162. A compound of formula (III), ##STR02185## or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from naphthyl and 8-12 membered bicyclic heteroaryl, wherein the naphthyl and 8-12 membered bicyclic are optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; Y.sub.1 is N or CR.sup.6; Y.sub.2 is N or CR.sup.4; Y.sub.3 is N or CR.sup.5, Y.sub.4 is N or CR.sup.3; Y.sub.5 is N or CR.sup.2; each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O, wherein each R.sup.h is independently H or C.sub.1-6 alkyl; is a single bond or double bond; each R.sup.x is independently C.sub.1-6 alkyl or halo; n is 1 or 2; m is 0, 1, or 2; each R.sup.1 is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and hydroxy, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four)NR.sup.AR.sup.B or 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, and hydroxy; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; and each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.

163. The compound of claim 162, wherein Ring A is naphthyl.

164. The compound of claim 163, wherein Ring A is ##STR02186##

165. The compound of any one of claims 162-164, wherein at least one of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are N.

166. The compound of any one of claims 162-165, wherein Y.sup.1 is N.

167. The compound of claim 166, wherein Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are not N.

168. The compound of any one of claims 162-165, wherein Y.sup.2 is N.

169. The compound of claim 168, wherein Y.sup.1, Y.sup.3, Y.sup.4, and Y.sup.5 are not N.

170. The compound of any one of claims 162-165, wherein Y.sup.3 is N.

171. The compound of claim 170, wherein Y.sup.1, Y.sup.2, Y.sup.4, and Y.sup.5 are not N.

172. The compound of any one of claims 162-165, wherein Y.sup.2 and Y.sup.3 are N.

173. The compound of claim 172, wherein Y.sup.1, Y.sup.4, and Y.sup.5 are not N.

174. The compound of any one of claims 162-173, wherein X is CH.sub.2.

175. The compound of any one of claims 162-174, wherein n is 1.

176. The compound of any one of claims 162-175, wherein m is 0.

177. The compound of any one of claims 162-176, wherein R.sup.2 is C.sub.1-6 alkyl, e.g., methyl.

178. The compound of any one of claims 162-177, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four)NR.sup.AR.sup.B, e.g., O(CH.sub.2).sub.2N(CH.sub.3).sub.2.

179. The compound of any one of claims 162-177, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

180. The compound of any one of claims 162-167 and 170-179, wherein R.sup.4 is H.

181. The compound of any one of claims 162-169 and 172-180, wherein R.sup.5 is H.

182. A compound of formula (IV), ##STR02187## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; n is 0, 1, or 2; (A) R.sup.2 is C.sub.1-6 alkyl or halo; R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C(O)C.sub.1-6alkyl; O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, neither R.sub.7 nor R.sub.8 is methyl; R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy; or (B) R.sup.2 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: i) an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position or two oxygens, or ii) an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R.sup.3 position, and the remaining atoms in the ring are carbon, wherein the 5 or 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; R.sup.7 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl; R.sup.8 is hydrogen or C.sub.1-6 alkyl; each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.eR.sup.f, and 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2, wherein if one of R.sup.A and R.sup.B is C(O)-unsubstituted C.sub.1-6 alkyl, the other of R.sup.A and R.sup.B is not H, and wherein R.sup.A and R.sup.B are not-(CH.sub.2).sub.2NH.sub.2 or CH.sub.2C(CH.sub.3).sub.2NH.sub.2; each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6 alkyl, and each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6alkyl, wherein the compound is not a compound represented by: ##STR02188## or a stereoisomer or a pharmaceutically acceptable salt thereof.

183. The compound of claim 182, wherein n is 0.

184. The compound of claim 182 or 183, wherein R.sup.2 is C.sub.1-6 alkyl.

185. The compound of claim 182 or 183, wherein R.sup.2 is methyl.

186. The compound of claim 182 or 183, wherein R.sup.2 is halo.

187. The compound of claim 182 or 183, wherein R.sup.2 is hydrogen.

188. The compound of any one of claims 182-187, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C(O)C.sub.1-6alkyl; O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, R.sup.7 is not methyl; and R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy.

189. The compound of any one of claims 182-187, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, R.sup.7 is not methyl; and R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy.

190. The compound of any one of claims 182-187, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a,

191. The compound of any one of claims 182-187, wherein R.sup.3 is hydroxy.

192. The compound of any one of claims 182-187, wherein R.sup.3 is C(O)C.sub.1-6alkyl.

193. The compound of any one of claims 182-187, wherein R.sup.3 is O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl.

194. The compound of any one of claims 182-187, wherein R.sup.3 is NR.sup.AR.sup.B.

195. The compound of any one of claims 182-187, wherein R.sup.3 is and nitro.

196. The compound of any one of claims 182-195, wherein R.sup.4 is H.

197. The compound of any one of claims 182-196, wherein R.sup.5 is H.

198. The compound of any one of claims 182-197, wherein R.sup.6 is H.

199. The compound of any one of claims 182-198, wherein R.sup.7 is hydrogen.

200. The compound of any one of claims 182-198, wherein R.sup.7 is C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy.

201. The compound of any one of claims 182-198, wherein R.sup.7 is C.sub.2-6 alkynyl.

202. The compound of any one of claims 182-198, wherein R.sup.7 is C.sub.1-6 haloalkyl.

203. The compound of any one of claims 182-198, wherein R.sup.7 is cyano.

204. The compound of any one of claims 182-198, wherein R.sup.7 is 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl.

205. The compound of any one of claims 182-204, wherein R.sup.8 is hydrogen.

206. The compound of any one of claims 182-204, wherein R.sup.8 is C.sub.1-6 alkyl.

207. The compound of any one of claims 182-190 and 196-206, wherein R.sup.3a is NR.sup.eR.sup.f.

208. The compound of any one of claims 182-190 and 196-206, wherein R.sup.3a is 3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.

209. The compound of any one of claims 182-189 and 196-206, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

210. The compound of any one of claims 182-189 and 196-206, wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

211. The compound of any one of claims 182-189 and 196-206, wherein R.sup.A is H and R.sup.B is H.

212. The compound of any one of claims 182-189 and 196-206, wherein R.sup.A is H and R.sup.B is C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

213. The compound of any one of claims 182-189 and 196-206, wherein R.sup.A is H and R.sup.B is S(O).sub.2C.sub.1-2 alkyl.

214. The compound of any one of claims 182-189 and 196-206, wherein R.sup.A is H and R.sup.B is 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy.

215. The compound of any one of claims 182-189 and 196-206, wherein each R.sup.A is H and R.sup.B is pyrazolyl.

216. The compound of any one of claims 182-189 and 196-206, wherein each R.sup.A is C.sub.1-6 alkyl and R.sup.B is C(O)-unsubstituted C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

217. The compound of any one of claims 182-187 and 197-216, wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position or two oxygens, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

218. The compound of any one of claims 182-187 and 197-216, wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

219. The compound of any one of claims 182-187 and 197-216, wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R.sup.3 position, and the remaining atoms in the ring are carbon, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

220. A compound of formula (VI): ##STR02189## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: ##STR02190## is ##STR02191## or an optionally substituted phenyl; X is NR.sup.9 or a bond; Y is NR.sup.9, CH.sub.2, or a bond; R.sup.9 is selected from H and C.sub.1-6alkyl; ##STR02192## is a nitrogen containing 4-6 membered heterocyclylene or 4-6 membered heterocycle fused to phenyl; each of X.sup.1, X.sup.2, x.sup.3, X.sup.4, X.sup.3, and X.sup.6 is CH or N, wherein the CH may be substituted with R.sup.1; wherein when ##STR02193## is ##STR02194## ##STR02195## is not a 6-membered monocyclic heterocyclylene; each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, NR.sup.eR.sup.f, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; n is 0, 1, or 2; each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; R.sup.7 is selected from the group consisting of C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl; R.sup.8 is hydrogen; or R.sup.7 and R.sup.8 may be taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl or heterocyclyl ring; and each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6alkyl.

221. The compound of claim 220, wherein ##STR02196## is ##STR02197##

222. The compound of claim 220, wherein ##STR02198## is phenyl optionally substituted with C.sub.1-6 alkyl.

223. The compound of claim 220 or 221, wherein X is NR.sup.9.

224. The compound of claim 220 or 221, wherein X is a bond.

225. The compound of any one of claims 220-224, wherein Y is NR.sup.9.

226. The compound of any one of claims 220-224, wherein Y is CH.sub.2.

227. The compound of any one of claims 220-224, wherein Y is a bond.

228. The compound of any one of claims 220-227, wherein R.sup.9 is H.

229. The compound of any one of claims 220-227, wherein R.sup.9 is C.sub.1-6alkyl.

230. The compound of any one of claims 220-229, wherein ##STR02199## is a nitrogen containing 4-6 membered heterocyclylene, e.g., 4-5 membered heterocyclylene, 4-membered heterocyclylene, 5-membered heterocyclylene, 6-membered heterocyclylene, e.g., 6-membered monocyclic heterocyclylene, 6-membered bicyclic heterocyclylene.

231. The compound of any one of claims 220-229, wherein ##STR02200## is a nitrogen containing 4-6 membered heterocycle fused to phenyl, e.g., 4-membered heterocycle fused to phenyl, 5-membered heterocycle fused to phenyl, 6-membered heterocycle fused to phenyl.

232. The compound of any one of claims 220, 221, and 223-231, wherein R.sup.1 is C.sub.1-6 alkoxy.

233. The compound of any one of claims 220, 221, and 223-231, wherein R.sup.1 is 5-6 membered heteroaryl.

234. The compound of any one of claims 220, 221, and 223-231, wherein n is 0.

235. The compound of any one of claims 220, 221, and 223-233, wherein n is 1.

236. The compound of any one of claims 220-235, wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen and halo.

237. The compound of any one of claims 220-236, wherein R.sup.7 is C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy and R.sup.8 is hydrogen.

238. The compound of any one of claims 220-236, wherein R.sup.7 is methyl and R.sup.8 is hydrogen.

239. The compound of any one of claims 220-236, wherein R.sup.7 and R.sup.8 are taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl ring.

240. The compound of any one of claims 220-236, wherein R.sup.7 and R.sup.8 are taken together with the carbon to which they are attached to form a 3-4 membered heterocyclyl ring.

241. A compound of formula (VII): ##STR02201## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from: ##STR02202## Z is CH.sub.2 or NH, wherein any hydrogen atom of the CH.sub.2 or NH may be substituted with R.sup.1; each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.t(C.sub.1-6alkyl; NR.sup.eR.sup.f, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; t is 0, 1, or 2; n is 0, 1, or 2; each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; or R.sup.3 and R.sup.4 may be taken together with the atoms to which they are attached to form an aromatic 5-6 membered monocyclic ring fused to the phenyl to which R.sup.3 and R.sup.4 are attached; wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d; R.sup.7 is hydrogen or C.sub.1-6 alkyl; R.sup.8 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6haloalkyl; R.sup.9 is hydrogen or C.sub.1-6 alkyl; R.sup.10 is (5-6 membered heteroarylene)-(C.sub.0-6alkylene)-R.sup.11; R.sup.11 is 3-7 membered heterocyclyl or NR.sup.gR.sup.h, and R.sup.12 and R.sup.13 are hydrogen; or R.sup.7 and R.sup.9 may be taken together with the atoms to which they are attached to form a 5-6 membered heterocycle fused to the phenyl to which R.sup.9 is attached; R.sup.9 and R.sup.10 may be taken together with the atoms to which they are attached to form 6-membered heterocycle or cyclohexane ring fused to the phenyl to which R.sup.9 and R.sup.10 are attached; R.sup.12 and R.sup.13 may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R.sup.12 and R.sup.13 are attached; each R.sup.c and R.sup.d are independently H or C.sub.1-6 alkyl; and each R.sup.e and R.sup.f are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy; each R.sup.g and R.sup.h are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy, wherein when R.sup.g is hydrogen, R.sup.h is not hydrogen; wherein when R.sup.10 is (5-6 membered heteroarylene)-(C.sub.0-6alkylene)-(3-7 membered heterocyclyl), and R.sup.3 is NR.sup.cR.sup.d, R.sup.8 is hydrogen; and wherein when R.sup.g or R.sup.h is C.sub.3-6 cycloalkyl or 3-7 membered heterocyclyl and R.sup.3 is NR.sup.eR.sup.f, R.sup.e or R.sup.f is not 3-7 membered heterocyclyl.

242. The compound of claim 241, wherein ring A is ##STR02203##

243. The compound of claim 241, wherein ring A is ##STR02204##

244. The compound of claim 241 or 243, wherein Z is CH.sub.2 wherein the CH.sub.2 may be substituted with R.sup.1.

245. The compound of claim 241 or 243, wherein Z is NH, wherein the NH may be substituted with R.sub.1.

246. The compound of any one of claims 241 and 243-245, wherein tis 0.

247. The compound of any one of claim 241 or 242, wherein n is 0.

248. The compound of any one of claims 241-247, wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from hydrogen and NR.sup.eR.sup.f.

249. The compound of any one of claims 241-247, wherein R.sup.3 and R.sup.4 are taken together with the atoms to which they are attached to form an aromatic 5-6 membered monocyclic ring fused to the phenyl to which R.sup.3 and R.sup.4 are attached, wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d.

250. The compound of any one of claims 241-249, wherein R.sup.7 is hydrogen.

251. The compound of any one of claims 241-249, wherein R.sup.7 is C.sub.1-6 alkyl.

252. The compound of any one of claims 241-251, wherein R.sup.8 is hydrogen.

253. The compound of any one of claims 241-251, wherein R.sup.8 is C.sub.1-6 alkyl.

254. The compound of any one of claims 241, 242, and 247-253, wherein R.sup.9 is hydrogen.

255. The compound of any one of claims 241, 242, and 247-253, wherein R.sup.9 is C.sub.1-6 alkyl.

256. The compound of any one of claims 241, 242, and 247-253, wherein R.sup.11 is 3-7 membered heterocyclyl.

257. The compound of any one of claims 241, 242, and 247-253, wherein R.sup.11 is NR.sup.gR.sup.h.

258. The compound of any one of claims 241, 242, 247-249, 252, and 253, wherein R.sup.7 and R.sup.9 may be taken together with the atoms to which they are attached to form a 5-6 membered heterocycle fused to the phenyl to which R.sup.9 is attached.

259. The compound of any one of claims 241, 242, 247-253, 256, and 257, wherein R.sup.9 and R.sup.10 may be taken together with the atoms to which they are attached to form 6-membered heterocycle or cyclohexane ring fused to the phenyl to which R.sup.9 and R.sup.10 are attached.

260. The compound of any one of claims 241 and 243-257, wherein R.sup.12 and R.sup.13 may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R.sup.12 and R.sup.13 are attached.

261. The compound of any one of claims 241-260, wherein each R.sup.e and R.sup.f are independently selected from H and C.sub.3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

262. The compound of any one of claims 241-260, wherein each R.sup.e and R.sup.f are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

263. The compound of any one of claims 241-260, wherein each R.sup.e and R.sup.f are independently selected from H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

264. The compound of any one of claims 241-260, wherein each R.sup.e and R.sup.f are independently selected from H and C.sub.1-6 alkyl.

265. The compound of any one of claims 241, 242, 247-259, and 261-264, wherein each R.sup.g and R.sup.h are independently selected from H and C.sub.1-6 alkyl.

266. The compound of any one of claims 241, 242, 247-259, and 261-264, wherein each R.sup.e and R.sup.h are independently selected from H and C.sub.3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

267. The compound of any one of claims 241, 242, 247-259, and 261-264 wherein each R.sup.g and R.sup.h are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

268. The compound of any one of claims 241, 242, 247-259, and 261-264 wherein each R.sup.g and R.sup.h are independently selected from the group consisting of H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy. 106.

269. A compound of formula (VIII): ##STR02205## or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein B is selected from: ##STR02206## each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; n is 0, 1, or 2; each of R.sup.2, R.sup.3, R.sup.4, R.sub.5, and R.sub.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; or R.sup.4 and R.sup.5 may be taken together with the atoms to which they are attached to form 5-membered heteroaryl fused to the phenyl to which R.sup.4 and R.sup.5 are attached; R.sup.9 is hydrogen or C.sub.1-6 alkyl; each R.sup.10 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, and C(O)NH(C.sub.1-6 alkylene) Ph wherein the Ph is optionally substituted with halogen; m is 0, 1, or 2; R.sup.6 and R.sup.9 may be taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R.sup.6 is attached; each of R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-6 alkyl, or C.sub.1-6haloalkyl, or R.sup.7 and R.sup.8 may be taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring; wherein when R.sup.9 is methyl, R.sup.7 and R.sup.8 are not methyl; wherein when R.sup.9 is hydrogen, at least one of R.sup.2 and R.sup.6 is not hydrogen; each of R.sup.e and R.sup.f is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, and C(O)CH.sub.2Ph.

270. The compound of claim 269, wherein B is ##STR02207##

271. The compound of claim 269, wherein B is ##STR02208##

272. The compound of any one of claims 269-271, wherein n is 0.

273. The compound of any one of claims 269, 270, and 272, wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, NR.sup.eR.sup.f, NO.sub.2, and C.sub.1-6 alkyl.

274. The compound of any one of claims 269, 270, 272, and 273, wherein R.sup.4 and R.sup.5 may be taken together with the atoms to which they are attached to form 5-membered heteroaryl fused to the phenyl to which R.sup.4 and R.sup.5 are attached.

275. The compound of any one of claims 269, 270, and 272-274, wherein R.sup.9 is hydrogen.

276. The compound of any one of claims 269, 270, and 272-274, wherein R.sup.9 is C.sub.1-6 alkyl.

277. The compound of any one of claims 269 and 271-276, wherein R.sup.10 is C(O)NH(C.sub.1-6 alkylene) Ph wherein the Ph is optionally substituted with halogen.

278. The compound of any one of claims 269 and 271-276, wherein m is 0.

279. The compound of any one of claims 269 and 271-276, wherein m is 1.

280. The compound of any one of claims 269, 270, and 272-276, wherein R.sup.6 and R.sup.9 are taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R.sup.6 is attached.

281. The compound of any one of claims 269-280, wherein each of R.sup.7 is hydrogen.

282. The compound of any one of claims 269-280, wherein each of R.sup.7 is C.sub.1-6 alkyl.

283. The compound of any one of claims 269-280, wherein R.sup.7 and R.sup.8 are taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring.

284. The compound of any one of claims 269-280, wherein each of R.sup.8 is hydrogen.

285. The compound of any one of claims 269-280, wherein each of R.sup.8 is C.sub.1-6 alkyl.

286. A compound of formula (IX): ##STR02209## or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; n is 0, 1, or 2; R.sup.2 is C.sub.1-6 alkyl; R.sup.3 is selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; R.sup.6 is hydrogen or C.sub.1-6 alkyl; and each of R.sup.e and R.sup.f is independently selected from hydrogen and C.sub.1-6 alkyl.

287. The compound of any one of claim 286, wherein n is 0.

288. The compound of claim 286 or 287, wherein R.sup.2 is methyl.

289. The compound of any one of claims 286-288, wherein R.sup.3 is NR.sup.eR.sup.f.

290. The compound of any one of claims 286-289, wherein R.sup.6 is hydrogen.

291. The compound of any one of claims 286-289, wherein R.sup.6 is C.sub.1-6 alkyl.

292. The compound of any one of claims 286-291, wherein R.sup.e and R.sup.f are hydrogen.

293. A compound of formula (X): ##STR02210## or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; n is 0, 1, or 2; R.sup.2 is C.sub.1-6 alkyl; and R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl or NR.sup.eR.sup.f; and R.sup.4 is hydrogen or C.sub.1-6 alkyl; R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6haloalkyl; R.sup.6 is hydrogen or C.sub.1-6 alkyl; or R.sup.5 and R.sup.6 may be taken together with the carbon to which they are attached to form 3-4 membered cycloalkyl or heterocycle ring; and each of R.sup.e and R.sup.f is independently selected from hydrogen and C.sub.1-6 alkyl.

294. The compound of any one of claim 293, wherein n is 0.

295. The compound of claim 293 or 294, wherein R.sup.2 is methyl.

296. The compound of any one of claims 293-295, wherein R.sup.3 is NR.sup.eR.sup.f.

297. The compound of any one of claims 293-295, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with NR.sup.eR.sup.f.

298. The compound of any one of claims 293-295, wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl.

299. The compound of any one of claims 293-298, wherein R.sup.4 is hydrogen.

300. The compound of any one of claims 293-298, wherein R.sup.4 is C.sub.1-6 alkyl.

301. The compound of any one of claims 293-300, wherein R.sup.5 is hydrogen.

302. The compound of any one of claims 293-300, wherein R.sup.5 is C.sub.1-6 alkyl.

303. The compound of any one of claims 293-302, wherein R.sup.6 is hydrogen.

304. The compound of any one of claims 293-302, wherein R.sup.6 is C.sub.1-6 alkyl.

305. The compound of any one of claims 293-300, wherein R.sup.5 and R.sup.6 are taken together with the carbon to which they are attached to form 3-4 membered cycloalkyl ring.

306. The compound of any one of claims 293-300, wherein R.sup.5 and R.sup.6 may be taken together with the carbon to which they are attached to form 3-4 membered heterocycle ring.

307. The compound of claim 1 or 2, wherein the compound is a compound of formula (Ie): ##STR02211## or a pharmaceutically acceptable salt thereof, wherein: ##STR02212## represents cyclopropylene or oxetan-3-ylene (i.e., ##STR02213## R.sup.1aa is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl; R.sup.1bb is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, and C.sub.1-6 alkyl; R.sup.3 is selected from C.sub.1-6 alkoxy or NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with C.sub.1-6 alkyl; and R.sup.A and R.sup.B are independently selected from the group consisting of H, C.sub.1-6 alkyl, and C.sub.1-6 alkylene-NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d are independently selected from H and C.sub.1-6 alkyl.

308. The compound of claim 307, wherein ##STR02214## is cyclopropylene (i.e., ##STR02215##

309. The compound of claim 307, wherein ##STR02216## represents oxetan-3-ylene (i.e., ##STR02217##

310. The compound of any one of claims 307-309, wherein R.sup.1aa is C.sub.1-6 alkoxy.

311. The compound of any one of claims 307-309, wherein R.sup.1aa is C.sub.2-6 alkenyl.

312. The compound of any one of claim 307-311, wherein R.sup.1bb is H.

313. The compound of any one of claim 307-311, wherein R.sup.1bb is C.sub.1-6 alkyl.

314. The compound of any one of claims 307-313, wherein R.sup.2 is C.sub.1-6 alkyl.

315. The compound of any one of claims 307-314, wherein R.sup.3 is C.sub.1-6 alkoxy.

316. The compound claim 315, wherein the C.sub.1-6 alkoxy is substituted with 3-8 membered heterocyclyl.

317. The compound claim 315, wherein the C.sub.1-6 alkoxy is substituted with 3-8 membered heterocyclyl substituted with methyl.

318. The compound of any one of claims 307-314, wherein R.sup.3 is NR.sup.AR.sup.B.

319. The compound of claim 318, wherein R.sup.A is C.sub.1-6 alkylene-NR.sup.cR.sup.d and R.sup.B is H or C.sub.1-6 alkyl.

320. The compound of claim 319, wherein R.sup.c and R.sup.d are C.sub.1-6 alkyl.

321. The compound of claim 319, wherein R.sup.c and R.sup.d are H.

322. The compound of claim 319, wherein R.sup.c is C.sub.1-6 alkyl and R.sup.d is H.

323. The compound of claim 318, wherein R.sup.A and R.sup.B are C.sub.1-6 alkyl.

324. The compound of claim 318, wherein R.sup.A and R.sup.B are H.

325. The compound of claim 318, wherein R.sup.A is C.sub.1-6 alkyl and R.sup.B is H.

326. A pharmaceutical composition comprising a compound of any one of claims 1-325, or a pharmaceutically salt thereof, and one or more pharmaceutically acceptable excipients.

327. A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-325, or the pharmaceutical composition of claim 326.

328. A method of preventing a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-325, or the pharmaceutical composition of claim 326.

329. The method of claim 327 or 328, wherein the viral infection is a coronaviral infection.

330. The method of claim 327 or 328, wherein the viral infection is caused by a coronavirus.

331. The method of claim 330, wherein the coronavirus is SARS-COV-2.

332. The method of any one of claims 327-331, wherein the viral infection is chronic.

333. The method of any one of claims 327-331, wherein the viral infection is acute.

334. A method of inhibiting PLPro in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-325, or the pharmaceutical composition of claim 326.

335. A method of preventing replication of a virus in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-325, or the pharmaceutical composition of claim 326.

336. The method of claim 335, wherein the virus is a coronavirus.

337. The method of claim 336, wherein the coronavirus is SARS-Cov-2.

Description

DETAILED DESCRIPTION

[0055] This invention provides compounds for the inhibition of papain-like proteases (PLpros) which are essential for viral replication. In certain embodiments inhibition of PLpro directly inhibits viral replication. In certain embodiments inhibition of PLpro inhibits the dysregulation of signaling cascades in infected cells that absent inhibition leads to cell death in surrounding uninfected cells.

Definitions

[0056] As used herein, the term alkyl refers to a saturated monovalent chain of carbon atoms, which may be optionally branched, the term alkenyl refers to an unsaturated monovalent chain of carbon atoms including at least one double bond, which may be optionally branched, the term alkylene refers to a saturated bivalent chain of carbon atoms, which may be optionally branched, and the term cycloalkylene refers to a saturated bivalent chain of carbon atoms, which may be optionally branched, a portion of which forms a ring.

[0057] As used herein, the term alkynyl refers to a monovalent chain of carbon atoms with one or more (e.g., one, two, three, or four) carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds).

[0058] As used herein, the term alkylene is generally refers to a bivalent saturated hydrocarbon group wherein the hydrocarbon group may be a straight-chained or a branched-chain hydrocarbon group. Non-limiting illustrative examples include methylene, 1,2-ethylene, 1-methyl-1,2-ethylene, 1,4-butylene, 2,3-dimethyl-1,4-butylene, 2-methyl-2-ethyl-1,5-pentylene, and the like.

[0059] The term cycloalkyl as used herein generally refers to a monovalent, saturated hydrocarbon ring. The term cycloalkenyl as used herein refers to a monovalent hydrocarbon ring containing one or more (e.g., one, two, three, or four) unsaturated bonds.

[0060] As used herein, the term carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (3-12 membered carbocyclyl) and zero heteroatoms in the non-aromatic ring system.

[0061] As used herein the term isotopic derivative refers to compounds wherein one or more (e.g., one, two, three, or four) atoms is isotopically enriched for example with more than about 50%, 60%, 70%, 80%, 90%, 95%, or 99% of an isotope. Isotopes are atoms with the same number of protons but a different number of neutrons (for example hydrogen has one proton and the isotope of hydrogen named deuterium has one proton and one neutron). Non-limiting examples of isotopes include isotopes of hydrogen (for example deuterium), carbon, nitrogen, oxygen, fluorine, and chlorine.

[0062] Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (C6-14 aryl). Aryl groups include, but are not limited to, phenyl and naphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an unsubstituted aryl) or substituted (a substituted aryl) with one or more (e.g., one, two, three, or four) substituents.

[0063] The terms bicycle and bicyclic as used herein include molecular fragments or radicals that include two fused cycles wherein the cycles are independently selected from aryl, heteroaryl, cycloalkyl, heterocycle, and cycloalkenyl.

[0064] The terms tricycle and tricyclic as used herein include molecular fragments or radicals that include three fused cycles wherein the cycles are independently selected from aryl, heteroaryl, cycloalkyl, heterocycle, and cycloalkenyl.

[0065] The terms heteroalkyl and heteroalkylene as used herein includes molecular fragments or radicals comprising monovalent and divalent, respectively, groups that are formed from a linear or branched chain of carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, such as alkoxyalkyl, alkyleneoxyalkyl, aminoalkyl, alkylaminoalkyl, alkyleneaminoalkyl, alkylthioalkyl, alkylenethioalkyl, alkoxyalkylaminoalkyl, alkylaminoalkoxyalkyl, alkyleneoxyalkylaminoalkyl, and the like. It is to be understood that neither heteroalkyl nor heteroalkylene includes oxygen-oxygen fragments. It is also to be understood that neither heteroalkyl nor heteroalkylene includes oxygen-sulfur fragments, unless the sulfur is oxidized as S(O) or S(O).sub.2.

[0066] As used herein, the terms heterocycle and heterocyclyl refer to a non-aromatic ring comprising one or more (e.g., one, two, three, or four) heteroatoms (e.g., N, O, and/or S), or monovalent radical thereof, respectively, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, such as, but not limited to, tetrahydrofuran, aziridine, pyrrolidine, oxazolidine, 3-methoxypyrrolidine, 3-methylpiperazine, and the like. A heterocycle or heterocyclyl may be optionally fused to an aromatic or non-aromatic ring. As used herein, the term heterocyclylene refers to a bivalent radical of a heterocycle.

[0067] As used herein, the term cycloheteroalkyl generally refers to an optionally branched chain of atoms that includes both carbon and at least one heteroatom, where the chain optionally includes one or more unsaturated bonds, and where at least a portion of the chain forms one or more rings. As used herein, it is understood that the term cycloheteroalkyl also includes heterocycloalkyl, heterocycle, and heterocyclyl. The term heterocycloalkenyl as used herein refers to a monovalent chain of carbon atoms and heteroatoms containing one or more unsaturated bonds, a portion of which forms a ring, wherein the heteroatoms are selected from nitrogen, oxygen or sulfur. Illustrative cycloheteroalkyls include, but are not limited to, tetrahydrofuryl, bis(tetrahydrofuranyl), pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, dihydrofuryl, pyrrollinyl, dihydropyranyl, and the like. It is also to be understood that cycloheteroalkyl includes polycyclic radicals, including fused bicycles, spiro bicycles, and the like.

[0068] As used herein, the term acyl refers to hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl attached as a substituent through a carbonyl group, such as, but not limited to, formyl, acetyl, pivalolyl, benzoyl, phenacetyl, and the like.

[0069] Heteroaryl refers to a radical of a 5-14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms (e.g., O, N, and/or S) provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (5-12 membered heteroaryl). In heteroaryl groups that contain one or more (e.g., one, two, three, or four) nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more (e.g., one, two, three, or four) heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more (e.g., one, two, three, or four) aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). As used herein, the term heteroarylene refers to a divalent radical of a heteroaryl.

[0070] As used herein, haloalkyl is generally taken to mean an alkyl group wherein one or more (e.g., one, two, three, or four) hydrogen atoms is replaced with a halogen atom, independently selected in each instance from the group consisting of fluorine, chlorine, bromine and iodine. Non-limiting, illustrative examples include, difluoromethyl, 2,2,2-trifluoroethyl, 2-chlorobutyl, 2-chloro-2-propyl, trifluoromethyl, bromodifluoromethyl, and the like.

[0071] Alkoxyl or alkoxy refers to an alkyl group singularly bonded to an oxygen atom, having the formula RO. Alkoxyls include, for example, methoxy (CH.sub.3O) and ethoxy, (CH.sub.3CH.sub.2O). A cycloalkoxyl refers to a cycloalkyl group singularly bonded to an oxygen atom, which includes aryloxy groups, in which an aryl group is singular bonded to oxygen, for example a phenoxy group (C.sub.6H.sub.5O). Similarly, the term heteroalkoxyl refers to a heteroalkyl group singularly bonded to an oxygen atom and the term cycloheteroalkoxyl refers to a cycloheteroalkyl singularly bonded to an oxygen atom.

[0072] As used herein, the term haloalkoxy refers to a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., OCHCF.sub.2 or OCF.sub.3.

[0073] Halo or halogen, independently or as part of another substituent, generally refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term halide by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom.

[0074] As used herein, the term optionally substituted includes a wide variety of groups that replace one or more (e.g., one, two, three, or four) hydrogens on a carbon, nitrogen, oxygen, or sulfur atom, including monovalent and divalent groups. For example, optional substitution of carbon includes, but is not limited to, halo, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, arylalkyl, acyl, acyloxy, and the like. In one aspect, optional substitution of aryl carbon includes, but is not limited to, halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like. Illustratively, optional substitution of nitrogen, oxygen, and sulfur includes, but is not limited to, alkyl, haloalkyl, aryl, arylalkyl, acyl, and the like, as well as protecting groups, such as alkyl, ether, ester, and acyl protecting groups, and pro-drug groups. It is further understood that each of the foregoing optional substituents may themselves be additionally optionally substituted, such as with halo, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, and the like.

[0075] It is understood that substitutions and any functional group may be independently ortho-, para-, or meta-. It is understood that cyclic groups may be aromatic or non-aromatic.

[0076] Stereoisomers: It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed isomers. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers and those that are non-superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or () isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a racemic mixture.

[0077] Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

Compounds

[0078] In one aspect, provided herein are compounds of formula (I),

##STR00022## [0079] or a pharmaceutically acceptable salt thereof, wherein: [0080] Ring A is selected from the group consisting of naphthyl, anthracenyl, 8-12 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-12 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R.sup.1; [0081] each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x); [0082] each R.sup.x is independently C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; [0083] m is 0, 1, or 2; [0084] is a single bond or double bond; [0085] n is 1 or 2; [0086] each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy optionally substituted with phenyl, OC.sub.1-6 alkylene-C.sub.1-6 alkoxy, C(O)OR.sup.i, S(O).sub.tC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.eR.sup.f, C(O)NR.sup.gR.sup.h, O-phenyl, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; wherein t is 0, 1, or 2; [0087] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0088] R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), and NR.sup.eR.sup.f), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-(5-6 membered heteroaryl), C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; [0089] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f, or [0090] R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, C(O)NCH.sub.3OCH.sub.3, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; [0091] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0092] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0093] each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, phenyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.0-6 alkylene-C.sub.1-6 alkoxy; [0094] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy; [0095] each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or [0096] R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; [0097] each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C(O)C.sub.1-6alkyl, and C(O)OC.sub.1-6alkyl; and [0098] each R.sup.g, R.sup.h, and R.sup.i are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0099] In another aspect, provided herein are compounds of formula (I),

##STR00023## [0100] or a pharmaceutically acceptable salt thereof, wherein: [0101] Ring A is selected from the group consisting of naphthyl, anthracenyl, phenanthrenyl, 8-14 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-14 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R.sup.1, [0102] wherein when ring A is 8-12 membered bicyclic heterocyclyl or 8-12 membered partially unsaturated bicyclic carbocyclyl, R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, [0103] each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x); [0104] each R.sup.x is independently D, C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; [0105] m is 0, 1, 2, 3, or 4; [0106] is a single bond or double bond; [0107] n is 1 or 2; [0108] each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, OC.sub.1-6 alkylene-C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, C(O)OR.sup.i, S(O).sub.tC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, OS(O).sub.tC.sub.1-6haloalkyl, NR.sup.jR.sup.k, C(O)NR.sup.gR.sup.h, O-phenyl, B(OR.sup.m).sub.2, and hydroxy, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, C.sub.1-6 alkyl, C.sub.1-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), C.sub.1-6alkylene substituted with hydroxy, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C(O)-3-6 membered heterocyclyl, hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C(O)C.sub.1-6 alkyl; wherein t is 0, 1, or 2; [0109] R.sup.1a is selected from the group consisting of oxo, halo, C.sub.1-6haloalkyl, and C.sub.1-6alkoxy; [0110] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0111] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0112] R.sup.7 is selected from H and C.sub.1-6 alkyl; [0113] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0114] R.sup.3 is selected from the group consisting of C.sub.1-20 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-(5-6 membered heteroaryl), C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AAR.sup.BB, wherein the C.sub.1-20 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; [0115] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, halo, hydroxy, and NR.sup.eR.sup.f, or [0116] R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, C(O)NCH.sub.3OCH.sub.3, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, wherein the aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl is not an imidazole; [0117] R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, (C.sub.0-20 alkylene)-(3-10 membered heterocyclyl), and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene, 3-10 membered heterocyclyl, and C.sub.3-6 cycloalkyl are each optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy and C.sub.1-6 alkoxy; [0118] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy; [0119] each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or [0120] R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; [0121] each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C(O)C.sub.1-6alkyl, C(O)OC.sub.1-6alkyl, and S(O).sub.2C.sub.1-6alkyl; [0122] each R.sup.g, R.sup.h, and R.sup.i are independently, for each occurrence, H or C.sub.1-6 alkyl; and [0123] each R.sup.j and R.sup.k are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl optionally substituted with phenyl, C.sub.1-6 haloalkyl, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, and C(O)OC.sub.1-6alkyl; [0124] each R.sup.3a is independently selected from the group consisting of D, C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-10 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, phenyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.0-6 alkylene-C.sub.1-6 alkoxy; and [0125] each R.sup.m is independently selected from hydrogen and C.sub.1-6alkyl or two (OR.sup.m) groups can be taken together with the boron atom to which they are attached to form pinacol ester,

##STR00024## [0126] with the proviso that, when ring A is naphthyl, R.sup.4 is selected from the group consisting of hydrogen, F, Cl, C.sub.1-6 alkyl, and NR.sup.eR.sup.f; R.sup.5 is hydrogen; R.sup.6 is hydrogen or halo; X is CH.sub.2; and n is 1; [0127] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0128] R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.1-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.XX), 3 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.XX, 4 membered heterocyclyl substituted with one or more (e.g., one, two, three, or four) R.sup.XX, 5 membered partially unsaturated heterocyclyl, 5 membered saturated heterocyclyl that has the point of attachment (to the phenyl) on the carbon atom of the heterocyclyl, 5 membered saturated heterocyclyl substituted with at least 2 (e.g., 2, 3, or 4) of R.sup.XX, 6-membered heterocyclyl with at least 2 (e.g., 2, 3, or 4) of R.sup.XX substituted on the carbon atoms of the heterocyclyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AAR.sup.BB, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a. [0129] each R.sup.XX is independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene)-OH, C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f; and [0130] R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy, and at least one of R.sup.AA and R.sup.BB is not hydrogen; or R.sup.AA is hydrogen and R.sup.BB is C.sub.1-6 alkylene-NR.sup.cR.sup.d.

[0131] In another aspect, provided herein are compounds of formula (I-A),

##STR00025## [0132] or a pharmaceutically acceptable salt thereof, wherein: [0133] Ring A is selected from the group consisting of naphthyl, anthracenyl, phenanthrenyl, 8-14 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-14 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R.sup.1, [0134] wherein when ring A is 8-12 membered bicyclic heterocyclyl or 8-12 membered partially unsaturated bicyclic carbocyclyl, R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, [0135] each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x); [0136] each R.sup.x is independently D, C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; [0137] m is 0, 1, 2, 3, or 4; [0138] is a single bond or double bond; [0139] n is 1 or 2; [0140] each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, OC.sub.1-6 alkylene-C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, C(O)OR.sup.i, S(O).sub.tC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, OS(O).sub.tC.sub.1-6haloalkyl, NR.sup.jR.sup.k, C(O)NR.sup.gR.sup.h, O-phenyl, B(OR.sup.m).sub.2, and hydroxy, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, C.sub.1-6 alkyl, C.sub.1-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), C.sub.1-6alkylene substituted with hydroxy, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C(O)-3-6 membered heterocyclyl, hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C(O)C.sub.1-6 alkyl; wherein t is 0, 1, or 2; [0141] R.sup.1a is selected from the group consisting of oxo, halo, C.sub.1-6haloalkyl, and C.sub.1-6alkoxy; [0142] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0143] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0144] R.sup.7 is selected from H and C.sub.1-6 alkyl; [0145] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0146] R.sup.3 is selected from the group consisting of C.sub.1-20 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-(5-6 membered heteroaryl), C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)O(C.sub.1-6alkyl), C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AAR.sup.BB, wherein the C.sub.1-20 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a; [0147] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, halo, hydroxy, and NR.sup.eR.sup.f, or [0148] R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, C(O)NCH.sub.3OCH.sub.3, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, wherein the aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl is not an imidazole; [0149] R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, (C.sub.0-20 alkylene)-(3-10 membered heterocyclyl), and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene, 3-10 membered heterocyclyl, and C.sub.3-6 cycloalkyl are each optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy and C.sub.1-6 alkoxy; [0150] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy; [0151] each R.sup.e and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or [0152] R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; [0153] each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C(O)C.sub.1-6alkyl, C(O)OC.sub.1-6alkyl, and S(O).sub.2C.sub.1-6alkyl; [0154] each R.sup.g, R.sup.h, and R.sup.i are independently, for each occurrence, H or C.sub.1-6 alkyl; and [0155] each R.sup.j and R.sup.k are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl optionally substituted with phenyl, C.sub.1-6 haloalkyl, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, and C(O)OC.sub.1-6alkyl; [0156] each R.sup.3a is independently selected from the group consisting of D, C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-10 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, phenyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.0-6 alkylene-C.sub.1-6 alkoxy; and [0157] each R.sup.m is independently selected from hydrogen and C.sub.1-6alkyl or two (OR.sup.m) groups can be taken together with the boron atom to which they are attached to form pinacol ester,

##STR00026##

and [0158] R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C(O)C.sub.1-6 alkyl, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy or C.sub.1-6 alkoxy, and at least one of R.sup.AA and R.sup.BB is not hydrogen; or R.sup.AA is hydrogen and R.sup.BB is C.sub.1-6 alkylene-NR.sup.cR.sup.d.

[0159] In some embodiments, the compound of formula (I), (I), or (I-A) is a compound of formula (Ia):

##STR00027##

[0160] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0161] In some embodiments, the compound of formula (I), (I), or (I-A) is a compound of formula (Ib):

##STR00028##

[0162] or a pharmaceutically acceptable salt thereof, wherein: [0163] each of G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 is independently selected from CH and N; [0164] s is 0, 1, 2, or 3;

[0165] wherein X, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined above.

[0166] In some embodiments, the compound of formula (I), (I), or (I-A) is a compound of formula (Ic):

##STR00029##

[0167] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0168] In some embodiments, the compound of formula (I), (I), or (I-A) is a compound of formula (Id):

##STR00030##

[0169] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0170] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein G.sup.1 is N, and G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH; or G.sup.2 is N, and G.sup.1, G.sup.3, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein G.sup.3 is N, and G.sup.1, G.sup.2, G.sup.4, G.sup.5, G.sup.6, and G.sup.7 are CH; or G.sup.6 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.5, G.sup.6, and G.sup.7 are CH. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein G.sup.5 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.6, and G.sup.7 are CH; or G.sup.6 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, and G.sup.7 are CH. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein G.sup.7 is N, and G.sup.1, G.sup.2, G.sup.3, G.sup.4, G.sup.5, and G.sup.6 are CH.

[0171] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein s is 0. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein s is 1. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein s is 2.

[0172] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is naphthyl.

[0173] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is selected from

##STR00031##

[0174] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein Ring A is anthracenyl. In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein Ring A is phenanthrenyl.

[0175] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein Ring A is 8-14 membered bicyclic or tricyclic heteroaryl. In some embodiments, Ring A is 10-membered bicyclic heteroaryl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is quinolinyl.

[0176] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is selected from the group consisting of

##STR00032##

[0177] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is

##STR00033##

[0178] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is isoquinolinyl,

##STR00034##

[0179] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein Ring A is selected from the group consisting of

##STR00035##

[0180] In some embodiments, the compound of formula (I) or (I-A) is a compound of formula (Ie):

##STR00036##

[0181] or a pharmaceutically acceptable salt thereof, wherein:

##STR00037##

represents cyclopropylene or oxetan-3-ylene (i.e.,

##STR00038## [0182] R.sup.1aa is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl; [0183] R.sup.1bb is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; [0184] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; [0185] R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; [0186] E is selected from the group consisting of O, N(H), and N(C.sub.1-6 alkyl)-; [0187] R.sup.CC is H or C.sub.1-2 alkyl; [0188] R.sup.DD is H or C.sub.1-2 alkyl; [0189] R.sup.c is H or C.sub.1-6 alkyl; or [0190] R.sup.CC is H, and R.sup.DD and R.sup.c can be taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle; and [0191] R.sup.d is H or C.sub.1-6 alkyl.

[0192] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein

##STR00039##

is cyclopropylene (i.e.,

##STR00040##

[0193] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein

##STR00041##

represents oxetan-3ylene (i.e.,

##STR00042##

[0194] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.1aa is C.sub.1-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.1aa is C.sub.2-6 alkenyl.

[0195] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein Rhu 1bb is H. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein Rhu 1bb is C.sub.1-6 alkyl.

[0196] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.2 is C.sub.1-6 alkyl.

[0197] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein E is O. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein E is N(H). In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein E is N(C.sub.1-6 alkyl)-.

[0198] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.CC is H, and R.sup.DD and R.sup.e are taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle.

[0199] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.d is H. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.d is C.sub.1-6 alkyl.

[0200] In some embodiments, the compound of formula (I), (I), or (I-A) is a compound of formula (Ie):

##STR00043##

or a pharmaceutically acceptable salt thereof, wherein:

##STR00044##

represents cyclopropylene or oxetan-3-ylene (i.e.,

##STR00045## [0201] R.sup.1aa is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl; [0202] R.sup.1bb is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl; [0203] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; [0204] R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, and C.sub.1-6 alkyl; [0205] R.sup.3 is selected from C.sub.1-6 alkoxy or NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with C.sub.1-6 alkyl; and [0206] R.sup.A and R.sup.B are independently selected from the group consisting of H, C.sub.1-6 alkyl, and C.sub.1-6 alkylene-NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d are independently selected from H and C.sub.1-6 alkyl.

[0207] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein

##STR00046##

is cyclopropylene (i.e.,

##STR00047##

[0208] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein

##STR00048##

represents oxetan-3-ylene (i.e.,

##STR00049##

[0209] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.1aa is C.sub.1-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.1aa is C.sub.2-6 alkenyl.

[0210] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein Rhu 1bb is H. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein Rhu 1bb is C.sub.1-6 alkyl.

[0211] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.2 is C.sub.1-6 alkyl.

[0212] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.3 is C.sub.1-6 alkoxy. In some embodiments, the C.sub.1-6 alkoxy is substituted with 3-8 membered heterocyclyl. In some embodiments, the C.sub.1-6 alkoxy is substituted with 3-8 membered heterocyclyl substituted with methyl.

[0213] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.3 is NR.sup.AR.sup.B.

[0214] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.A is C.sub.1-6 alkylene-NR.sup.cR.sup.d and R.sup.B is H or C.sub.1-6 alkyl.

[0215] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.c and R.sup.d are C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.c and R.sup.d are H. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.e is C.sub.1-6 alkyl and R.sup.d is H.

[0216] In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.A and R.sup.B are C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.A and R.sup.B are H. In some embodiments, compounds of the disclosure have a structure of formula (Ie), wherein R.sup.A is C.sub.1-6 alkyl and R.sup.B is H.

[0217] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein X is CH.sub.2. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein X is CH. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein X is NH. In some embodiments, compounds of the disclosure have a structure of f formula (I), (I), or (I-A), wherein X is O.

[0218] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein n is 2 and one of X is O and the other X is CH.sub.2.

[0219] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein m is 1. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein m is 2. In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein m is 3. In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein m is 4.

[0220] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein is a single bond. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein is a double bond.

[0221] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein n is 1. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein n is 2.

[0222] In some embodiments, compounds of the disclosure have a structure of f formula (I), (I), or (I-A), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, S(O)C.sub.1-6alkyl, NR.sup.eR.sup.f, and hydroxy.

[0223] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, halo, CN, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl; optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, S(O), C.sub.1-6alkyl, C(O)C.sub.1-6 alkyl, OS(O).sub.tC.sub.1-6haloalkyl, NR.sup.jR.sup.k and hydroxy.

[0224] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, and C.sub.1-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

[0225] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, and C.sub.1-6 alkyl, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

[0226] In some embodiments, compounds of the disclosure have a structure of formula (I), or (I-A), wherein each R.sup.1 is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1a, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.2-6 alkenyl optionally substituted with C.sub.3-6 cycloalkyl or phenyl substituted with C.sub.0-6alkyl, C.sub.2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, C.sub.1-6 alkoxy optionally substituted with phenyl, NR.sup.jR.sup.k, wherein the 5-9 membered heteroaryl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, C.sub.1-6 alkyl, C.sub.1-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), C.sub.1-6alkylene substituted with hydroxy, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C(O)-3-6 membered heterocyclyl, hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C(O)C.sub.1-6 alkyl.

[0227] In some embodiments, compounds of the disclosure have a structure of formula (I), or (I-A), wherein each R.sup.1 is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, and NR.sup.jR.sup.k.

[0228] In some embodiments, compounds of the disclosure have a structure of formula (I), or (I-A), wherein each R.sup.1 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, 5- or 6-membered monocyclic heteroaryl, and 4- or 5-membered heterocyclyl.

[0229] In some embodiments, compounds of the disclosure have a structure of formula (I), or (I-A), wherein each R.sup.1 is selected from the group consisting of H, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl.

[0230] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sub.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sub.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.2 is halo. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.2 is C.sub.1-6 alkyl.

[0231] In some embodiments, compounds of the disclosure have a structure of formula (I), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), and NR.sup.eR.sup.f), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-(O-3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl benzyl, and C(O)OC.sub.1-6 alkyl), and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0232] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C.sub.0-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6alkyl, (C.sub.1-6alkylene-OH), C(O)OC.sub.1-6 alkyl, and NR.sup.eR.sup.f, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, (C.sub.0-6alkylene)-(O-3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl benzyl, and C(O)OC.sub.1-6 alkyl), and NR.sup.AAR.sup.BB, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0233] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0234] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl), OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0235] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.3 is NR.sup.AAR.sup.BB or C.sub.1-20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0236] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.3 is C.sub.1-20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0237] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.A and R.sup.B are each independently H or C.sub.1-6 alkyl.

[0238] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.3 is NR.sup.AAR.sup.BB.

[0239] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, and (C.sub.0-20 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, and C.sub.1-6 alkoxy.

[0240] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.AA and R.sup.BB are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-20 alkylene-NR.sup.cR.sup.d, and (C.sub.1-20 alkylene)-(3-5 membered heterocyclyl), wherein the 3-5 membered heterocyclyl is optionally substituted with C.sub.1-6 alkyl.

[0241] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein each R.sup.e and R.sup.d are independently, H or C.sub.1-6 alkyl.

[0242] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0243] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.3 is (C.sub.0-6alkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl).

[0244] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.3 is (C.sub.0-6alkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, benzyl and C(O)OC.sub.1-6 alkyl).

[0245] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, and halo.

[0246] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, and halo.

[0247] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.4 is selected from the group consisting of H, hydroxy, NR.sup.eR.sup.f, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I) of (I-A), wherein R.sup.4 is selected from the group consisting of H, hydroxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkyl.

[0248] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.4 is H.

[0249] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0250] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.5 is H or C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.5 is H. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.5 is C.sub.1-6 alkyl.

[0251] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.6 is H or C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.6 is H. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.6 is C.sub.1-6 alkyl.

[0252] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.3a is independently selected from the group consisting of NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0253] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein each R.sup.3a is independently selected from the group consisting of D, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-10 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0254] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.3a is NR.sup.AR.sup.B. In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0255] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein each R.sup.3a is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, C(O)OC.sub.1-6 alkyl, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0256] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy.

[0257] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkylene-NR.sup.cR.sup.d.

[0258] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.A and R.sup.B are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0259] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.e and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl.

[0260] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.e and R.sup.d are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0261] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.e and R.sup.d are H.

[0262] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each R.sup.e and R.sup.f are H.

[0263] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein each of R.sup.g and R.sup.h are H.

[0264] In some embodiments, compounds of the disclosure have a structure of formula (I), (I), or (I-A), wherein R.sup.i is H.

[0265] In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.x is C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.x is halo. In some embodiments, compounds of the disclosure have a structure of formula (I) or (I-A), wherein R.sup.x is D.

[0266] In another aspect, provided herein are compounds of formula (I-1),

##STR00050## [0267] or a pharmaceutically acceptable salt thereof, wherein: [0268] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; [0269] n is 0, 1, or 2; [0270] each of R.sup.2, R.sup.3, R.sup.4, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; and [0271] R.sup.5 is C.sub.1-6 alkylene-C(O)NH.sub.2, wherein each hydrogen of NH.sub.2 is optionally substituted.

[0272] In some embodiments, compounds of the disclosure have a structure of formula (I-1), wherein n is 0.

[0273] In some embodiments, compounds of the disclosure have a structure of formula (I-1), wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.6 are hydrogen.

[0274] In some embodiments, compounds of the disclosure have a structure of formula (I-1), wherein R.sup.5 is C.sub.1-6 alkylene-C(O)NHNHC(O)C.sub.2-6alkenylene-C(O)OC.sub.1-6 alkyl.

[0275] In some embodiments, compounds of the disclosure have a structure of formula (I-1), wherein R.sup.5 is C.sub.2 alkylene-C(O)NHNHC(O)-Czalkenylene-C(O)OCH.sub.3.

[0276] In another aspect, provided herein are compounds of formula (II),

##STR00051## [0277] or a pharmaceutically acceptable salt thereof, [0278] wherein [0279] Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; [0280] each X is independently selected from the group consisting of CH.sup.2, CH, NH, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x); [0281] each R.sup.x is independently C.sub.1-6 alkyl or halo when R.sup.m is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; [0282] m is 0, 1, or 2; [0283] is a single bond or double bond; [0284] n is 1 or 2; [0285] each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, O(C.sub.0-6 alkylene)-phenyl, SC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.eR.sup.f, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl optionally substituted with 3-7 membered heterocyclyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; [0286] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0287] R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-CN, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, [0288] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f; or [0289] R.sub.3 and R.sub.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; [0290] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0291] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl;

[0292] each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy, [0293] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy; [0294] each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or [0295] R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and [0296] each R.sup.e and R.sup.f are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0297] In another aspect, provided herein are compounds of formula (II),

##STR00052## [0298] or a pharmaceutically acceptable salt thereof, wherein [0299] Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; [0300] each X is independently selected from the group consisting of CH.sub.2, CH, NH, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x); [0301] each R.sup.x is independently C.sub.1-6 alkyl or halo when R.sup.x is substituted on a carbon atom or each R.sup.x is independently C.sub.1-6 alkyl when R.sup.x is substituted on a nitrogen atom; [0302] m is 0, 1, or 2; [0303] is a single bond or double bond; [0304] n is 1 or 2; [0305] each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, 3-7 membered heterocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, O(C.sub.0-6 alkylene)-phenyl, SC.sub.1-6alkyl, SC.sub.1-6 haloalkyl, NR.sup.cR.sup.f, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, C.sub.1-6 alkyl optionally substituted with 3-7 membered heterocyclyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; [0306] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl; [0307] R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.2-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein R.sup.3 is not-N(H) C(O)CH.sub.3 or NH.sub.2; [0308] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, hydroxy, and NR.sup.eR.sup.f; or [0309] R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; [0310] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0311] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0312] each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, C(O)NR.sup.cR.sup.d, 3-8 membered heterocyclyl, phenyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy, [0313] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo or C(O)OC.sub.1-6 alkyl, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy; [0314] each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl, or [0315] R.sup.c and R.sup.d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and [0316] each R.sup.e and R.sup.f are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0317] In some embodiments, the compound of formula (II) or (II) is a compound of formula (IIa):

##STR00053##

[0318] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0319] In some embodiments, the compound of formula (II) or (II) is a compound of formula (IIb):

##STR00054## [0320] or a pharmaceutically acceptable salt thereof, wherein: [0321] s is 0, 1, 2, or 3; and [0322] R.sup.1-R.sup.6 are as defined above.

[0323] In some embodiments, the compound of formula (II) or (II) is a compound of formula (IIc):

##STR00055##

[0324] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0325] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein X is CH.sub.2. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein X is NH. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein X is O.

[0326] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein m is 1. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein m is 2.

[0327] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein is a single bond. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein is a double bond.

[0328] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein n is 1. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein n is 2.

[0329] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, SC.sub.1-6alkyl, NR.sup.eR.sup.f, and hydroxy.

[0330] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.1 is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-7 carbocyclyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkylene-NR.sup.AR.sup.B, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.

[0331] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.3-6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.2 is halo. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.2 is C.sub.1-6 alkyl.

[0332] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0333] In some embodiments, compounds of the disclosure have a structure of formula (II), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-3-8 membered heterocyclyl optionally substituted with C(O)OC.sub.1-6 alkyl, C.sub.2-6 alkyl optionally substituted with NR.sup.cR.sup.d, O-5-6 membered heteroaryl, C.sub.0-6 alkylene-C(O)NR.sup.eR.sup.f, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein R.sup.3 is not-N(H) C(O)CH.sub.3 or NH.sub.2.

[0334] In some embodiments, compounds of the disclosure have a structure of formula (II), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, O-(3-8 membered heterocycly) optionally substituted with C(O)OC.sub.1-6 alkyl, and NR.sup.AR.sup.B, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0335] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl, OC.sub.3-7 cycloalkyl optionally substituted with NR.sup.cR.sup.d, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0336] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0337] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.3 is 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0338] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, and halo.

[0339] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.4 is H.

[0340] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C.sub.0-6 alkylene)-C(O)NR.sup.eR.sup.f, C(O)C.sub.1-6heteroalkyl, (C.sub.0-6 alkylene)-NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-OH, oxo, C(O)OH, and (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0341] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.5 is H or C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.5 is H. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.5 is C.sub.1-6 alkyl.

[0342] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.6 is H or C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.6 is H. In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein R.sup.6 is C.sub.1-6 alkyl.

[0343] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.3a is independently selected from the group consisting of NR.sup.AR.sup.B, C.sub.1-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and (C.sub.0-6 alkylene)-(C.sub.3-6 cycloalkyl optionally substituted with NR.sup.cR.sup.d), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0344] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.3a is NR.sup.AR.sup.B.

[0345] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OC.sub.1-6 alkyl, C.sub.1-6 alkyelene-C.sub.3-7 cycloalkyl, benzyl, C.sub.1-6 alkylene-OH, and C.sub.1-6 alkylene-C.sub.1-6 alkoxy.

[0346] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy.

[0347] In some embodiments, compounds of the disclosure have a structure of formula (II), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylene-NR.sup.cR.sup.d, 3-6 membered heterocyclyl optionally substituted with oxo or C(O)OC.sub.1-6 alkyl, 5-6 membered heteroaryl optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, (C.sub.0-6 alkylene)-phenyl, and (C.sub.0-6 alkylene)-C.sub.3-6 cycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.3-6 cycloalkyl are each optionally substituted with hydroxy.

[0348] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkylene-NR.sup.cR.sup.d.

[0349] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.A and R.sup.B are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0350] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.c and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, benzyl, and C(O)OC.sub.1-6 alkyl.

[0351] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.e and R.sup.d are independently, for each occurrence, H or C.sub.1-6 alkyl.

[0352] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.e and R.sup.d are H.

[0353] In some embodiments, compounds of the disclosure have a structure of formula (II) or (II), wherein each R.sup.e and R.sup.f are H.

[0354] In another aspect, provided herein are compounds of formula (III),

##STR00056## [0355] or a pharmaceutically acceptable salt thereof, wherein: [0356] Ring A is selected from naphthyl and 8-12 membered bicyclic heteroaryl, wherein the naphthyl and 8-12 membered bicyclic are optionally substituted with one or more (e.g., one, two, three, or four) R.sup.1; [0357] Y.sub.1 is N or CR.sup.6; [0358] Y.sub.2 is N or CR.sup.4; [0359] Y.sub.3 is N or CR.sup.5; [0360] Y.sub.4 is N or CR.sup.3; [0361] Y.sub.5 is N or CR.sub.2; [0362] each X is independently selected from the group consisting of CH.sub.2, CH, NR.sup.h, and O (any hydrogen atom of the NH.sub.2, CH, NR.sub.h (when R.sub.h=H) may be substituted with R.sub.x), wherein each R.sup.h is independently H or C.sub.1-6 alkyl; [0363] is a single bond or double bond; each R is independently C.sub.1-6 alkyl or halo; [0364] n is 1 or 2; [0365] m is 0, 1, or 2; [0366] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, and CN; [0367] R.sup.2 is selected from the group consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; [0368] R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and hydroxy, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four)-NR.sup.AR.sup.B or 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; [0369] R.sup.4 is selected from the group consisting of H, C.sub.1-6 alkyl, halo, and hydroxy; [0370] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0371] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; and [0372] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.

[0373] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Ring A is naphthyl. In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Ring A is

##STR00057##

[0374] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein at least one of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are N. In some embodiments, Y.sup.1 is N.

[0375] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are not N. In some embodiments, Y.sup.2 is N.

[0376] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Y.sup.1, Y.sup.3, Y.sup.4, and Y.sup.5 are not N. In some embodiments, Y.sup.3 is N.

[0377] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Y.sup.1, Y.sup.2, Y.sup.4, and Y.sup.5 are not N. In some embodiments, Y.sup.2 and Y.sup.3 are N.

[0378] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein Y.sup.1, Y.sup.4, and Y.sup.5 are not N.

[0379] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein X is CH.sub.2.

[0380] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein n is 1.

[0381] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein m is 0.

[0382] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein R.sup.2 is C.sub.1-6 alkyl, e.g., methyl.

[0383] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four)NR.sup.AR.sup.B, e.g., O(CH.sub.2).sub.2N(CH.sub.3).sub.2.

[0384] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0385] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein R.sup.4 is H.

[0386] In some embodiments, compounds of the disclosure have a structure of formula (III), wherein R.sup.5 is H.

[0387] In another aspect, provided herein are compounds of formula (IV),

##STR00058##

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: [0388] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; [0389] n is 0, 1, or 2; [0390] (A) R.sup.2 is C.sub.1-6 alkyl or halo; [0391] R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C(O)C.sub.1-6alkyl; O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, neither R.sup.7 nor R.sup.8 is methyl; [0392] R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy; or [0393] (B) R.sup.2 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy; [0394] R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: [0395] i) an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position or two oxygens, or [0396] ii) an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R.sup.3 position, and the remaining atoms in the ring are carbon, [0397] wherein the 5 or 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl; [0398] R.sup.5 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0399] R.sup.6 is selected from the group consisting of H, halo, and C.sub.1-6 alkyl; [0400] R.sup.7 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl; [0401] R.sup.8 is hydrogen or C.sub.1-6 alkyl; [0402] each R.sup.3a is independently selected from the group consisting of C.sub.1-6 alkyl, NR.sup.eR.sup.f, and 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl; [0403] each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2, wherein if one of R.sup.A and R.sup.B is C(O)-unsubstituted C.sub.1-6 alkyl, the other of R.sup.A and R.sup.B is not H, and wherein R.sup.A and R.sup.B are not-(CH.sub.2).sub.2NH.sub.2 or CH.sub.2C(CH.sub.3).sub.2NH.sub.2; [0404] each R.sup.e and R.sup.d are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6 alkyl, and [0405] each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6alkyl,
wherein the compound is not a compound represented by:

##STR00059##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0406] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein n is 0.

[0407] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.2 is C.sub.1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.2 is methyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.2 is halo. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.2 is hydrogen.

[0408] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, C(O)C.sub.1-6alkyl; O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, R.sup.7 is not methyl; and R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy.

[0409] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkoxy, hydroxy, O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl, NR.sup.AR.sup.B, and nitro, wherein the C.sub.1-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a, and wherein if R.sup.3 is hydroxy, nitro, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2, R.sup.7 is not methyl; and R.sup.4 is H, C.sub.1-6 alkyl, halo, and hydroxy.

[0410] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R.sup.3a.

[0411] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is hydroxy. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is C(O)C.sub.1-6alkyl.

[0412] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl.

[0413] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is NR.sup.AR.sup.B. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 is and nitro.

[0414] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.4 is H.

[0415] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.5 is H.

[0416] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.6 is H.

[0417] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is C.sub.2-6 alkynyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is C.sub.1-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is cyano. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.7 is 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl.

[0418] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.8 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.8 is C.sub.1-6 alkyl.

[0419] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3a is NR.sup.eR.sup.f. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3a is 3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.

[0420] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

[0421] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein each R.sup.A and R.sup.B are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-2 alkyl, C(O)-unsubstituted C.sub.1-6 alkyl, 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and pyrazolyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

[0422] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.A is H and R.sup.B is H. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.A is H and R.sup.B is C.sub.1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.A is H and R.sup.B is S(O).sub.2C.sub.1-2 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.A is H and R.sup.B is 5-6 membered heteroaryl substituted with C.sub.1-6 alkyl or C.sub.1-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein each R.sup.A is H and R.sup.B is pyrazolyl. In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein each R.sup.A is C.sub.1-6 alkyl and R.sup.B is C(O)-unsubstituted C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH.sub.2.

[0423] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position or two oxygens, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0424] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5-membered ring has at least one nitrogen connected to the phenyl at the R.sup.3 position, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0425] In some embodiments, compounds of the disclosure have a structure of formula (IV), wherein R.sup.3 and R.sup.4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R.sup.3 position, and the remaining atoms in the ring are carbon, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, (C.sub.0-6 alkylene)-3-7 membered heterocyclyl optionally substituted with C.sub.1-6alkyl.

[0426] In another aspect, provided here are compounds of formula (VI):

##STR00060##

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

##STR00061##

is

##STR00062##

or an optionally substituted phenyl; [0427] X is NR.sup.9 or a bond; [0428] Y is NR.sup.9, CH.sub.2, or a bond; [0429] R.sup.9 is selected from H and C.sub.1-6alkyl;

##STR00063##

is a nitrogen containing 4-6 membered heterocyclylene or 4-6 membered heterocycle fused to phenyl; [0430] each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, and X.sup.6 is CH or N, wherein the CH may be substituted with R.sup.1; [0431] wherein [0432] when

##STR00064##

##STR00065##

is not a 6-membered monocyclic heterocyclylene; [0433] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, NR.sup.eR.sup.f, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; [0434] n is 0, 1, or 2; [0435] each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; [0436] R.sup.7 is selected from the group consisting of C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with C.sub.1-6 alkyl; [0437] R.sup.8 is hydrogen; or [0438] R.sup.7 and R.sup.8 may be taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl or heterocyclyl ring; and [0439] each R.sup.e and R.sup.f are independently, for each occurrence, selected from the group consisting of H, C.sub.1-6 alkyl, and C(O)OC.sub.1-6alkyl.

[0440] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein

##STR00066##

[0441] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein

##STR00067##

is phenyl optionally substituted with C.sub.1-6 alkyl.

[0442] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein X is NR.sup.9. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein X is a bond.

[0443] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein Y is NR.sup.9. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein Y is CH.sub.2. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein Y is a bond.

[0444] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.9 is H. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.9 is C.sub.1-6alkyl.

[0445] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein

##STR00068##

is a nitrogen containing 4-6 membered heterocyclylene, e.g., 4-membered heterocyclylene, 5-membered heterocyclylene, 6-membered heterocyclylene.

[0446] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein

##STR00069##

is a nitrogen containing 4-6 membered heterocyclylene, e.g., 4-5 membered heterocyclylene, 4-membered heterocyclylene, 5-membered heterocyclylene, 6-membered heterocyclylene, e.g., 6-membered monocyclic heterocyclylene, 6-membered bicyclic heterocyclylene.

[0447] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.1 is C.sub.1-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.1 is 5-6 membered heteroaryl.

[0448] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein n is 0. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein n is 1.

[0449] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen and halo.

[0450] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.7 is C.sub.1-6 alkyl optionally substituted with C.sub.1-6 alkoxy and R.sup.8 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.7 is methyl and R.sup.8 is hydrogen.

[0451] In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.7 and R.sup.8 are taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl ring. In some embodiments, compounds of the disclosure have a structure of formula (VI), wherein R.sup.7 and R.sup.8 are taken together with the carbon to which they are attached to form a 3-4 membered heterocyclyl ring.

[0452] In another aspect, provided herein are compounds of formula (VII):

##STR00070##

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: [0453] ring A is selected from:

##STR00071## [0454] Z is CH.sub.2 or NH, wherein any hydrogen atom of the CH.sub.2 or NH may be substituted with R.sup.1; [0455] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, S(O).sub.tC.sub.1-6alkyl; NR.sup.eR.sup.f, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; [0456] t is 0, 1, or 2; [0457] n is 0, 1, or 2; [0458] each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; or R.sup.3 and R.sup.4 may be taken together with the atoms to which they are attached to form an aromatic 5-6 membered monocyclic ring fused to the phenyl to which R.sup.3 and R.sup.4 are attached; [0459] wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d, [0460] R.sup.7 is hydrogen or C.sub.1-6 alkyl; [0461] R.sup.8 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6haloalkyl; [0462] R.sup.9 is hydrogen or C.sub.1-6 alkyl; [0463] R.sup.10 is (5-6 membered heteroarylene)-(C.sub.0-6alkylene)-R.sup.11; [0464] R.sup.11 is 3-7 membered heterocyclyl or NR.sup.gR.sup.h, and [0465] R.sup.12 and R.sup.13 are hydrogen; or [0466] R.sup.7 and R.sup.9 may be taken together with the atoms to which they are attached to form a 5-6 membered heterocycle fused to the phenyl to which R.sup.9 is attached; [0467] R.sup.9 and R.sup.10 may be taken together with the atoms to which they are attached to form 6-membered heterocycle or cyclohexane ring fused to the phenyl to which R.sup.9 and R.sup.10 are attached; [0468] R.sup.12 and R.sup.13 may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R.sup.12 and R.sup.13 are attached; [0469] each R.sup.c and R.sup.d are independently H or C.sub.1-6 alkyl; and [0470] each R.sup.e and R.sup.f are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy; [0471] each R.sup.g and R.sup.h are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy, wherein when R.sup.g is hydrogen, R.sup.h is not hydrogen; [0472] wherein when R.sup.10 is (5-6 membered heteroarylene)-(C.sub.0-6alkylene)-(3-7 membered heterocyclyl), and R.sup.3 is NR.sup.cR.sup.d, R.sup.8 is hydrogen; and [0473] wherein when R.sup.g or R.sup.h is C.sub.3-6 cycloalkyl or 3-7 membered heterocyclyl and R.sup.3 is NR.sup.eR.sup.f, R.sup.e or R.sup.f is not 3-7 membered heterocyclyl.

[0474] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein ring A is

##STR00072##

[0475] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein ring A is

##STR00073##

[0476] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein Z is CH.sub.2 wherein the CH.sub.2 may be substituted with R.sup.1. In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein Z is NH, wherein the NH may be substituted with R.sup.1.

[0477] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein t is 0.

[0478] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein n is 0.

[0479] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from hydrogen and NR.sup.eR.sup.f.

[0480] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.3 and R.sup.4 are taken together with the atoms to which they are attached to form an aromatic 5-6 membered monocyclic ring fused to the phenyl to which R.sup.3 and R.sup.4 are attached, wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) C.sub.1-6 alkyl optionally substituted with hydroxy or NR.sup.cR.sup.d.

[0481] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.7 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.7 is C.sub.1-6 alkyl.

[0482] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.8 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.8 is C.sub.1-6 alkyl.

[0483] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.9 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.9 is C.sub.1-6 alkyl.

[0484] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.11 is 3-7 membered heterocyclyl. In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.11 is NR.sup.gR.sup.h.

[0485] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.7 and R.sup.9 may be taken together with the atoms to which they are attached to form a 5-6 membered heterocycle fused to the phenyl to which R.sup.9 is attached.

[0486] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.9 and R.sup.10 may be taken together with the atoms to which they are attached to form 6-membered heterocycle or cyclohexane ring fused to the phenyl to which R.sup.9 and R.sup.10 are attached.

[0487] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein R.sup.12 and R.sup.13 may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R.sup.12 and R.sup.13 are attached.

[0488] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.e and R.sup.f are independently selected from H and C.sub.3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0489] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.e and R.sup.f are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0490] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.e and R.sup.f are independently selected from H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0491] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.e and R.sup.f are independently selected from H and C.sub.1-6 alkyl.

[0492] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.g and R.sup.h are independently selected from H and C.sub.1-6 alkyl.

[0493] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.g and R.sup.h are independently selected from H and C.sub.3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0494] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.g and R.sup.h are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0495] In some embodiments, compounds of the disclosure have a structure of formula (VII), wherein each R.sup.g and R.sup.h are independently selected from the group consisting of H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C.sub.1-6 alkyl, halogen, OH, C(O)OC.sub.1-6alkyl, and C.sub.1-6 alkoxy.

[0496] In another aspect, provided herein are compounds of formula (VIII)

##STR00074##

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein [0497] B is selected from:

##STR00075## [0498] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; [0499] n is 0, 1, or 2; [0500] each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; or [0501] R.sup.4 and R.sup.5 may be taken together with the atoms to which they are attached to form 5-membered heteroaryl fused to the phenyl to which R.sup.4 and R.sup.5 are attached; [0502] R.sup.9 is hydrogen or C.sub.1-6 alkyl; [0503] each R.sup.10 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, and C(O)NH(C.sub.1-6 alkylene)Ph wherein the Ph is optionally substituted with halogen; [0504] m is 0, 1, or 2; [0505] R.sup.6 and R.sup.9 may be taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R.sup.6 is attached; [0506] each of R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-6 alkyl, or C.sub.1-6haloalkyl, or R.sup.7 and R.sup.8 may be taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring; [0507] wherein when R.sup.9 is methyl, R.sup.7 and R.sup.8 are not methyl; [0508] wherein when R.sup.9 is hydrogen, at least one of R.sup.2 and R.sup.6 is not hydrogen; [0509] each of R.sup.e and R.sup.f is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, and C(O)CH.sub.2Ph.

[0510] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein B is

##STR00076##

[0511] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein B is

##STR00077##

[0512] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein n is 0.

[0513] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, NR.sup.eR.sup.f, NO.sub.2, and C.sub.1-6 alkyl.

[0514] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.4 and R.sup.5 may be taken together with the atoms to which they are attached to form 5-membered heteroaryl fused to the phenyl to which R.sup.4 and R.sup.5 are attached.

[0515] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.9 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.9 is C.sub.1-6 alkyl.

[0516] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.10 is C(O)NH(C.sub.1-6 alkylene)Ph wherein the Ph is optionally substituted with halogen.

[0517] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein m is 1.

[0518] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.6 and R.sup.9 are taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R.sup.6 is attached.

[0519] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein each of R.sup.7 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein each of R.sup.7 is C.sub.1-6 alkyl.

[0520] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein R.sup.7 and R.sup.8 are taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring.

[0521] In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein each of R.sup.8 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII), wherein each of R.sup.8 is C.sub.1-6 alkyl.

[0522] In another aspect, provided herein are compounds of formula (IX):

##STR00078##

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein [0523] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; [0524] n is 0, 1, or 2; [0525] R.sup.2 is C.sub.1-6 alkyl; [0526] R.sup.3 is selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl; [0527] R.sup.6 is hydrogen or C.sub.1-6 alkyl; and each of R.sup.e and R.sup.f is independently selected from hydrogen and C.sub.1-6 alkyl.

[0528] In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein n is 0.

[0529] In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein R.sup.2 is methyl.

[0530] In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein R.sup.3 is NR.sup.eR.sup.f.

[0531] In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein R.sup.6 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein R.sup.6 is C.sub.1-6 alkyl.

[0532] In some embodiments, compounds of the disclosure have a structure of formula (IX), wherein R.sup.e and R.sup.f are hydrogen.

[0533] In another aspect, provided herein are compounds of formula (X)

##STR00079##

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein [0534] each R.sup.1 is independently selected from the group consisting of C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, and C.sub.1-6 alkyl; [0535] n is 0, 1, or 2; [0536] R.sup.2 is C.sub.1-6 alkyl; and [0537] R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, halo, CN, NR.sup.eR.sup.f, NO.sub.2, C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl or NR.sup.eR.sup.f, and [0538] R.sup.4 is hydrogen or C.sub.1-6 alkyl; [0539] R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6haloalkyl; [0540] R.sup.6 is hydrogen or C.sub.1-6 alkyl; or [0541] R.sup.5 and R.sup.6 may be taken together with the carbon to which they are attached to form 3-4 membered cycloalkyl or heterocycle ring; and [0542] each of R.sup.e and R.sup.f is independently selected from hydrogen and C.sub.1-6 alkyl.

[0543] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein n is 0.

[0544] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.2 is methyl.

[0545] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.3 is NR.sup.eR.sup.f. In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with NR.sup.eR.sup.f. In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.3 is C.sub.1-6 alkoxy optionally substituted with 3-8 membered heterocyclyl.

[0546] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.4 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.4 is C.sub.1-6 alkyl.

[0547] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.5 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.5 is C.sub.1-6 alkyl.

[0548] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.6 is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.6 is C.sub.1-6 alkyl.

[0549] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.5 and R.sup.6 are taken together with the carbon to which they are attached to form 3-4 membered cycloalkyl ring.

[0550] In some embodiments, compounds of the disclosure have a structure of formula (X), wherein R.sup.5 and R.sup.6 may be taken together with the carbon to which they are attached to form 3-4 membered heterocycle ring.

[0551] In certain aspects the present invention provides a compound of Formula I:

##STR00080##

or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, or a pharmaceutical composition thereof;

[0552] In other aspects the present invention provides a compound of Formula VIII, Formula IX, Formula X, Formula XI, or Formula XIII:

##STR00081##

or a pharmaceutically acceptable salt, isotopic derivative prodrug, or pharmaceutical composition thereof;

[0553] In other aspects the present invention provides a compound of Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XIX, Formula XX, Formula XXI, Formula XXI, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVII, Formula XXVIII, or Formula XXIX:

##STR00082## ##STR00083##

or a pharmaceutically acceptable salt, isotopic derivative, prodrug, or pharmaceutical composition thereof;
wherein: [0554] Q.sup.1 is O or NR.sup.2; [0555] Q.sup.2 is O, NR.sup.2, or CR.sup.3R.sup.4; [0556] Q.sup.3 is S, O, or NR.sup.2; [0557] Q.sup.4 is bond, O, NR.sup.2, or CR.sup.3R.sup.4; [0558] z is 0, 1, 2, or 3; [0559] x is 0, 1, 2, 3, or 4; [0560] each

##STR00084##

is an aryl, heteroaryl, heterocycle, cycloalkene, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.10 and optionally substituted with 1 R.sup.11 substituent;

##STR00085##

is an aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.10 and substituted with 1 R.sup.11 substituent;

##STR00086##

is an aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.20;

##STR00087##

is a cycloalkyl, aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.20 and optionally substituted with 1 R.sup.11 substituent;

##STR00088##

is a tricycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.20; [0561] X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, and X.sup.7 are independently selected from the group consisting of CR.sup.10, CH, and N, wherein no more than four of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, and X.sup.7 are N; [0562] X.sup.8, X.sup.9, X.sup.10, X.sup.11, and X.sup.12 are independently selected from the group consisting of CH, CR.sup.10, CR.sup.11, and N, wherein no more than four of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, and X.sup.7 are N; [0563] each R.sup.1 is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; [0564] each R.sup.2 is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, alkyl-heterocycle, alkyl-heteroaryl, alkyl-aryl, or C(O)R.sup.7; [0565] R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; [0566] R.sup.3b is alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; [0567] or R.sup.3 and R.sup.4 or R.sup.3b and R.sup.4 are combined with the carbon to which they are attached to form a spirocyclopropyl, wherein the spirocyclopropyl group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.6; [0568] R.sup.5 is alkenyl or alkynyl; [0569] R.sup.5b is haloalkyl; [0570] each R.sup.6 is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; [0571] each R.sup.7 and R.sup.8 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, NR.sup.1R.sup.12, OR.sup.12, and SR.sup.12; [0572] each R.sup.10 is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR.sup.1R.sup.2, -alkyl-OR.sup.2,
C(O)R.sup.7, NR.sup.2C(O)R.sup.7, OC(O)R.sup.7, NR.sup.1R.sup.2, OR.sup.2, SR.sup.2, S(O)R.sup.7, S(O).sub.2R.sup.7, and P(O)R.sup.7R.sup.8, each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.21; [0573] R.sup.10b is selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR.sup.1R.sup.2, -alkyl-OR.sup.2, C(O)R.sup.7, NR.sup.2C(O)R.sup.7, OC(O)R.sup.7, NR.sup.1R.sup.2, OR.sup.2, SR.sup.2, S(O)R.sup.7, S(O).sub.2R.sup.7, and P(O)R.sup.7R.sup.8, each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.21;

##STR00089##

or CH.SUP.2.CN;

[0574] each R.sup.12 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; [0575] R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, CH.sub.2OR.sup.2, and CH.sub.2NR.sup.1R.sup.2; [0576] or R.sup.13 and R.sup.14 are combined with the carbon to which they are attached to form a spirocyclopropyl; [0577] or R.sup.15 and R.sup.16 are combined with the carbon to which they are attached to form a spirocyclopropyl; [0578] R.sup.16b is alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; [0579] R.sup.17 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylcycloalkyl, CH.sub.2CH.sub.2OR.sup.2, CH.sub.2CH.sub.2NR.sup.1R.sup.2, -alkyl-aryl, -alkyl-heteroaryl, or cycloalkyl; [0580] R.sup.18 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or C(O)R.sup.7; [0581] or R.sup.17 and R.sup.18 together with the nitrogen to which they are attached form a heterocycle; [0582] R.sup.19 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or C(O)R.sup.7; [0583] each R.sup.20 is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, oxo, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR.sup.1R.sup.2, -alkyl-OR.sup.2, C(O)R.sup.7, NR.sup.2C(O)R.sup.7,
OC(O)R.sup.7, NR.sup.1R.sup.2, OR.sup.2, SR.sup.2, S(O)R.sup.7, S(O).sub.2R.sup.7, and P(O)R.sup.7R.sup.8, each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R.sup.22; [0584] each R.sup.21 is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, C(O)R.sup.7, NR.sup.2C(O)R.sup.7, OC(O)R.sup.7, NR.sup.1R.sup.2, OR.sup.2, SR.sup.2, S(O)R.sup.7, S(O).sub.2R.sup.7, and P(O)R.sup.7R.sup.8; and [0585] each R.sup.22 is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, C(O)R.sup.7, NR.sup.2C(O)R.sup.7, OC(O)R.sup.7, NR.sup.1R.sup.2, OR.sup.2, SR.sup.2, S(O)R.sup.7, S(O).sub.2R.sup.7, and P(O)R.sup.7R.sup.8.

[0586] The present invention provides a compound of Formula (Z):

##STR00090##

or a pharmaceutically acceptable salt, prodrug, or pharmaceutical composition thereof.

[0587] In the compound of Formula (Z), A100 may be selected from the group consisting of Formulas (A1), (A2), (A3), (A4), (A5), (A6), (A7), (A8), (A9), (A10), (A11), (A12), (A13), (A14), (A15), (A16), (A17), (A18), (A19), and (A20):

##STR00091## ##STR00092##

[0588] In the compound of Formula (Z), L.sup.1 may be CH.sub.2, or may be absent.

[0589] In the compound of Formula (Z), L.sup.2 may be CONH, NHCO, NHSO.sub.2, SO.sub.2NH, NH, CO, NR.sup.114- or may be absent.

[0590] In the compound of Formula (Z), L.sup.3 may be:

##STR00093##

or may be absent.

[0591] In the compound of Formula (Z), L.sup.4 may be CR.sub.120R.sub.121 or may be absent.

[0592] In the compound of Formula (Z), B100 may be:

##STR00094##

[0593] In the compound of Formula (Z), R.sup.101 may be H, halo, OH, CONH.sub.2, OR.sup.124, NR.sup.124R.sup.125, NO.sub.2, NS(O).sub.2CH.sup.3, C.sub.1-C.sub.6 alkoxyl, C.sub.3-C.sub.6 cycloalkoxyl, C.sub.3-C.sub.6 cycloheteroalkoxyl, C.sub.1-C.sub.6 heteroalkoxyl, C(O)CH.sub.3,

##STR00095##

[0594] R.sup.102 may be H, OH, halo, or an alkyne, including substituted alkynes, for example

##STR00096##

[0595] R.sup.103 may be H or halo, or alkyl.

[0596] R.sup.104 may be H, halo, or alkyl.

[0597] R.sup.106 may be H, halo or C.sub.1-C.sub.6 alkyl, or a C.sub.1-C.sub.6 cycloheteroalkyl.

[0598] R.sup.107 may be H, Me, COH, CH.sub.2OH, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 heteroalkyl, or C.sub.1-C.sub.4 cycloheteroalkyl, for example:

##STR00097##

[0599] R.sup.108 may be H, halo, CO.sub.2H, CONH.sub.2, aryl, C.sub.3-C.sub.6 heteroaryl (for example pyridine), C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.6 cycloheteroalkyl (for example morpholine), or for example

##STR00098##

or may be

##STR00099##

[0600] R.sup.109 may be H, halo, or Me.

[0601] R.sup.110 may be H or Me.

[0602] R.sup.112 may be NO.sub.2 or NH.sub.2.

[0603] R.sup.114 may be Me.

[0604] R.sup.118 may be

##STR00100##

[0605] R.sup.120 may be H, Me, halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.6 cycloheteroalkyl, aryl, or heteroaryl.

[0606] R.sup.121 may be H.

[0607] In alternative aspects of the invention, R.sup.120 and R.sup.121 may together with the carbon atoms to which they are attached form a C.sub.3-C.sub.6 cycloalkyl or a C.sub.3-C.sub.6 cycloheteroalkyl.

[0608] R.sup.122 may be H, Me, halo, aryl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloheteroalkyl, for example a phenyl, benzyl, or thiophene or,

##STR00101##

or may be

##STR00102##

[0609] R.sup.122 may be OR.sup.123.

[0610] R.sup.123 may be aryl, C.sub.3-C.sub.6 cycloalkyl, or C.sub.3-C.sub.6 cycloheteroalkyl (for example, phenyl or benzyl).

[0611] R.sup.124 may be H, S(O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.6 cycloheteroalkyl, or heteroaryl, or

##STR00103##

or may be

##STR00104##

[0612] R.sup.125 may be H, C(O)CH.sub.3, or may be absent.

[0613] In the compound of Formula (Z), each alkoxyl, alkyl, aryl, cycloalkoxyl, cycloalkyl, cycloheteroalkoxyl, cycloheteroalkyl, haloalkyl, heteroalkoxyl, heteroalkyl, and heteroaryl group may be optionally substituted.

[0614] Aspects of the invention include salt forms of the compound of Formula (Z). Salt forms may comprise any pharmaceutically acceptable salt, for example hydrochloric acid (HCl), trifluoroacetic acid (TFA), or formic acid (FA).

[0615] In preferred embodiments, R.sup.106 may be CH.sub.3.

[0616] L.sup.2 may be NHCO.

[0617] L.sup.4 may be CR.sup.120R.sup.121. R.sup.120 may be CH.sub.3 and R.sup.121 may be H.

[0618] In alternative aspects, L.sup.4 may be CR.sup.120R.sup.121, and R.sup.120 and R.sup.121 together with the carbon atoms to which they are attached form a (hetero)cycloalkyl of formula (Y1), (Y2), or (Y3):

##STR00105##

[0619] B100 may be

##STR00106##

[0620] In further alternative aspects, L.sup.4 may be CR.sup.120R.sup.121, wherein R.sup.120 may be CH.sub.2F, CHF, CF.sup.3, or may be selected from the group consisting may be of the formula (X6):

##STR00107##

and R.SUP.121 .may be H.

[0621] In certain embodiments a compound of the present invention is of Formula:

##STR00108##

or a pharmaceutically acceptable salt thereof.

[0622] In certain embodiments a compound of the present invention is of Formula:

##STR00109##

or a pharmaceutically acceptable salt thereof; [0623] In certain embodiments a compound of the present invention is of Formula:

##STR00110##

or a pharmaceutically acceptable salt thereof;

[0624] In certain embodiments a compound of the present invention is of Formula:

##STR00111## ##STR00112##

or a pharmaceutically acceptable salt thereof.

[0625] In certain embodiments a compound of the present invention is of Formula:

##STR00113##

or a pharmaceutically acceptable salt thereof.

[0626] Aspects of the invention provide a composition comprising the compounds according to the invention.

[0627] Aspects of the invention provide a pharmaceutically acceptable salt or a prodrug of the compounds of the invention.

[0628] Aspects of the invention provide a method of treating a subject afflicted with a viral infection, the method comprising administering to the subject a compound according to the invention.

[0629] Aspects of the invention provide a method of preventing a viral infection in a subject, the method comprising administering to the subject a compound according to the invention.

[0630] Aspects of the invention provide a method of preventing viral replication in a subject, the method comprising administering to the subject a compound according to the invention.

[0631] Aspects of the invention provide a method of inhibiting PLpro in the subject, the method comprising administering to the subject a compound according to the invention

Embodiments of the Present Invention

[0632] In certain embodiments a compound of the present invention is of Formula:

##STR00114##

or a pharmaceutically acceptable salt thereof, wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, x.sup.9, X.sup.10, X.sup.11, X.sup.12, R.sup.1, R.sup.6, R.sup.10, R.sup.11, Q.sup.3, Ring B, and x are as defined herein.

Embodiments of

##STR00115##

[0633] In certain embodiments,

##STR00116##

are selected from:

##STR00117##

[0634] In certain embodiments,

##STR00118##

are selected from:

##STR00119## ##STR00120##

[0635] In certain embodiments,

##STR00121##

are selected from:

##STR00122## ##STR00123##

[0636] In certain embodiments,

##STR00124##

are selected from:

##STR00125## ##STR00126##

[0637] In certain embodiments,

##STR00127##

are selected from:

##STR00128## ##STR00129##

[0638] In certain embodiments,

##STR00130##

are selected from:

##STR00131## ##STR00132##

[0639] In certain embodiments,

##STR00133##

are selected from:

##STR00134## ##STR00135##

[0640] In certain embodiments,

##STR00136##

are selected from:

##STR00137##

[0641] In certain embodiments,

##STR00138##

are selected from:

##STR00139##

[0642] In certain embodiments,

##STR00140##

are selected from:

##STR00141##

[0643] In certain embodiments,

##STR00142##

are:

##STR00143##

In certain embodiments,

##STR00144##

is selected from:

##STR00145## ##STR00146## ##STR00147##

[0644] In certain embodiments,

##STR00148##

is selected from:

##STR00149## ##STR00150##

[0645] In certain embodiments,

##STR00151##

is selected from:

##STR00152##

Embodiments of

##STR00153##

[0646] In certain embodiments,

##STR00154##

is selected from:

##STR00155## ##STR00156##

Non-Limiting Embodiments of R.SUP.1

[0647] In certain embodiments, R.sup.1 is hydrogen.

[0648] In certain embodiments, R.sup.1 is alkyl.

[0649] In certain embodiments, R.sup.1 is haloalkyl.

[0650] In certain embodiments, R.sup.1 is alkenyl.

[0651] In certain embodiments, R.sup.1 is alkynyl.

[0652] In certain embodiments, R.sup.1 is aryl.

[0653] In certain embodiments, R.sup.1 is heteroaryl.

[0654] In certain embodiments, R.sup.1 is hydrogen.

[0655] In certain embodiments, R.sup.1 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.2

[0656] In certain embodiments, R.sup.2 is hydrogen.

[0657] In certain embodiments, R.sup.2 is alkyl.

[0658] In certain embodiments, R.sup.2 is haloalkyl.

[0659] In certain embodiments, R.sup.2 is alkenyl.

[0660] In certain embodiments, R.sup.2 is alkynyl.

[0661] In certain embodiments, R.sup.2 is aryl.

[0662] In certain embodiments, R.sup.2 is heteroaryl.

[0663] In certain embodiments, R.sup.2 is cycloalkyl.

[0664] In certain embodiments, R.sup.2 is C(O)R.sup.7.

Non-Limiting Embodiments of R.SUP.3

[0665] In certain embodiments, R.sup.3 is hydrogen

[0666] In certain embodiments, R.sup.3 is halogen

[0667] In certain embodiments, R.sup.3 is alkyl.

[0668] In certain embodiments, R.sup.3 is haloalkyl.

[0669] In certain embodiments, R.sup.3 is alkenyl.

[0670] In certain embodiments, R.sup.3 is alkynyl.

[0671] In certain embodiments, R.sup.3 is aryl.

[0672] In certain embodiments, R.sup.3 is heteroaryl.

[0673] In certain embodiments, R.sup.3 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.3b

[0674] In certain embodiments, R.sup.3b is alkyl.

[0675] In certain embodiments, R.sup.3b is haloalkyl.

[0676] In certain embodiments, R.sup.3b is alkenyl.

[0677] In certain embodiments, R.sup.3b is alkynyl.

[0678] In certain embodiments, R.sup.3b is aryl.

[0679] In certain embodiments, R.sup.3b is heteroaryl.

[0680] In certain embodiments, R.sup.3b is cycloalkyl.

Non-Limiting Embodiments of R.SUP.4

[0681] In certain embodiments, R.sup.4 is hydrogen.

[0682] In certain embodiments, R.sup.4 is halogen.

[0683] In certain embodiments, R.sup.4 is alkyl.

[0684] In certain embodiments, R.sup.4 is haloalkyl.

[0685] In certain embodiments, R.sup.4 is alkenyl.

[0686] In certain embodiments, R.sup.4 is alkynyl.

[0687] In certain embodiments, R.sup.4 is aryl.

[0688] In certain embodiments, R.sup.4 is heteroaryl.

[0689] In certain embodiments, R.sup.4 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.5

[0690] In certain embodiments, R.sup.5 is alkenyl.

[0691] In certain embodiments, R.sup.5 is alkynyl.

[0692] In certain embodiments, R.sup.5 is

##STR00157##

[0693] In certain embodiments, R.sup.5 is

##STR00158##

[0694] In certain embodiments, R.sup.5 is

##STR00159##

[0695] In certain embodiments, R.sup.5 is

##STR00160##

[0696] In certain embodiments, R.sup.5 is

##STR00161##

[0697] In certain embodiments, R.sup.5 is

##STR00162##

[0698] In certain embodiments, R.sup.5 is

##STR00163##

[0699] In certain embodiments, R.sup.5 is

##STR00164##

[0700] In certain embodiments, R.sup.5 is

##STR00165##

Non-Limiting Embodiments of R.SUP.5b

[0701] In certain embodiments, R.sup.5b is haloalkyl.

[0702] In certain embodiments, R.sup.5b is

##STR00166##

[0703] In certain embodiments, R.sup.5b is

##STR00167##

[0704] In certain embodiments, R.sup.5b is CF.sub.3.

Non-Limiting Embodiments of R.SUP.6

[0705] In certain embodiments, R.sup.6 is halogen.

[0706] In certain embodiments, R.sup.6 is alkyl.

[0707] In certain embodiments, R.sup.6 is haloalkyl.

[0708] In certain embodiments, R.sup.6 is alkenyl.

[0709] In certain embodiments, R.sup.6 is alkynyl.

[0710] In certain embodiments, R.sup.6 is aryl.

[0711] In certain embodiments, R.sup.6 is heteroaryl.

[0712] In certain embodiments, R.sup.6 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.7

[0713] In certain embodiments, R.sup.7 is hydrogen.

[0714] In certain embodiments, R.sup.7 is alkyl.

[0715] In certain embodiments, R.sup.7 is haloalkyl.

[0716] In certain embodiments, R.sup.7 is alkenyl.

[0717] In certain embodiments, R.sup.7 is alkynyl.

[0718] In certain embodiments, R.sup.7 is aryl.

[0719] In certain embodiments, R.sup.7 is heteroaryl.

[0720] In certain embodiments, R.sup.7 is cycloalkyl.

[0721] In certain embodiments, R.sup.7 is NR.sup.1R.sup.12.

[0722] In certain embodiments, R.sup.7 is OR.sup.12

[0723] In certain embodiments, R.sup.7 is SR.sup.12.

Non-Limiting Embodiments of R.SUP.8

[0724] In certain embodiments, R.sup.8 is hydrogen.

[0725] In certain embodiments, R.sup.8 is alkyl.

[0726] In certain embodiments, R.sup.8 is haloalkyl.

[0727] In certain embodiments, R.sup.8 is alkenyl.

[0728] In certain embodiments, R.sup.8 is alkynyl.

[0729] In certain embodiments, R.sup.8 is aryl.

[0730] In certain embodiments, R.sup.8 is heteroaryl.

[0731] In certain embodiments, R.sup.8 is cycloalkyl.

[0732] In certain embodiments, R.sup.8 is NR.sup.1R.sup.12.

[0733] In certain embodiments, R.sup.8 is OR.sup.12.

[0734] In certain embodiments, R.sup.8 is SR.sup.12.

Non-Limiting Embodiments of R.SUP.10

[0735] In certain embodiments, R.sup.10 is hydrogen.

[0736] In certain embodiments, R.sup.10 is halogen.

[0737] In certain embodiments, R.sup.10 is alkyl.

[0738] In certain embodiments, R.sup.10 is haloalkyl.

[0739] In certain embodiments, R.sup.10 is cyano.

[0740] In certain embodiments, R.sup.10 is nitro.

[0741] In certain embodiments, R.sup.10 is alkenyl.

[0742] In certain embodiments, R.sup.10 is alkynyl.

[0743] In certain embodiments, R.sup.10 is aryl.

[0744] In certain embodiments, R.sup.10 is heteroaryl.

[0745] In certain embodiments, R.sup.10 is cycloalkyl.

[0746] In certain embodiments, R.sup.10 is C(O)R.sup.7.

[0747] In certain embodiments, R.sup.10 is NR.sup.2C(O)R.sup.7.

[0748] In certain embodiments, R.sup.10 is OC(O)R.sup.7.

[0749] In certain embodiments, R.sup.10 is NR.sup.1R.sup.2.

[0750] In certain embodiments, R.sup.10 is OR.sup.2.

[0751] In certain embodiments, R.sup.10 is SR.sup.2.

[0752] In certain embodiments, R.sup.10 is S(O)R.sup.7.

[0753] In certain embodiments, R.sup.10 is S(O).sub.2R.sup.7.

[0754] In certain embodiments, R.sup.10 is P(O)R.sup.7R.sup.8.

Non-Limiting Embodiments of R.SUP.10b.:

[0755] In certain embodiments, R.sup.10b is hydrogen.

[0756] In certain embodiments, R.sup.10b is halogen.

[0757] In certain embodiments, R.sup.10b is alkyl.

[0758] In certain embodiments, R.sup.10b is haloalkyl.

[0759] In certain embodiments, R.sup.10b is cyano.

[0760] In certain embodiments, R.sup.10b is nitro.

[0761] In certain embodiments, R.sup.10b is alkenyl.

[0762] In certain embodiments, R.sup.10b is alkynyl.

[0763] In certain embodiments, R.sup.10b is aryl.

[0764] In certain embodiments, R.sup.10b is heteroaryl.

[0765] In certain embodiments, R.sup.10b is cycloalkyl.

[0766] In certain embodiments, R.sup.10b is C(O)R.sup.7.

[0767] In certain embodiments, R.sup.10b is NR.sup.2C(O)R.sup.7.

[0768] In certain embodiments, R.sup.10b is OC(O)R.sup.7.

[0769] In certain embodiments, R.sup.10b is NR.sup.1R.sup.2.

[0770] In certain embodiments, R.sup.10b is OR.sup.2.

[0771] In certain embodiments, R.sup.10b is SR.sup.2.

[0772] In certain embodiments, R.sup.10b is S(O)R.sup.7.

[0773] In certain embodiments, R.sup.10b is S(O).sub.2R.sup.7.

[0774] In certain embodiments, R.sup.10b is P(O)R.sup.7R.sup.8.

Non-limiting embodiments of R.sup.11:

[0775] In certain embodiments, R.sup.11 is

##STR00168##

[0776] In certain embodiments, R.sup.11 is

##STR00169##

[0777] In certain embodiments, R.sup.11 is

##STR00170##

[0778] In certain embodiments, R.sup.11 is

##STR00171##

[0779] In certain embodiments, R.sup.11 is

##STR00172##

[0780] In certain embodiments, R.sup.11 is

##STR00173##

[0781] In certain embodiments, R.sup.11 is

##STR00174##

[0782] In certain embodiments, R.sup.11 is

##STR00175##

[0783] In certain embodiments, R.sup.11 is

##STR00176##

[0784] In certain embodiments, R.sup.11 is

##STR00177##

Non-Limiting Embodiments of R.SUP.12

[0785] In certain embodiments, R.sup.12 is hydrogen.

[0786] In certain embodiments, R.sup.12 is alkyl.

[0787] In certain embodiments, R.sup.12 is haloalkyl.

[0788] In certain embodiments, R.sup.12 is alkenyl.

[0789] In certain embodiments, R.sup.12 is alkynyl.

[0790] In certain embodiments, R.sup.12 is aryl.

[0791] In certain embodiments, R.sup.12 is heteroaryl.

[0792] In certain embodiments, R.sup.12 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.13

[0793] In certain embodiments, R.sup.13 is hydrogen.

[0794] In certain embodiments, R.sup.13 is alkyl.

[0795] In certain embodiments, R.sup.13 is haloalkyl.

[0796] In certain embodiments, R.sup.13 is alkenyl.

[0797] In certain embodiments, R.sup.13 is alkynyl.

[0798] In certain embodiments, R.sup.13 is aryl.

[0799] In certain embodiments, R.sup.13 is heteroaryl.

[0800] In certain embodiments, R.sup.13 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.14

[0801] In certain embodiments, R.sup.14 is hydrogen.

[0802] In certain embodiments, R.sup.14 is alkyl.

[0803] In certain embodiments, R.sup.14 is haloalkyl.

[0804] In certain embodiments, R.sup.14 is alkenyl.

[0805] In certain embodiments, R.sup.14 is alkynyl.

[0806] In certain embodiments, R.sup.14 is aryl.

[0807] In certain embodiments, R.sup.14 is heteroaryl.

[0808] In certain embodiments, R.sup.14 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.15

[0809] In certain embodiments, R.sup.15 is hydrogen.

[0810] In certain embodiments, R.sup.15 is alkyl.

[0811] In certain embodiments, R.sup.15 is haloalkyl.

[0812] In certain embodiments, R.sup.15 is alkenyl.

[0813] In certain embodiments, R.sup.15 is alkynyl.

[0814] In certain embodiments, R.sup.15 is aryl.

[0815] In certain embodiments, R.sup.15 is heteroaryl.

[0816] In certain embodiments, R.sup.15 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.16

[0817] In certain embodiments, R.sup.16 is hydrogen.

[0818] In certain embodiments, R.sup.16 is alkyl.

[0819] In certain embodiments, R.sup.16 is haloalkyl.

[0820] In certain embodiments, R.sup.16 is alkenyl.

[0821] In certain embodiments, R.sup.16 is alkynyl.

[0822] In certain embodiments, R.sup.16 is aryl.

[0823] In certain embodiments, R.sup.16 is heteroaryl.

[0824] In certain embodiments, R.sup.16 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.16b

[0825] In certain embodiments, R.sup.16b is alkyl.

[0826] In certain embodiments, R.sup.16b is haloalkyl.

[0827] In certain embodiments, R.sup.16b is alkenyl.

[0828] In certain embodiments, R.sup.16b is alkynyl.

[0829] In certain embodiments, R.sup.16b is aryl.

[0830] In certain embodiments, R.sup.16b is heteroaryl.

[0831] In certain embodiments, R.sup.16b is cycloalkyl.

Non-Limiting Embodiments of R.SUP.17

[0832] In certain embodiments, R.sup.17 is hydrogen.

[0833] In certain embodiments, R.sup.17 is alkyl.

[0834] In certain embodiments, R.sup.17 is haloalkyl.

[0835] In certain embodiments, R.sup.17 is alkenyl.

[0836] In certain embodiments, R.sup.17 is alkynyl.

[0837] In certain embodiments, R.sup.17 is heteroaryl.

[0838] In certain embodiments, R.sup.17 is -alkylcycloalkyl.

[0839] In certain embodiments, R.sup.17 is CH.sub.2CH.sub.2OR.sup.2.

[0840] In certain embodiments, R.sup.17 is CH.sub.2CH.sub.2NR.sup.1R.sup.2.

[0841] In certain embodiments, R.sup.17 is -alkyl-aryl.

[0842] In certain embodiments, R.sup.17 is -alkyl-heteroaryl.

[0843] In certain embodiments, R.sup.17 is cycloalkyl.

Non-Limiting Embodiments of R.SUP.18

[0844] In certain embodiments, R.sup.18 is hydrogen.

[0845] In certain embodiments, R.sup.18 is alkyl.

[0846] In certain embodiments, R.sup.18 is haloalkyl.

[0847] In certain embodiments, R.sup.18 is alkenyl.

[0848] In certain embodiments, R.sup.18 is aryl.

[0849] In certain embodiments, R.sup.18 is heteroaryl.

[0850] In certain embodiments, R.sup.18 is cycloalkyl.

[0851] In certain embodiments, R.sup.18 is C(O)R.sup.7.

Non-Limiting Embodiments of R.SUP.19

[0852] In certain embodiments, R.sup.19 is hydrogen.

[0853] In certain embodiments, R.sup.19 is alkyl.

[0854] In certain embodiments, R.sup.19 is haloalkyl.

[0855] In certain embodiments, R.sup.19 is alkenyl.

[0856] In certain embodiments, R.sup.19 is alkynyl.

[0857] In certain embodiments, R.sup.19 is aryl.

[0858] In certain embodiments, R.sup.19 is heteroaryl.

[0859] In certain embodiments, R.sup.19 is cycloalkyl.

[0860] In certain embodiments, R.sup.19 is cycloalkyl.

[0861] In certain embodiments, R.sup.19 is C(O)R.sup.7.

Non-Limiting Embodiments of R.SUP.20

[0862] In certain embodiments, R.sup.20 is hydrogen.

[0863] In certain embodiments, R.sup.20 is halogen.

[0864] In certain embodiments, R.sup.20 is alkyl.

[0865] In certain embodiments, R.sup.20 is haloalkyl.

[0866] In certain embodiments, R.sup.20 is cyano.

[0867] In certain embodiments, R.sup.20 is nitro.

[0868] In certain embodiments, R.sup.20 is alkenyl.

[0869] In certain embodiments, R.sup.20 is alkynyl.

[0870] In certain embodiments, R.sup.20 is aryl.

[0871] In certain embodiments, R.sup.20 is heteroaryl.

[0872] In certain embodiments, R.sup.20 is cycloalkyl.

[0873] In certain embodiments, R.sup.20 is C(O)R.sup.7.

[0874] In certain embodiments, R.sup.20 is NR.sup.2C(O)R.sup.7.

[0875] In certain embodiments, R.sup.20 is OC(O)R.sup.7.

[0876] In certain embodiments, R.sup.20 is NR.sup.1R.sup.2.

[0877] In certain embodiments, R.sup.20 is OR.sup.2.

[0878] In certain embodiments, R.sup.20 is SR.sup.2.

[0879] In certain embodiments, R.sup.20 is S(O)R.sup.7.

[0880] In certain embodiments, R.sup.20 is S(O).sub.2R.sup.7.

[0881] In certain embodiments, R.sup.20 is P(O)R.sup.7R.sup.8.

[0882] In certain embodiments, R.sup.20 is heteroaryl

Non-Limiting Embodiments of R.SUP.21

[0883] In certain embodiments, R.sup.21 is heteroaryl

[0884] In certain embodiments, R.sup.21 is hydrogen.

[0885] In certain embodiments, R.sup.21 is halogen.

[0886] In certain embodiments, R.sup.21 is alkyl.

[0887] In certain embodiments, R.sup.21 is haloalkyl.

[0888] In certain embodiments, R.sup.21 is cyano.

[0889] In certain embodiments, R.sup.21 is nitro.

[0890] In certain embodiments, R.sup.21 is alkenyl.

[0891] In certain embodiments, R.sup.21 is alkynyl.

[0892] In certain embodiments, R.sup.21 is aryl.

[0893] In certain embodiments, R.sup.21 is heteroaryl.

[0894] In certain embodiments, R.sup.21 is cycloalkyl.

[0895] In certain embodiments, R.sup.21 is C(O)R.sup.7.

[0896] In certain embodiments, R.sup.21 is NR.sup.2C(O)R.sup.7.

[0897] In certain embodiments, R.sup.21 is OC(O)R.sup.7.

[0898] In certain embodiments, R.sup.21 is NR.sup.1R.sup.2.

[0899] In certain embodiments, R.sup.21 is OR.sup.2.

[0900] In certain embodiments, R.sup.21 is SR.sup.2.

[0901] In certain embodiments, R.sup.21 is S(O)R.sup.7.

[0902] In certain embodiments, R.sup.21 is S(O).sub.2R.sup.7.

[0903] In certain embodiments, R.sup.21 is P(O)R.sup.7R.sup.8.

[0904] In certain embodiments, R.sup.21 is heteroaryl.

Non-Limiting Embodiments of R.SUP.22

[0905] In certain embodiments, R.sup.22 is hydrogen.

[0906] In certain embodiments, R.sup.22 is halogen.

[0907] In certain embodiments, R.sup.22 is alkyl.

[0908] In certain embodiments, R.sup.22 is haloalkyl.

[0909] In certain embodiments, R.sup.22 is cyano.

[0910] In certain embodiments, R.sup.22 is nitro.

[0911] In certain embodiments, R.sup.22 is alkenyl.

[0912] In certain embodiments, R.sup.22 is alkynyl.

[0913] In certain embodiments, R.sup.22 is aryl.

[0914] In certain embodiments, R.sup.22 is heteroaryl.

[0915] In certain embodiments, R.sup.22 is cycloalkyl.

[0916] In certain embodiments, R.sup.22 is C(O)R.sup.7.

[0917] In certain embodiments, R.sup.22 is NR.sup.2C(O)R.sup.7.

[0918] In certain embodiments, R.sup.22 is OC(O)R.sup.7.

[0919] In certain embodiments, R.sup.22 is NR.sup.1R.sup.2.

[0920] In certain embodiments, R.sup.22 is OR.sup.2.

[0921] In certain embodiments, R.sup.22 is SR.sup.2.

[0922] In certain embodiments, R.sup.22 is S(O)R.sup.7.

[0923] In certain embodiments, R.sup.22 is S(O).sub.2R.sup.7.

[0924] In certain embodiments, R.sup.22 is P(O)R.sup.7R.sup.8.

REPRESENTATIVE COMPOUNDS OF THE PRESENT INVENTION

TABLE-US-00001 Compd No. Example No. Structure 172 1 [00178] 168 2 [00179] 155 3 [00180] 101 4 [00181] 136 5 [00182] 132 6 [00183] 158 7 [00184] 159 8 [00185] 160 9 [00186] 152 10 [00187] 141 11 [00188] 164 12 [00189] 162 13 [00190] 100 14 [00191] 121 15 [00192] 107 16 [00193] 115 17 [00194] 119 18 [00195] 165 19 [00196] 153 20 [00197] 189 21 [00198] 148 22 [00199] 156 23 [00200] 192 24 [00201] 206 25 [00202] 125 26 [00203] 102 27 [00204] 128 28 [00205] 131 29 [00206] 124 30 [00207] 142 31 [00208] 150 32 [00209] 167 33 [00210] 145 34 [00211] 163 35 [00212] 195 36 [00213] 200 37 [00214] 185 38 [00215] 183 39 [00216] 191 40 [00217] 281 41 [00218] 241 42 [00219] 147 43 [00220] 219 44 [00221] 177 45 [00222] 313 46 [00223] 378 47 [00224] 257 48 [00225] 312 49 [00226] 398 50 [00227] 399 51 [00228] 373 52 [00229] 215 53 [00230] 211 54 [00231] 316 55 [00232] 233 56 [00233] 386 57 [00234] 214 58 [00235] 351 59 [00236] 247 60 [00237] 362 61 [00238] 361 62 [00239] 315 63 [00240] 360 64 [00241] 359 65 [00242] 358 66 [00243] 300 67 [00244] 254 68 [00245] 284 69 [00246] 209 70 [00247] 324 71 [00248] 343 72 [00249] 400 73 [00250] 367 74 [00251] 322 75 [00252] 352 76 [00253] 256 77 [00254] 274 78 [00255] 310 79 [00256] 309 80 [00257] 387 81 [00258] 349 82 [00259] 314 83 [00260] 396 84 [00261] 331 85 [00262] 330 86 [00263] 323 87 [00264] 332 88 [00265] 348 89 [00266] 341 90 [00267] 394 91 [00268] 393 92 [00269] 285 93 [00270] 171 94 [00271] 265 95 [00272] 263 96 [00273] 283 97 [00274] 268 98 [00275] 289 99 [00276] 339 100 [00277] 288 101 [00278] 293 101 [00279] 286 102 [00280] 302 103 [00281] 376 105 [00282] 303 106 [00283] 269 107 [00284] 337 108 [00285] 353 109 [00286] 311 110 [00287] 216 111 [00288] 369 112 [00289] 366 113 [00290] 350 114 [00291] 275 115 [00292] 199 116 [00293] 240 117 [00294] 180 118 [00295] 170 119 [00296] 248 120 [00297] 246 121 [00298] 244 122 [00299] 232 123 [00300] 221 124 [00301] 173 125 [00302] 273 126 [00303] 260 127 [00304] 202 128 [00305] 222 129 [00306] 213 130 [00307] 229 131 [00308] 204 132 [00309] 205 133 [00310] 225 134 [00311] 226 135 [00312] 234 136 [00313] 201 137 [00314] 296 138 [00315] 218 139 [00316] 290 140 [00317] 239 141 [00318] 295 142 [00319] 203 143 [00320] 212 144 [00321] 292 145 [00322] 207 146 [00323] 210 147 [00324] 249 148 [00325] 243 149 [00326] 262 150 [00327] 190 151 [00328] 231 152 [00329] 176 153 [00330] 304 154 [00331] 305 154 [00332] 197 155 [00333] 198 156 [00334] 220 157 [00335] 235 158 [00336] 236 158 [00337] 230 159 [00338] 224 160 [00339] 397 161 [00340] 223 162 [00341] 280 163 [00342] 245 164 [00343] 238 165 [00344] 237 166 [00345] 297 167 [00346] 227 168 [00347] 334 169 [00348] 194 170 [00349] 272 171 [00350] 252 172 [00351] 259 173 [00352] 251 174 [00353] 261 175 [00354] 258 176 [00355] 326 177 [00356] 282 178 [00357] 255 179 [00358] 253 180 [00359] 321 181 [00360] 364 182 [00361] 344 183 [00362] 267 184 [00363] 294 185 [00364] 271 186 [00365] 298 187 [00366] 270 188 [00367] 279 189 [00368] 327 190 [00369] 308 191 [00370] 307 192 [00371] 291 193 [00372] 264 194 [00373] 276 195 [00374] 338 196 [00375] 266 197 [00376] 355 198 [00377] 325 199 [00378] 169 200 [00379] 187 201 [00380] 186 202 [00381] 196 203 [00382] 318 204 [00383] 335 205 [00384] 317 206 [00385] 336 207 [00386] 340 208 [00387] 329 209 [00388] 370 210 [00389] 357 211 [00390] 368 212 [00391] 356 213 [00392] 403 214 [00393] 346 215 [00394] 354 216 [00395] 395 217 [00396] 301 218 [00397] 374 219 [00398] 385 220 [00399] 381 221 [00400] 383 222 [00401] 391 223 [00402] 390 224 [00403] 380 225 [00404] 379 226 [00405] 371 227 [00406] 382 228 [00407] 299 229 [00408] 375 230 [00409] 402 231 [00410] 333 232 [00411] 388 233 [00412] 363 234 [00413] 320 235 [00414] 345 236 [00415] 347 237 [00416] 384 238 [00417] 401 239 [00418] 319 240 [00419] 392 241 [00420] 377 242 [00421] 389 243 [00422] 365 244 [00423] 120 245 [00424] 126 246 [00425] 134 247 [00426] 137 248 [00427] 140 249 [00428] 146 250 [00429] 151 251 [00430] 154 252 [00431] 143 253 [00432] 144 254 [00433] 149 255 [00434] 135 256 [00435] 139 257 [00436] 404 258 [00437] 406 259 [00438] 416 260 [00439] 414 261 [00440] 412 262 [00441] 421 263 [00442] 413 264 [00443] 407 265 [00444] 410 266 [00445] 418 267 [00446] 411 268 [00447] 405 269 [00448] 409 270 [00449] 415 271 [00450] 417 272 [00451] 408 273 [00452] 419 274 [00453] 420 275 [00454] 459 276 [00455] 448 277 [00456] 453 278 [00457] 499 279 [00458] 451 280 [00459] 450 281 [00460] 425 282 [00461] 424 283 [00462] 439 284 [00463] 440 285 [00464] 438 286 [00465]/ 437 287 [00466] 442 288 [00467] 441 289 [00468] 491 290 [00469] 492 290 [00470] 534 291 [00471] 533 292 [00472] 487 293 [00473] 435 294 [00474] 447 295 [00475] 449 296 [00476] 455 297 [00477] 431 298 [00478] 452 299 [00479] 472 300 [00480] 463 301 [00481] 505 302 [00482] 426 303 [00483] 432 304 [00484] 457 305 [00485] 445 306 [00486] 490 307 [00487] 489 308 [00488] 433 309 [00489] 474 310 [00490] 461 311 [00491] 541 312 [00492] 443 313 [00493] 484 314 [00494] 482 315 [00495] 496 316 [00496] 495 317 [00497] 520 318 [00498] 481 319 [00499] 501 320 [00500] 508 321 [00501] 521 322 [00502] 423 323 [00503] 471 324 [00504] 486 325 [00505] 539 326 [00506] 468 327 [00507] 470 328 [00508] 475 329 [00509] 477 330 [00510] 465 331 [00511] 483 332 [00512] 434 333 [00513] 530 334 [00514] 526 335 [00515] 560 336 [00516] 575 337 [00517] 511 338 [00518] 527 339 [00519] 462 340 [00520] 528 341 [00521] 550 342 [00522] 561 343 [00523] 584 344 [00524] 597 345 [00525] 587 346 [00526] 598 347 [00527] 563 348 [00528] 497 349 [00529] 581 350 [00530] 600 351 [00531] 568 352 [00532] 551 353 [00533] 588 354 [00534] 436 355 [00535] 529 356 [00536] 547 357 [00537] 545 358 [00538] 544 359 [00539] 548 360 [00540] 555 361 [00541] 467 362 [00542] 565 363 [00543] 542 364 [00544] 586 365 [00545] 538 366 [00546] 509 367 [00547] 549 368 [00548] 522 369 [00549] 524 370 [00550] 106 371 [00551] 178 372 [00552] 184 373 [00553] 208 374 [00554] 179 375 [00555] 577 376 [00556] 580 377 [00557] 111 378 [00558] 116 379 [00559] 161 380 [00560] 166 381 [00561] 108 382 [00562] 118 383 [00563] 105 384 [00564] 109 385 [00565] 242 386 [00566] 138 387 [00567] 217 388 [00568] 624 389 [00569] 729 390 [00570] 627 391 [00571] 611 392 [00572] 743 393 [00573] 744 394 [00574] 786 395 [00575] 757 396 [00576] 713 397 [00577] 748 398 [00578] 749 399 [00579] 800 400 [00580] 726 401 [00581] 746 402 [00582] 785 403 [00583] 796 404 [00584] 660 405 [00585] 638 406 [00586] 676 407 [00587] 697 408 [00588] 620 409 [00589] 696 410 [00590] 803 411 [00591] 738 412 [00592] 677 413 [00593] 692 414 [00594] 761 415 [00595] 626 416 [00596] 797 417 [00597] 732 418 [00598] 775 419 [00599] 776 419 [00600] 789 420 [00601] 790 420 [00602] 783 421 [00603] 784 421 [00604] 799 422 [00605] 794 423 [00606] 750 424 [00607] 737 425 [00608] 625 426 [00609] 791 427 [00610] 817 428 [00611] 809 429 [00612] 795 430 [00613] 815 431 [00614] 648 432 [00615] 683 433 [00616] 630 434 [00617] 608 435 [00618] 753 436 [00619] 780 437 [00620] 669 438 [00621] 767 439 [00622] 812 440 [00623] 814 441 [00624] 782 442 [00625] 806 443 [00626] 619 444 [00627] 653 445 [00628] 689 446 [00629] 821 447 [00630] 808 448 [00631] 181 449 [00632] 104 450 [00633] 188 451 [00634] 127 452 [00635] 739 453 [00636] 110 454 [00637] 123 455 [00638] 113 456 [00639] 114 457 [00640] 117 458 [00641] 182 459 [00642] 607 460 [00643] 606 461 [00644] 513 462 [00645] 430 463 [00646] 428 464 [00647] 429 465 [00648] 277 466 [00649] 278 467 [00650] 569 468 [00651] 427 469 [00652] 306 470 [00653] 572 471 [00654] 567 472 [00655] 571 473 [00656] 444 474 [00657] 559 475 [00658] 596 476 [00659] 454 477 [00660] 473 478 [00661] 456 479 [00662] 458 480 [00663] 507 481 [00664] 488 482 [00665] 617 483 [00666] 498 484 [00667] 446 485 [00668] 566 486 [00669] 464 487 [00670] 485 488 [00671] 506 489 [00672] 479 490 [00673] 502 491 [00674] 480 492 [00675] 478 493 [00676] 476 494 [00677] 787 495 [00678] 493 496 [00679] 514 497 [00680] 518 498 [00681] 500 499 [00682] 510 500 [00683] 512 501 [00684] 556 502 [00685] 517 503 [00686] 503 504 [00687] 578 505 [00688] 554 506 [00689] 516 507 [00690] 504 508 [00691] 558 509 [00692] 531 510 [00693] 532 511 [00694] 557 512 [00695] 553 513 [00696] 535 514 [00697] 536 515 [00698] 537 516 [00699] 543 517 [00700] 540 518 [00701] 552 519 [00702] 593 520 [00703] 599 521 [00704] 573 522 [00705] 562 523 [00706] 579 524 [00707] 570 525 [00708] 603 526 [00709] 650 527 [00710] 668 528 [00711] 632 529 [00712] 623 530 [00713] 604 531 [00714] 652 532 [00715] 670 533 [00716] 633 534 [00717] 651 535 [00718] 582 536 [00719] 644 537 [00720] 659 538 [00721] 609 539 [00722] 621 540 [00723] 594 541 [00724] 574 542 [00725] 592 543 [00726] 590 544 [00727] 591 545 [00728] 612 546 [00729] 613 547 [00730] 667 548 [00731] 704 549 [00732] 640 550 [00733] 643 551 [00734] 658 552 [00735] 673 553 [00736] 645 554 [00737] 641 555 [00738] 646 556 [00739] 694 557 [00740] 698 558 [00741] 680 559 [00742] 636 560 [00743] 635 561 [00744] 649 562 [00745] 634 563 [00746] 656 564 [00747] 664 565 [00748] 642 566 [00749] 665 567 [00750] 695 568 [00751] 711 569 [00752] 662 570 [00753] 675 571 [00754] 666 572 [00755] 674 573 [00756] 637 574 [00757] 682 575 [00758] 688 576 [00759] 686 577 [00760] 685 578 [00761] 822 579 [00762] 615 580 [00763] 616 581 [00764] 639 582 [00765] 647 583 [00766] 802 584 [00767] 717 585 [00768] 813 586 [00769] 719 587 [00770] 684 588 [00771] 690 589 [00772] 721 590 [00773] 657 591 [00774] 754 592 [00775] 764 593 [00776] 691 594 [00777] 654 595 [00778] 655 596 [00779] 671 597 [00780] 716 598 [00781] 693 599 [00782] 820 600 [00783] 718 601 [00784] 736 602 [00785] 663 603 [00786] 678 604 [00787] 687 605 [00788] 672 606 [00789] 681 607 [00790] 701 608 [00791] 699 609 [00792] 702 610 [00793] 700 611 [00794] 661 612 [00795] 735 613 [00796] 734 614 [00797] 751 615 [00798] 756 616 [00799] 805 617 [00800] 752 618 [00801] 793 619 [00802] 781 620 [00803] 807 621 [00804] 771 622 [00805] 722 623 [00806] 723 624 [00807] 811 625 [00808] 810 626 [00809] 816 627 [00810] 826 628 [00811] 712 629 [00812] 740 630 [00813] 714 631 [00814] 733 632 [00815] 715 633 [00816] 824 634 [00817] 763 635 [00818] 745 636 [00819] 759 637 [00820] 747 638 [00821] 760 639 [00822] 755 640 [00823] 762 641 [00824] 758 642 [00825] 774 643 [00826] 788 644 [00827] 798 645 [00828] 818 646 [00829] 825 647 [00830] 819 648 [00831] 804 649 [00832] 823 650 [00833] 801 651 [00834]

Pharmaceutical Compositions

[0925] Also disclosed herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, or four) pharmaceutically acceptable excipients. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0926] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

[0927] Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0928] Pharmaceutically acceptable salt refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4 chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4 methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. (See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66 (1): 1-79, the entirety of the contents of which are incorporated by reference herein).

[0929] A subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0930] The terms human, patient, and subject are used interchangeably herein.

[0931] Disease, disorder, and condition are used interchangeably herein.

[0932] As used herein, and unless otherwise specified, the terms treat, treating and treatment contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (therapeutic treatment), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (prophylactic treatment).

[0933] In general, the effective amount of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0934] As used herein, and unless otherwise specified, a therapeutically effective amount of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more (e.g., one, two, three, or four) symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0935] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0936] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.st Edition (Lippincott Williams & Wilkins, 2005).

[0937] The compounds and pharmaceutical compositions provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.

[0938] In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

Methods of Treatment

[0939] Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a coronaviral infection. In particular, in certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound described herein. In one aspect, the compounds described herein are contemplated as PLpro inhibitors. In certain embodiments, the disclosure provides a method of treating a viral infection in a patient in need thereof, comprising inhibiting PLpro by administering a compound described herein.

[0940] SARS-COV-2 is a positive strand RNA betacoronavirus. The genome of SARS-COV-2 contains 16 nonstructural proteins (Nsp1 to Nsp16) that are initially expressed as a viral polyprotein (See Thiel, et al., Journal of General Virology 2003, 84 (9), 2305-2315; Barretto, et al, J Virol 2005, 79 (24), 15189-98; and Harcourt, et al., Journal of Virology 2004, 78 (24), 13600-13612, the entirety of the contents of each of which are incorporated by reference herein). During viral replication in coronaviruses, this polyprotein is processed by viral-encoded proteases to facilitate the formation of the membrane-bound replicase complex that carries out viral RNA replication (See Mielech, et al, Journal of Virology 2015, 89 (9), 4907-4917, the entirety of the contents of which are incorporated by reference herein). One of the main proteases from CoV, the 3C-like protease, is known for its ability to cleave Nsp4-Nsp16. In addition to the 3C-like protease, CoVs can also encode up to two papain-like proteases (PLpros), one of which cleaves Nsp1-3. For example, CoVs such as the mouse hepatitis virus (MHV) and other human coronaviruses, including NL63, OC43, HKU1, and 229E, encode for PLP1 and PLP29. For SARS-COV-2, its genome mirrors that of the Middle East respiratory syndrome CoV (MERS-COV) and SARS-COV by coding for a single papain-like protease. Without being limited to a mechanism of action, the dual viral polypeptide cleavage and immune suppression roles of PLpros are potential targets for small molecule antiviral development. PLpro is discussed in Mclain and Vabret, Signal Transduction and Targeted Therapy 2020, 5:223; and Rut et al., Sci. Adv. 2020, 6: eabd4596, the entirety of the contents of each of which are incorporated by reference herein.

[0941] In some embodiments, the infection is chronic. As used herein, chronic refers to an infection that persists for an extended period of time, or recurs. In some embodiments, the infection is acute. As used herein, acute refers to an infection that is of short duration.

[0942] Methods to quantify viral replication are known in the art. In some embodiments, viral count is determined using a plaque assay. In some embodiments, viral count is determined using a focus forming assay (FFA). In some embodiments, viral count is determined using an endpoint dilution assay. In some embodiments, viral count is determined using an enzyme-linked-63-immunosorbent assay (ELISA). In some embodiments, viral count is determined using Tunable resistive pulse sensing (TRPS) to detect individual virus particles. In some embodiments, viral replication is determined by quantifying the amount or percentage of host cell death, e.g., in vitro, for example, using propidium iodide (PI) to identify dead cells, quantifying the amount of morphologically rounded cells, or by immunofluorescence microscopy for apoptotic markers. In some embodiments, viral count is determined by measuring viral titer or multiplicity of infection (MOI) or by performing a plaque assay, a focus forming assay, and endpoint dilution assay, a viral protein quantification assay (for example, a hemagglutination assay, a bicinchoninic acid assay (BCA), or a single radial immunodiffusion assay (SRID) assay), transmission electron microscopy analysis, a tunable resistive pulse sensing (TRPS) assay, a flow cytometry assay, a quantitative PCR (qPCR) assay, or an Enzyme-linked immunosorbent assay (ELISA). In some embodiments, viral replication is determined by quantification of viral nucleic acid (for example, viral DNA or viral RNA) content.

[0943] Methods to quantify viral transmission are known in the art. In some embodiments, viral transmission is quantified using epidemiological modeling (see, e.g., Graw F. et al., (2016) Modeling Viral Spread. Annu Rev Virol, 3 (1)). In some embodiments, viral transmission is assessed in vitro, e.g., in cell culture, e.g., using microscopy, e.g., using transmission electron microscopy (TEM).

[0944] Methods to quantify viral assembly are known in the art. In some embodiments, viral assembly is determined using statistical modeling (see, e.g., Clement N et al., (2018) Viral Capsid Assembly: A Quantified Uncertainty Approach. J Comp Biol, 25 (1)). In some embodiments, viral assembly is determined using biochemical techniques to determine capsid complex formation, e.g., co-immunoprecipitation, e.g., western blotting. In some embodiments, viral assembly is determined by flow cytometry for detection of colocalized viral protein (see, e.g., Stoffel, C. L. et al. (2005). Rapid Determination of Baculovirus Titer by a Dual Channel Virus Counter American Biotechnology Laboratory. 37 (22): 24-25).

[0945] Viral genes encode elements necessary for the process of viral infection, a multi-step process, including, for example, attachment to the host cell, penetration, de-envelopment, viral gene transcription cascade, viral protein expression, viral genome replication, viral packaging and assembly, envelopment, transport and maturation, release and egress, and host cell-to-cell transmission. genes are those genes corresponding to early steps of viral infection, e.g., viral genome replication. genes are those genes corresponding to late steps of viral infection, e.g., egress. Methods to quantify viral gene expression are known in the art. In some embodiments, viral gene expression is determined using reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR). In some embodiments, RNA sequencing (RNA-Seq) is used to determine viral gene expression. In some embodiments, viral DNA is quantified using a Southern blot. In some embodiments, gene expression is quantified. In some embodiments, gene expression is quantified. In some embodiments, gene expression and gene expression are quantified. In some embodiments, expression of the entire viral genome is quantified.

[0946] Methods to quantify virus release are known in the art. In some embodiments, viral release is determined by biochemical assay, e.g., western blotting, e.g., metabolic labeling (see, e.g., Yadav et al., (2012). A facile quantitative assay for viral particle genesis reveals cooperativity in virion assembly and saturation of an antiviral protein. Virology. 429 (2): 155-162). In some embodiments, viral release is determined by ELISA. In some embodiments, viral release is determined using electron microscopy, e.g., transmission electron microscopy (TEM). In some embodiments, viral release is determined by infectivity measurements for the detection of virions in a sample, e.g., serum. In some embodiments, viral release is determined by quantification of viral DNA or viral RNA in serum in vivo or culture supernatant in vitro.

[0947] Methods of treatment of the present invention can be used as a monotherapy or in combination with one or more (e.g., one, two, three, or four) other therapies (for example, anti-infective agents) that can be used to treat a disease or disorder, for example, an infection. The term combination, as used herein, is understood to mean that two or more different treatments are delivered to the subject during the course of the subject's affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as simultaneous or concurrent delivery. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In certain embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In certain embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0948] Accordingly, in certain embodiments, the subject has received, is receiving, or is scheduled to receive one or more (e.g., one, two, three, or four) other therapies suitable for use in treating the disease or disorder. In certain embodiments, the method of treatment of the present invention further comprises administering to the subject one or more (e.g., one, two, three, or four) other therapies suitable for use in treating a disease or disorder, for example, an infection. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise an agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of infection with an intracellular pathogen. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise surgical removal of an infected tissue.

[0949] Accordingly, in certain embodiments, the subject has received, is receiving, or is scheduled to receive one or more (e.g., one, two, three, or four) other therapies suitable for use in treating the disease or disorder. In certain embodiments, the method of treatment of the present invention further comprises administering to the subject one or more (e.g., one, two, three, or four) other therapies suitable for use in treating a disease or disorder, for example, an infection. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise an agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of infection with an intracellular pathogen. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise surgical removal of an infected tissue.

[0950] It is understood that a method of use disclosed herein can be used in combination with an agent, for example, an anti-infective agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of a disease or disorder associated with an intracellular pathogen. For example, a method of use disclosed herein can be used in combination with another antiviral agent.

[0951] In some embodiments, the additional therapeutic agents can be therapeutic anti-viral vaccines.

Synthetic Procedures

List of Abbreviations

TABLE-US-00002 Abbreviation list Full name CAS number ACN Acetonitrile 75-05-8 BnBr Benzyl bromide 100-39-0 Boc.sub.2O di-tert-Butyl dicarbonate 24424-99-5 CDI 1,1-Carbonyldiimidazole 530-62-1 CMBP 2-(Tributylphosphoranylidene)acetonitrile 157141-27-0 DABCO 1,4-Diazabicyclo[2.2.2]octane 280-57-9 DCC Dicyclohexylcarbodiimide 538-75-0 DCE 1,2-Dichloroethane 107-06-2 DCM Dichloromethane 75-09-2 DIAD Diisopropyl azodicarboxylate 2446-83-5 DIEA N-Ethyl-N,N-diisopropylamine 7087-68-5 DMA N,N-Dimethylacetamide 127-19-5 DME 1,2-Dimethoxyethane 110-71-4 DPPF 1,1-Bis(diphenylphosphino)ferrocene 12150-46-8 EDCI N-(3-Dimethylaminopropyl)-N- 1892-57-5 ethylcarbodiimide HATU N-[(Dimethylamino)-3-oxo-1H-1,2,3- 148893-10-1 triazolo[4,5-b]pyridin-1-yl-methylene]-N- methylmethanaminium hexafluorophosphate HOBt 1-Hydroxybenzotriazole 2592-95-2 m-CPBA 3-Chloroperoxybenzoic acid 937-14-4 MsCl Methanesulfonyl chloride 124-63-0 MTBE Methyl tert-butyl ether 1634-04-4 NIS N-Iodosuccinimide 516-12-1 NMI 1-Methyl-1H-imidazole 616-47-7 NMM 4-Methylmorpholine 109-02-4 PCy.sub.3 Tricyclohexylphosphine 2622-14-2 Pd(dppf)Cl.sub.2 (1,1- 72287-26-4 Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(dtbupf)Cl.sub.2 Dichloro[1,1-bis(di-tert- 95408-45-0 butylphosphino)ferrocene]palladium(II) Py Pyridine SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride 76513-69-4 T.sub.3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane- 68957-94-8 2,4,6-trioxide TBAC Tetrabutylammonium chloride 1112-67-0 TBAF Tetrabutylammonium fluoride 429-41-4 tBuXPhos Pd G3 Methanesulfonato(2-di-tert-butylphosphino- 1447963-75-8 2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1- biphenyl-2-yl)palladium(II) TCFH [Chloro(dimethylamino)methylidene]- 94790-35-9 dimethylazanium;hexafluorophosphate TEA Triethylamine 121-44-8 Tf.sub.2O Trifluoromethanesulfonic anhydride 358-23-6 TFA Trifluoroacetic acid 76-05-1 TFE 2,2,2-Trifluoroethanol 132248-58-9 THE Tetrahydrofuran TMAD (3E)-3-(Dimethylcarbamoylimino)-1,1- 10465-78-8 dimethylurea TMSN.sub.3 Trimethylsilyl azide 4648-54-8 TsOHH.sub.2O para-Toluenesulfonic acid monohydrate 6192-52-5 Xantphos 4,5-Bis(diphenylphosphino)-9,9- 161265-03-8 dimethylxanthene

Example 1: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)benzamide (Compound 172)

##STR00835##

Step 1: tert-Butyl 3-((3-(methoxycarbonyl)-4-methylphenyl)amino)azetidine-1-carboxylate (1A-2)

[0952] To a solution of methyl 5-amino-2-methylbenzoate (1.10 g, 6.66 mmol, 1.1 eq) and tert-butyl 3-oxoazetidine-1-carboxylate (1.00 g, 5.84 mmol, 1.0 eq) in DME (30 mL) was added NaBH(OAc) 3 (1.49 g, 7.01 mmol, 1.2 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (40 mL) and extracted with DCM (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl 3-((3-(methoxycarbonyl)-4-methylphenyl)amino)azetidine-1-carboxylate (700 mg, 2.18 mmol, 37% yield) was obtained as a white solid. M56+H.sup.+=265.2.

Step 2: 5-((1-(tert-Butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (1A-3)

[0953] To a solution of tert-butyl 3-((3-(methoxycarbonyl)-4-methylphenyl)amino)azetidine-1-carboxylate (700 mg, 2.18 mmol, 1.0 eq) in a mixture of H.sub.2O (10 mL) and THF (30 mL) was added LiOH.Math.H.sub.2O (458 mg, 10.9 mmol, 5.0 eq). The mixture was stirred at 70 C. for 16 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with TMBE (10 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with 2-methyltetrahydrofuran (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (700 mg) as a white solid.

Step 3: N-Methoxy-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (1A-5)

[0954] To a solution of N,O)-dimethylhydroxylamine hydrochloride (775 mg, 7.95 mmol, 2.0 eq) in DCM (15 mL) was added 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (700 mg, 3.97 mmol, 1.0 eq), followed by HATU (1.81 g, 4.76 mmol, 1.2 eq) and DIEA (1.95 g, 15.1 mmol, 2.63 mL, 3.8 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with saturated aqueous NaHCO.sub.3 (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. N-Methoxy-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (440 mg, 2.01 mmol, 51% yield) was obtained as a colorless oil. M+H.sup.+=220.3 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.15-7.01 (m, 3H), 4.00-2.96 (m, 7H), 2.85-2.68 (m, 4H), 1.81-1.77 (m, 3H).

Step 4: 1-(5,6,7,8-Tetrahydronaphthalen-1-yl)ethanone (1A-6)

[0955] To a solution of N-methoxy-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (400 mg, 1.82 mmol, 1.0 eq) in THF (10 mL) at 0 C. was added MeMgBr (3 M in Et.sub.2O, 912 L, 1.5 eq). The resulting mixture was stirred at 20 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 1-(5,6,7,8-Tetrahydronaphthalen-1-yl)ethanone (120 mg, 689 mol, 38% yield) was obtained as colorless oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.49-7.41 (m, 1H), 7.24-7.12 (m, 2H), 3.00-2.92 (m, 2H), 2.88-2.76 (m, 2H), 2.60-2.52 (m, 3H), 1.85-1.70 (m, 4H).

Step 5: 1-(5,6,7,8-Tetrahydronaphthalen-1-yl)ethanamine (1A-7)

[0956] To a solution of 1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethanone (100 mg, 574 mol, 1.0 eq) in MeOH (6.0 mL) was added NH.sub.4OAc (531 mg, 6.88 mmol, 12 eq), followed by NaBH.sub.3CN (144 mg, 2.30 mmol, 4.0 eq). The resulting mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethanamine (90.0 mg, 513 mol, 89% yield) as a colorless oil. M17+H.sup.+=159.0 (LCMS).

Step 6: tert-Butyl 3-((4-methyl-3-((1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (1A-8)

[0957] To a solution of 1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethanamine (60.0 mg, 342 mol, 1.0 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (94.4 mg, 308 mol, 0.9 eq) in DCM (5.0 mL) were added EDCI (98.4 mg, 514 mol, 1.5 eq), HOBt (69.4 mg, 514 mol, 1.5 eq) and TEA (69.3 mg, 685 mol, 95.3 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl 3-((4-methyl-3-((1-(5,6,7,8-tetrahydro naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (80.0 mg, 162 mol, 47%) was obtained as a yellow solid. M+Na.sup.+=486.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.23 (d, J=7.1 Hz, 1H), 7.12-7.07 (m, 1H), 7.03-6.95 (m, 2H), 6.56-6.49 (m, 2H), 5.43-5.36 (m, 1H), 4.61-4.58 (m, 1H), 4.29-4.17 (m, 3H), 3.74-3.69 (m, 2H), 3.10-3.02 (m, 1H), 2.83-2.77 (m, 3H), 2.21-2.18 (m, 3H), 1.95-1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.48 (m, 11H).

Step 7: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)benzamide (Compound 172)

[0958] To a solution of tert-butyl 3-((4-methyl-3-((1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl) carbamoyl)phenyl)amino)azetidine-1-carboxylate (60.0 mg, 129 mol, 1.0 eq) in DCM (8.0 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 313 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(azetidin-3-ylamino)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)benzamide (22.7 mg, 47.6 mol, 37% yield, TFA salt) as a yellow solid. M+H.sup.+=364.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.22-7.18 (m, 1H), 7.10-7.00 (m, 2H), 6.98-6.94 (m, 1H), 6.58-6.53 (m, 1H), 6.50-6.48 (m, 1H), 5.41-5.38 (m, 1H), 4.50-4.45 (m, 1H), 4.38-4.32 (m, 2H), 3.96-3.89 (m, 2H), 3.12-2.98 (m, 1H), 2.82-2.76 (m, 3H), 2.21-2.18 (m, 3H), 1.92-1.84 (m, 2H), 1.82-1.76 (m, 2H), 1.46-1.42 (m, 3H).

Example 2: 5-(Azetidin-3-ylamino)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)-2-methylbenzamide (Compound 168)

##STR00836##

Step 1: N-Methoxy-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (2A-2)

[0959] To a solution of 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (1.00 g, 5.55 mmol, 1.0 eq) and N,O)-dimethylhydroxylamine hydrochloride (596 mg, 6.11 mmol, 1.1 eq) in DCM (20 mL) were added TEA (1.69 g, 16.7 mmol, 2.32 mL, 3.0 eq), EDCI (1.28 g, 6.66 mmol, 1.2 eq) and HOBt (900 mg, 6.66 mmol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. N-Methoxy-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (600 mg, 2.69 mmol, 48% yield) was obtained as a white solid. M+H.sup.+=224.0 (LCMS).

Step 2: 1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)ethanone (2A-3)

[0960] A mixture of N-methoxy-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (200 mg, 896 mol, 1.0 eq) in THF (3.0 mL) was degassed and purged with N.sub.2 three times, and to this mixture was added MeMgBr (3 M in Et.sub.2O, 388 L, 1.3 eq) at 0 C. The mixture was warmed to 20 C. and stirred at the same temperature for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethanone (150 mg), which was used in the next step without any further purification.

Step 3: 1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)ethanamine (2A-4)

[0961] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethanone (100 mg, 561 mol, 1.0 eq) in MeOH (1.0 mL) was added NH.sub.4OAc (519 mg, 6.73 mmol, 12 eq), followed by NaBH.sub.3CN (141 mg, 2.24 mmol, 4.0 eq) at 20 C. The mixture was stirred at the same temperature for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected as a main peak. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethanamine (150 mg), which was used in the next step without any further purification. M+H.sup.+=180.0 (LCMS).

Step 4: tert-Butyl-((3-((1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (2A-5)

[0962] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethanamine (130 mg, 725 mol, 1.1 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (202 mg, 659 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (267 mg, 2.64 mmol, 367 L, 4.0 eq), EDCI (379 mg, 1.98 mmol, 3.0 eq) and HOBt (267 mg, 1.98 mmol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. tert-Butyl-((3-((1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (123 mg, 263 mol, 40% yield) was obtained as a white oil. M+H.sup.+=468.0 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)-2-methylbenzamide (Compound 168)

[0963] To a solution of tert-butyl 3-((3-((1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (20.0 mg, 42.8 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 316 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(azetidin-3-ylamino)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethyl)-2-methylbenzamide (12.0 mg, 24.6 mol, 58% yield, TFA salt) as a white solid. M+H.sup.+=368.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.54-8.47 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.88-6.86 (m, 1H), 6.81-6.73 (m, 2H), 6.59-6.54 (m, 2H), 5.48-5.40 (m, 1H), 4.53-4.45 (m, 1H), 4.39-4.30 (m, 4H), 4.27-4.24 (m, 2H), 3.96-3.91 (m, 2H), 2.22 (s, 3H), 1.46 (d, J=7.0 Hz, 3H).

Example 3: (R)-5-Acetyl-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 155)

##STR00837##

Step 1: 5-Acetyl-2-methylbenzoic acid (3A-2)

[0964] To a solution of 5-bromo-2-methylbenzoic acid (300 mg, 1.40 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 1.12 mL, 2.0 eq) at 78 C. The mixture was stirred at 78 C. for 30 min. To the mixture was added a solution of N-methoxy-N-methylacetamide (158 mg, 1.53 mmol, 163 L, 1.1 eq) in THF (3.0 mL). The mixture was stirred at 78 C. for 1 h, then warmed to 20 C. and stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into HCl (1 M aqueous, 10 mL) and extracted with MTBE (10 mL2). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-acetyl-2-methylbenzoic acid (70.0 mg), which was used in the next step without any further purification. M+H.sup.+=179.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 13.1 (br d, J=5.4 Hz, 1H), 8.3 (d, J=2.0 Hz, 1H), 8.0 (dd, J=8.0, 2.0 Hz, 1H), 7.5 (d, J=8.0 Hz, 1H), 2.6 (s, 6H).

Step 2: (R)-5-Acetyl-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 155)

[0965] To a solution of 5-acetyl-2-methylbenzoic acid (60.0 mg, 337 mol, 1.0 eq) in DCM (3.0 mL) were added (R)-1-(naphthalen-1-yl)ethanamine (57.7 mg, 337 mol, 53.9 L, 1.0 eq), EDCI (77.5 mg, 404 mol, 1.2 eq), HOBt (54.6 mg, 404 mol, 1.2 eq) and TEA (102 mg, 1.01 mmol, 141 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 35%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (R)-5-Acetyl-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (11.5 mg, 34.5 mol, 10% yield) was obtained as a white solid. M+H.sup.+=332.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.3 (d, J=8.4 Hz, 1H), 7.9-8.0 (m, 3H), 7.8 (d, J=8.1 Hz, 1H), 7.6-7.7 (m, 2H), 7.5-7.5 (m, 2H), 7.4 (d, J=8.0 Hz, 1H), 6.1 (q, J=6.9 Hz, 1H), 2.5-2.6 (m, 3H), 2.4 (s, 3H), 1.7 (d, J=7.0 Hz, 3H).

Example 4: (R)-5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 101)

##STR00838##

Step 1: (R)-5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 101)

[0966] A mixture of (R)-1-(naphthalen-1-yl)ethanamine (56.3 mg, 329 mol, 52.6 L, 1.0 eq) and 5-hydroxy-2-methylbenzoic acid (50.0 mg, 329 mol, 1.0 eq) in DCM (3.0 mL) were added HATU (250 mg, 657 mol, 2.0 eq) and DIEA (127 mg, 986 mol, 172 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile) to give (R)-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (50.2 mg, 164 mol, 50% yield) as a white solid. M+H.sup.+=306.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.19 (br d, J=8.3 Hz, 1H), 7.91-7.76 (m, 2H), 7.60-7.40 (m, 4H), 6.97 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 6.73 (br d, J=8.3 Hz, 1H), 6.09 (br s, 2H), 2.29 (s, 3H), 1.76 (br d, J=5.7 Hz, 3H).

Example 5: (R)-5-Methoxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 136)

##STR00839##

Step 1: (R)-5-Methoxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 136)

[0967] To a mixture of (R)-1-(naphthalen-1-yl)ethanamine (50 mg, 292 mol, 47.0 L, 1.0 eq) and 5-methoxy-2-methylbenzoic acid (48.6 mg, 292 mol, 1.0 eq) in DCM (2.0 mL) were added EDCI (67.2 mg, 350 mol, 1.2 eq), HOBt (47.4 mg, 350 mol, 1.2 eq) and TEA (88.6 mg, 876 mol, 100 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile). (R)-5-Methoxy-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (36.1 mg, 112 mol, 38% yield) was obtained as a white solid. M+H.sup.+=320.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.24 (d, J=8.4 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.63-7.43 (m, 4H), 7.09 (d, J=8.3 Hz, 1H), 6.87-6.78 (m, 2H), 6.19-6.08 (m, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 1.80 (d, J=6.7 Hz, 3H).

Example 6: (R)-2-Chloro-5-methoxy-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 132)

##STR00840##

Step 1: (R)-2-Chloro-5-methoxy-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 132)

[0968] To a mixture of (R)-1-(naphthalen-1-yl)ethanamine (60.0 mg, 350 mol, 56.0 L, 1.0 eq) and 2-chloro-5-methoxybenzoic acid (65.4 mg, 350 mol, 1.0 eq) in DCM (3.0 mL) were added EDCI (80.6 mg, 420 mol, 1.2 eq) and HOBt (56.8 mg, 420 mol, 1.2 eq) and TEA (106 mg, 1.05 mmol, 146 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 50%-80% B over 8 min; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile). (R)-2-Chloro-5-methoxy-N-(1-(naphthalen-1-yl)ethyl)benzamide (56.3 mg, 161 mol, 46% yield) was obtained as a white solid. M+H.sup.+=340.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.23 (d, J=8.5 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.63-7.42 (m, 4H), 7.25 (d, J=8.9 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.88 (dd, J=3.1, 8.8 Hz, 1H), 6.14 (q, J=6.9 Hz, 1H), 3.79 (s, 3H), 1.82 (d, J=6.8 Hz, 3H).

Example 7: (R)-tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (Compound 158)

##STR00841##

Step 1: Methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (7A-2)

[0969] A mixture of tert-butyl(2-hydroxyethyl)carbamate (2.43 g, 15.0 mmol, 2.33 mL, 1.0 eq), methyl 5-hydroxy-2-methylbenzoate (2.50 g, 15.0 mmol, 1.0 eq) and PPh.sub.3 (4.34 g, 16.6 mmol, 1.1 eq) in THF (30 mL) was degassed and purged with N.sub.2 three times. To the mixture was added DIAD (3.35 g, 16.6 mmol, 3.22 mL, 1.1 eq) dropwise at 20 C. The resulting mixture was stirred at 70 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. Methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (2.50 g, 8.08 mmol, 54% yield) was obtained as a yellow oil. M+Na.sup.+=332.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.43 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.94 (dd, J=2.8, 8.3 Hz, 1H), 5.11-4.95 (m, 1H), 4.02 (s, 2H), 3.88 (s, 3H), 3.53 (br d, J=5.1 Hz, 2H), 2.51 (s, 3H), 1.45 (s, 9H).

Step 2: 5-(2-((tert-Butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (7A-3)

[0970] To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (1.60 g, 5.17 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and THF (24 mL) was added NaOH (2 M aqueous, 10 mL, 4.0 eq). The mixture was stirred at 70 C. for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, H.sub.2O (30 mL) was added, and the mixture was washed with MTBE (15 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methyl benzoic acid (1.1 g), which was used in the next step without any further purification. M+Na.sup.+=318.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 13.49 (br s, 1H), 9.33 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 7.28 (br s, 1H), 7.00-6.92 (m, 1H), 6.70 (t, J=8.4 Hz, 2H), 5.18-5.11 (m, 1H), 2.64-2.54 (m, 2H), 2.00-1.90 (m, 1H), 1.87-1.72 (m, 3H).

Step 3: (R)-tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (Compound 158)

[0971] To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (50.0 mg, 169 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (34.8 mg, 203 mol, 32.5 L, 1.2 eq) in DCM (3.0 mL) were added TEA (51.4 mg, 508 mol, 70.7 L, 3.0 eq), EDCI (48.7 mg, 254 mol, 1.5 eq) and HOBt (34.3 mg, 254 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were washed with brine (3.0 mL3), dried over Na.sub.2SO.sub.4, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). (R)-tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl) phenoxy)ethyl)carbamate (77.2 mg, 143 mol, 84% yield) was obtained as a white oil. M56+H.sup.+=393.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.24 (d, J=8.6 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.62-7.45 (m, 4H), 7.09 (d, J=8.4 Hz, 1H), 6.85-6.77 (m, 2H), 6.18-6.09 (m, 1H), 5.98-5.91 (m, 1H), 4.94 (br d, J=4.9 Hz, 1H), 3.98-3.90 (m, 2H), 3.52-3.43 (m, 2H), 2.35 (s, 3H), 1.81 (d, J=6.7 Hz, 3H), 1.44 (s, 9H).

Example 8: (R)-5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 159)

##STR00842##

Step 1: (R)-5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 159)

[0972] To a mixture of (R)-tert-butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)ethyl) carbamoyl)phenoxy)ethyl)carbamate (20.0 mg, 44.6 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (6.21 mg, 16.1 mol, 36% yield, HCl salt) was obtained as a white solid. M+H.sup.+=349.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.26 (d, J=8.4 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.70-7.44 (m, 4H), 7.17 (d, J=8.5 Hz, 1H), 6.97 (dd, J=2.8, 8.4 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.06 (q, J=7.0 Hz, 1H), 4.59 (br s, 2H), 4.28-4.11 (m, 2H), 3.33 (d, J=5.1 Hz, 2H), 2.27 (s, 3H), 1.71 (d, J=6.9 Hz, 3H).

Example 9: (R)-5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 160)

##STR00843##

Step 1: (R)-5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 160)

[0973] To a solution of (R)-5-(2-aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (20.0 mg, 57.4 mol, 1.0 eq, HCl salt) in MeOH (3.0 mL) was added TEA (900 L), followed by the addition of formaldehyde (9.32 mg, 115 mol, 8.55 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (7.21 mg, 115 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) at 25 C. and extracted with EtOAc (3.0 mL3). The combined organic layers were washed with brine (3.0 mL3), dried over Na.sub.2SO.sub.4, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (15.9 mg, 42.2 mol, 74% yield, HCl salt) was obtained as a white solid. M+H.sup.+=377.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.85 (br d, J=7.8 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.63 (d, J=6.8 Hz, 1H), 7.60-7.43 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 6.98 (dd, J=2.8, 8.4 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 6.11-5.97 (m, 1H), 4.35-4.25 (m, 2H), 3.61-3.51 (m, 2H), 2.95 (s, 6H), 2.28 (s, 3H), 1.71 (d, J=6.8 Hz, 3H).

Example 10: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(oxetan-3-yloxy)benzamide (Compound 152)

##STR00844##

Step 1: Methyl 2-methyl-5-(oxetan-3-yloxy)benzoate (10A-1)

[0974] To a solution of methyl 5-hydroxy-2-methylbenzoate (150 mg, 903 mol, 1.0 eq) and 3-iodooxetane (199 mg, 1.08 mmol, 1.2 eq) in DMF (4 mL) was added Cs.sub.2CO.sub.3 (588 mg, 1.81 mmol, 2.0 eq). The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give methyl 2-methyl-5-(oxetan-3-yloxy)benzoate (1.10 g), which was used in the next step without any further purification.

Step 2: 2-Methyl-5-(oxetan-3-yloxy)benzoic acid (10A-2)

[0975] To a solution of methyl 2-methyl-5-(oxetan-3-yloxy)benzoate (80.0 mg, 360 mol, 1.0 eq) in a mixture of THF (3.0 mL) and H.sub.2O (1.0 mL) was added LiOH.Math.H.sub.2O (45.3 mg, 1.08 mmol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material completely consumed, and desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with petroleum ether (3.0 mL2). The aqueous phase was adjusted to pH 4 with HCl (1 M aqueous) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(oxetan-3-yloxy)benzoic acid (60.0 mg) as a colorless oil, which was used in the next step without any further purification. M+H.sup.+=209.2 (LCMS).

Step 3: (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(oxetan-3-yloxy)benzamide (Compound 152)

[0976] To a solution of 2-methyl-5-(oxetan-3-yloxy)benzoic acid (50.0 mg, 240 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (41.1 mg, 240 mol, 38.4 L, 1.0 eq) in DCM (3.0 mL) were added TEA (48.6 mg, 480 mol, 2.0 eq), EDCI (55.2 mg, 288 mol, 1.2 eq) and HOBt (38.9 mg, 288 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (EtOAc/petroleum ether=2/1) to give (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(oxetan-3-yloxy)benzamide (12.2 mg, 33.2 mol) as a white solid. M+H.sup.+=362.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.22 (d, J=8.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.66-7.43 (m, 4H), 7.10-7.04 (m, 1H), 6.66-6.62 (m, 1H), 6.62-6.56 (m, 1H), 6.18-6.06 (m, 1H), 5.98-5.88 (m, 1H), 5.16-5.05 (m, 1H), 4.93-4.82 (m, 2H), 4.72-4.62 (m, 2H), 2.40-2.31 (m, 3H), 1.84-1.75 (m, 3H).

Example 11: (R)-5-(Azetidin-3-yloxy)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 141)

##STR00845##

Step 1: tert-Butyl 3-(3-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (11A-1)

[0977] To a stirred solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) in DMF (10 mL) were added Cs.sub.2CO.sub.3 (1.18 g, 3.61 mmol, 2.0 eq) and tert-butyl 3-iodoazetidine-1-carboxylate (613 mg, 2.17 mmol, 1.2 eq). The mixture was stirred at 110 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl 3-(3-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (450 mg, 1.40 mmol, 78% yield) was obtained as a colorless oil. .sup.1H NMR (400 MHZ, CD.sub.3Cl) 7.29 (s, 1H), 7.19-7.17 (d, J=8.4 Hz, 1H), 6.87-6.84 (m, 1H), 4.93-4.89 (m, 1H), 4.35-4.31 (m, 2H), 4.03-4.01 (m, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H).

Step 2: 5-((1-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)-2-methylbenzoic acid (11A-2)

[0978] To a stirred solution of tert-butyl 3-(3-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (200 mg, 622 mol, 1.0 eq) in a mixture of THF (5.0 mL) and H.sub.2O (1.0 mL) was added LiOH.Math.H.sub.2O (52.2 mg, 1.24 mmol, 2.0 eq) at 20 C. for 2 h then at 70 C. for another 14 h. Another 10.0 mg of LiOH.Math.H.sub.2O was added and the reaction mixture was stirred at 70 C. for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and washed with TBME (5.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with DCM (3.0 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product 5-((1-(tert-butoxy carbonyl)azetidin-3-yl)oxy)-2-methylbenzoic acid (150 mg, 488 mol, 78% yield) as a colorless oil, which was used in the next step without any further purification. MH.sup.=306.1 (LCMS).

Step 3: (R)-tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)azetidine-1-carboxylate (11A-3)

[0979] To a mixture of 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-2-methyl-benzoic acid (90.0 mg, 292 mol, 1.0 eq) in DCM (5.0 mL) was added (1R)-1-(1-naphthyl)ethanamine (55.2 mg, 322 mol, 51.6 L, 1.1 eq), followed by TEA (88.9 mg, 879 mol, 122 L, 3.0 eq) and T.sub.3P (280 mg, 439 mol, 261 L, 50% in EtOAc, 1.5 eq). The resulting mixture was stirred at 20 C. for 1.5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (3.0 mL). The product was extracted with DCM (8.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. (R)-tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)azetidine-1-carboxylate (120 mg, 261 mol, 89% yield) was obtained as a colorless oil. M+H.sup.+=461.4 (LCMS).

Step 4: (R)-tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)azetidine-1-carboxylate (Compound 141)

[0980] To a mixture of (R)-tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy) azetidine-1-carboxylate (50.0 mg, 109 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 10 mL) at 0 C. The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-tert-Butyl3-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)azetidine-1-carboxylate (14.0 mg, 38.8 mol, 36% yield) was obtained as a white solid. M+H.sup.+=361.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.27-8.21 (m, 1H), 7.94-7.89 (m, 1H), 7.85-7.78 (m, 1H), 7.64-7.45 (m, 4H), 7.20-7.16 (m, 1H), 6.84-6.79 (m, 1H), 6.77-6.71 (m, 1H), 6.10-6.00 (m, 1H), 5.15-5.06 (m, 1H), 4.55-4.43 (m, 2H), 4.13-4.04 (m, 2H), 2.31-2.20 (m, 3H), 1.76-1.65 (m, 3H).

Example 12: (R)-tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy) piperidine-1-carboxylate (Compound 164)

##STR00846##

Step 1: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenoxy) piperidine-1-carboxylate (12A-1)

[0981] To a solution of methyl 5-hydroxy-2-methylbenzoate (200 mg, 1.20 mmol, 1.0 eq) in THF (20 mL) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (266 mg, 1.32 mmol, 1.1 eq) and PPh.sub.3 (379 mg, 1.44 mmol, 1.2 eq), followed by DIAD (316 mg, 1.56 mmol, 304 L, 1.3 eq) at 0 C. under a N.sub.2 atomsphere. The resulting mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl 4-(3-(methoxycarbonyl)-4-methyl phenoxy) piperidine-1-carboxylate (200 mg, 572 mol, 48% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.48-7.45 (m, 1H), 7.18-7.12 (m, 1H), 7.00-6.95 (m, 1H), 4.50-4.44 (m, 1H), 3.92-3.87 (m, 3H), 3.74-3.65 (m, 2H), 3.40-3.31 (m, 2H), 2.55-2.50 (m, 3H), 1.96-1.86 (m, 2H), 1.80-1.69 (m, 2H), 1.51-1.46 (m, 9H).

Step 2: 5-((1-(tert-Butoxycarbonyl) piperidin-4-yl)oxy)-2-methylbenzoic acid (12A-2)

[0982] To a stirred solution of tert-butyl 4-(3-methoxycarbonyl-4-methyl-phenoxy) piperidine-1-carboxylate (120 mg, 343 mol, 1.0 eq) in a mixture of THF (6.0 mL) and H.sub.2O (2.0 mL) was added LiOH.Math.H.sub.2O (36.0 mg, 859 mol, 2.5 eq) at 20 C. for 8 h and then at 70 C. for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (5.0 mL3). The aqueous was acidified to pH 5 with HCl (1 M aqueous) and the product was extracted with DCM (5.0 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-((1-(tert-butoxycarbonyl) piperidin-4-yl)oxy)-2-methylbenzoic acid (85.0 mg) as a colorless oil, which was used in the next step without any further purification. MH.sup.=334.2 (LCMS).

Step 3: (R)-tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)piperidine-1-carboxylate (Compound 164)

[0983] To a suspension of (1R)-1-(1-naphthyl)ethanamine (65.1 mg, 380 mol, 60.8 L, 1.5 eq) in DCM (5.0 mL) were added 5-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]-2-methyl-benzoic acid (85.0 mg, 253 mol, 1.0 eq) and TEA (76.9 mg, 760 mol, 106 L, 3.0 eq), followed by EDCI (72.9 mg, 380 mol, 1.5 eq) and HOBt (51.4 mg, 380 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.5). (R)-tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy) piperidine-1-carboxylate (110 mg, 218 mol, 86% yield) was obtained as a white solid. M56+H.sup.+=433.1; 1H NMR (400 MHZ, CDCl.sub.3) 8.26-8.22 (m, 1H), 7.91-7.88 (m, 1H), 7.86-7.81 (m, 1H), 7.60 (s, 5H), 7.10-7.06 (m, 1H), 6.85 (s, 1H), 4.39-4.33 (m, 1H), 3.71-3.62 (m, 2H), 3.31-3.23 (m, 2H), 2.36-2.33 (m, 3H), 1.83-1.78 (m, 4H), 1.47-1.46 (m, 9H), 1.31-1.20 (m, 3H).

Example 13: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(piperidin-4-yloxy)benzamide (Compound 162)

##STR00847##

Step 1: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(piperidin-4-yloxy)benzamide (Compound 162)

[0984] To a mixture of (R)-tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy) piperidine-1-carboxylate (80.0 mg, 164 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 40.9 L). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated at 30 C. under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(piperidin-4-yloxy)benzamide (40.0 mg, 103 mol, 63% yield, HCl salt) was obtained as a white solid. M+H.sup.+=389.1; 1H NMR (400 MHZ, CD.sub.3OD) 8.29-8.13 (m, 1H), 7.92-7.83 (m, 1H), 7.82-7.73 (m, 1H), 7.62-7.57 (m, 1H), 7.57-7.53 (m, 1H), 7.53-7.49 (m, 1H), 7.49-7.45 (m, 1H), 7.45-7.42 (m, 1H), 7.15-7.09 (m, 1H), 6.97-6.90 (m, 1H), 6.87-6.84 (m, 1H), 6.04-5.94 (m, 1H), 4.64-4.56 (m, 1H), 3.29 (br d, J=3.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.24-2.20 (m, 3H), 2.14-2.01 (m, 2H), 2.01-1.83 (m, 2H), 1.69-1.62 (m, 3H).

Example 14: (R)-2-Methyl-5-(methylsulfonamido)-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 100)

##STR00848##

Step 1: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide (14A-2)

[0985] To a solution of 2-methyl-5-nitrobenzoic acid (1.00 g, 5.52 mmol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (940 mg, 5.52 mmol, 880 L, 1.0 eq) in DCM (20 mL) were added TEA (1.12 g, 11.0 mmol, 1.54 mL, 2.0 eq) and T.sub.3P (10.5 g, 16.6 mmol, 10.0 mL, 50% in EtOAc, 3.0 eq) at 0 C. The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide (1.50 g, 4.49 mmol, 81% yield) as a white solid. M+H.sup.+=335.2 (LCMS).

Step 2: (R)-5-Amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (14A-3)

[0986] To a solution of (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide (1.00 g, 2.99 mmol, 1.0 eq), 10% palladium on carbon (200 mg) in a mixture of EtOAc (20 mL) and MeOH (20 mL) was degassed and purged with H.sub.2 for three times, then the mixture was stirred at 20 C. for 16 h under H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (5.0 mL3). The combined filtrates were concentrated under vacuum to give (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (800 mg, 2.58 mmol, 86% yield) as a white solid. M+H.sup.+=305.2 (LCMS).

Step 3: (R)-2-Methyl-5-(methylsulfonamido)-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 100)

[0987] To a solution of (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (100 mg, 329 mol, 1.0 eq) in Py (2.0 mL) was added MsCl (41.4 mg, 361 mol, 28 L, 1.1 eq) at 0 C. The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-2-Methyl-5-(methylsulfonamido)-N-(1-(naphthalen-1-yl)ethyl)benzamide (38.5 mg, 100 mol, 30% yield) as a white solid. M+H.sup.+=383.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.21 (d, J=8.5 Hz, 1H), 7.91-7.86 (m, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.61-7.42 (m, 4H), 7.17-7.09 (m, 3H), 6.80 (br s, 1H), 6.17-6.06 (m, 2H), 2.88 (s, 3H), 2.37 (s, 3H), 1.83-1.73 (m, 3H)

Example 15: (R)-5-((1H-Pyrazol-4-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 121)

##STR00849##

Step 1: 2-Methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (15A-2)

[0988] To a stirred solution of methyl 5-amino-2-methylbenzoate (50.0 mg, 303 mol, 1.0 eq) and 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (83.9 mg, 363 mol, 1.2 eq) in dioxane (2.0 mL) were added/BuXphos Pd G3 (24.0 mg, 30.3 mol, 0.1 eq) and sodium 1-butanolate (145 mg, 1.51 mmol, 5.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and washed with MTBE (3.0 mL2). The aqueous was acidified to pH 6 with HCl (1 M aqueous) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (100 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=302.3 (LCMS).

Step 2: 2-Methyl-N((R)-1-(naphthalen-1-yl)ethyl)-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (15A-3)

[0989] To a stirred solution of 2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (130 mg, 431 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (111 mg, 647 mol, 104 L, 1.5 eq) in DCM (5 mL) were added EDCI (124 mg, 647 mol, 1.5 eq) and HOBt (87.4 mg, 647 mol, 1.5 eq), followed by TEA (131 mg, 1.29 mmol, 180 L, 3.0 eq). The mixture was stirred at 20 C. for 2 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.2). 2-Methyl-N((R)-1-(naphthalen-1-yl)ethyl)-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (90.0 mg, 198 mol, 46% yield) was obtained as a yellow oil.

Step 3: (R)-5-((1H-Pyrazol-4-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 121)

[0990] To a stirred solution of 2-methyl-N((R)-1-(naphthalen-1-yl)ethyl)-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (90.0 mg, 198 mol, 1.0 eq) in MeOH (2.0 mL) was added 4-methylbenzenesulfonic acid hydrate (113 mg, 594 mol, 3.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15040 mm, 10 m); flow rate: 60 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-5-((1H-Pyrazol-4-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (30.0 mg, 80.7 mol, 41% yield) was obtained as a white solid. M+H.sup.+=371.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 12.57 (br s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.01-7.92 (m, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.68-7.45 (m, 6H), 7.37 (br s, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 8.2 Hz, 1H), 5.89 (quin, J=7.1 Hz, 1H), 2.14 (s, 3H), 1.55 (d, J=6.8 Hz, 3H).

Example 16: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(thiazol-2-ylamino)benzamide (Compound 107)

##STR00850##

Step 1: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(thiazol-2-ylamino)benzamide (Compound 107)

[0991] To a mixture of (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (100 mg, 329 mol, 1.5 eq) and 2-chlorothiazole (26.2 mg, 219 mol, 1.0 eq) in propan-2-ol (2.0 mL) was added TOH.Math.H.sub.2O (62.5 mg, 329 mol, 1.5 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile). (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-(thiazol-2-ylamino)benzamide (16.8 mg, 43.4 mol, 20% yield) was as an off-white solid. M+H.sup.+=388.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.25 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.62-7.43 (m, 5H), 7.33-7.27 (m, 2H), 7.20 (d, J=3.5 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.59 (d, J=3.7 Hz, 1H), 6.19-6.10 (m, 1H), 6.02 (br d, J=8.4 Hz, 1H), 2.40 (s, 3H), 1.82 (d, J=6.7 Hz, 3H).

Example 17: (R)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 115)

##STR00851##

Step 1: Methyl 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoate (17A-1)

[0992] A mixture of methyl 5-amino-2-methylbenzoate (400 mg, 2.42 mmol, 1.2 eq), 3-bromo-2-methoxypyridine (379 mg, 2.02 mmol, 1.0 eq) and Cs.sub.2CO.sub.3 (1.31 g, 4.04 mmol, 2.0 eq) in dioxane (6.0 mL) was degassed and purged with N.sub.2 three times. To the mixture were added Pd.sub.2 (dba) 3 (185 mg, 202 mol, 0.1 eq) and Xantphos (234 mg, 404 mol, 0.2 eq) at 20 C. The resulting mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoate (400 mg, 1.47 mmol, 73% yield) was obtained as a yellow solid. M+H.sup.+=273.3 (LCMS).

Step 2: 5-((2-Methoxypyridin-3-yl)amino)-2-methylbenzoic acid (17A-2)

[0993] To a solution of methyl 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoate (400 mg, 1.47 mmol, 1.0 eq) in a mixture of MeOH (9.0 mL) and THF (27 mL) was added LiOH.Math.H.sub.2O (185 mg, 4.41 mmol, 3.0 eq). The mixture was stirred at 70 C. for 5 h. TLC indicated that most of the starting material still remained. The mixture was allowed to cool to room temperature and NaOH (58.75 mg, 1.47 mmol, 1.0 eq) was added. The resulting mixture was stirred at 70 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (18 mL) and the mixture was washed with petroleum ether (6.0 mL5). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoic acid (210 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=259.3 (LCMS).

Step 3: (R)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (Compound 115)

[0994] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (66.3 mg, 387 mol, 1.0 eq) and 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoic acid (100 mg, 387 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (206 mg, 2.03 mmol, 283 L, 3.0 eq), EDCI (325 mg, 1.69 mmol, 2.5 eq) and HOBt (229 mg, 1.69 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.6). (R)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (90.0 mg, 219 mol, 57% yield) was obtained as a yellow solid. M+H.sup.+=412.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.28-8.21 (m, 1H), 7.92-7.81 (m, 2H), 7.69-7.63 (m, 1H), 7.61-7.42 (m, 4H), 7.30-7.15 (m, 1H), 7.20-7.15 (m, 1H), 7.13-7.06 (m, 2H), 6.78-5.72 (m, 1H), 6.19-6.12 (m, 1H), 6.01-5.92 (m, 2H), 4.03 (s, 3H), 2.38 (s, 3H), 1.77-1.84 (m, 3H).

Example 18: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-((2-oxo-1,2-dihydropyridin-3-yl)amino)benzamide (Compound 119)

##STR00852##

Step 1: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-((2-oxo-1,2-dihydropyridin-3-yl)amino)benzamide (Compound 119)

[0995] A mixture of (R)-5-((2-methoxypyridin-3-yl)amino)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (45 mg, 109 mol, 1.0 eq) in DCM (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added BBr.sub.3 (219 mg, 875 mol, 8.0 eq) in DCM (2 mL) at 78 C. The mixture was stirred at 20 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue. The residue was diluted with MeOH (2 mL) and basified to pH 8 using NH.sub.3.Math.H.sub.2O (37% aqueous). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-((2-oxo-1,2-dihydropyridin-3-yl)amino)benzamide (11.5 mg, 28.8 mol, 26% yield, TFA salt) was obtained as a white solid. M+H.sup.+=398.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.32-8.19 (m, 1H), 7.98-7.77 (m, 2H), 7.69-7.43 (m, 4H), 7.25-7.10 (m, 4H), 6.98-6.78 (m, 1H), 6.32-6.21 (m, 1H), 6.13-5.93 (m, 1H), 2.34-2.24 (m, 3H), 1.79-1.59 (m, 3H).

Example 19: 5-(N-(1-Amino-3-hydroxypropan-2-yl) acetamido)-2-methyl-N((R)-1-(naphthalen-1-yl)ethyl)benzamide (Compound 165)

##STR00853##

Step 1: (R)-tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (19A-1)

[0996] To a solution of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (100 mg, 326 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (61.5 mg, 359 mol, 1.1 eq) in DCM (5.0 mL) were added TEA (99.1 mg, 979 mol, 136 L, 3.0 eq), EDCI (75.1 mg, 392 mol, 1.2 eq) and HOBt (52.9 mg, 392 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product (R)-tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (150 mg), which was used in the next step without any further purification. M+H.sup.+=460.4 (LCMS).

Step 2: (R)-tert-Butyl 3-(N-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl)acetamido)azetidine-1-carboxylate (19A-2)

[0997] To a solution of (R)-tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (40.0 mg, 87.0 mol, 1.0 eq) and acetyl chloride (7.52 mg, 95.7 mol, 6.83 L, 1.1 eq) in DCM (1.0 mL) was added pyridine (6.88 mg, 87.0 mol, 7.03 L, 1.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (1.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product (R)-tert-butyl 3-(N-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl) acetamido)azetidine-1-carboxylate (38.2 mg), which was used in the next step without any further purification. M+H.sup.+=502.4 (LCMS).

Step 3: 5-(N-(1-Amino-3-hydroxypropan-2-yl) acetamido)-2-methyl-N((R)-1-(naphthalen-1-yl)ethyl)benzamide (Compound 165)

[0998] To a solution of (R)-tert-butyl 3-(N-(4-methyl-3-((1-(naphthalen-1-yl)ethyl)carbamoyl)phenyl) acetamido)azetidine-1-carboxylate (10.0 mg, 19.9 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (154 mg, 1.35 mmol, 100 L). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (1.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(N-(1-Amino-3-hydroxypropan-2-yl) acetamido)-2-methyl-N((R)-1-(naphthalen-1-yl)ethyl)benzamide (3.00 mg, 6.58 mol, 33% yield, HCl salt) was obtained as a yellow gum. M+H.sup.+=420.1 (LCMS); .sup.1H NMR (400 MHz, CD.sub.3OD) 8.25 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.60-7.42 (m, 3H), 7.03 (d, J=8.2 Hz, 1H), 6.79-6.66 (m, 2H), 6.05 (q, J=7.3 Hz, 1H), 4.20 (dd, J=4.0, 11.2 Hz, 1H), 4.04-3.89 (m, 2H), 3.23 (br dd, J=3.5, 13.1 Hz, 1H), 3.04-2.90 (m, 1H), 2.22 (s, 3H), 2.01 (d, J=4.4 Hz, 3H), 1.70 (dd, J=2.8, 6.9 Hz, 3H).

Example 20: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 153)

##STR00854##

Step 1: Methyl 5-amino-4-iodo-2-methylbenzoate (20A-1)

[0999] To a solution of methyl 5-amino-2-methylbenzoate (15.0 g, 90.8 mmol, 1.0 eq) in AcOH (80 mL) was added NIS (22.5 g, 99.9 mmol, 1.1 eq). The mixture was stirred at 20 C. for 1 h. TLC indicated that the starting material was consumed. The reaction mixture was poured into H.sub.2O (200 mL) and extracted with EtOAc (100 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. Methyl 5-amino-4-iodo-2-methylbenzoate (2.40 g, 9.18 mmol, 89% yield) was obtained as a brown oil. M+H.sup.+=293.0 (LCMS).

Step 2: Methyl 5-amino-2-methyl-4-((trimethylsilyl)ethynyl)benzoate (20A-2)

[1000] A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (3.00 g, 10.3 mmol, 1.0 eq), TEA (2.09 g, 20.6 mmol, 2.87 mL, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (217 mg, 309 mol, 0.03 eq), CuI (19.6 mg, 103 mol, 0.01 eq) and ethynyltrimethylsilane (1.52 g, 15.5 mmol, 2.14 mL, 1.5 eq) in a mixture of toluene (80 mL) and H.sub.2O (40 mL) was degassed and purged with N.sub.2 for three times. The resulting mixture was stirred at 70 C. for 3 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. Methyl 5-amino-2-methyl-4-((trimethylsilyl)ethynyl)benzoate (2.40 g, 9.18 mmol, 89% yield) was obtained as a brown oil. M+H.sup.+=262.1 (LCMS).

Step 3: Methyl 5-methyl-1H-indole-6-carboxylate (20A-3)

[1001] A mixture of methyl 5-amino-2-methyl-4-((trimethylsilyl)ethynyl)benzoate (1.00 g, 3.83 mmol, 1.0 eq), Cu(OAc) 2 (1.39 g, 7.65 mmol, 2.0 eq) in DCE (50 mL) was degassed and purged with N.sub.2 for three times, and then the mixture was stirred at 130 C. for 1 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (100 mL) and extracted with DCM (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-methyl-1H-indole-6-carboxylate (500 mg, 2.64 mmol, 18% yield) was obtained as a yellow solid. M+H.sup.+=190.1 (LCMS).

Step 4: 5-Methyl-1H-indole-6-carboxylic acid (20A-4)

[1002] To a solution of methyl 5-methyl-1H-indole-6-carboxylate (40.0 mg, 211 mol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 529 L, 5.0 eq). The mixture was stirred at 20 C. for 30 min. The mixture was stirred at 80 C. for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and washed with MTBE (3.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 5-methyl-1H-indole-6-carboxylic acid (30.0 mg, 171 mol, 81% yield) as a white solid, which was used in the next step without any further purification.

Step 5: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 153)

[1003] To a solution of 5-methyl-1H-indole-6-carboxylic acid (30.0 mg, 171 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (35.2 mg, 206 mol, 33.0 L, 1.2 eq) in DCM (2.0 mL) were added EDCI (39.4 mg, 206 mol, 1.2 eq), HOBt (30.1 mg, 223 mol, 1.3 eq) and TEA (52.0 mg, 514 mol, 72.0 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.6). (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (13.2 mg, 35.8 mol, 21% yield) was obtained as a yellow solid. M+H.sup.+=329.0 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.29 (d, J=8.5 Hz, 1H), 8.18-8.09 (m, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.62-7.45 (m, 4H), 7.43 (s, 1H), 7.38-7.33 (m, 1H), 7.22-7.17 (m, 1H), 6.49-6.39 (m, 1H), 6.22-6.13 (m, 1H), 6.02 (br d, J=8.4 Hz, 1H), 2.53 (s, 3H), 1.82 (d, J=6.8 Hz, 3H).

Example 21: (R)-tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (Compound 189)

##STR00855##

Step 1: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methyl benzoate (21A-1)

[1004] To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (1.00 g, 3.44 mmol, 1.0 eq), tert-butyl prop-2-yn-1-ylcarbamate (533 mg, 3.44 mmol, 1.0 eq), CuI (262 mg, 1.37 mmol, 0.4 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (482 mg, 687 mol, 0.2 eq) was added TEA (10 mL) under a N.sub.2 atmosphere. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (20 mL) and extracted with DCM (15 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methyl benzoate (1.50 g, 4.71 mmol, 51% yield) was obtained as a white solid. M+H.sup.+=319.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.13-7.10 (m, 1H), 4.86-4.78 (m, 1H), 4.23-4.17 (m, 2H), 3.89-3.85 (m, 3H), 2.45-2.40 (m, 3H), 1.48 (s, 9H).

Step 2: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (21A-2)

[1005] To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methyl benzoate (500 mg, 1.57 mmol, 1.0 eq) in DCE (30 mL) was added Cu(OAc) 2 (713 mg, 3.93 mmol, 2.5 eq). The mixture was stirred at 130 C. for 1 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The hot reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (1.10 g, 3.46 mmol, 73% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.08-9.00 (m, 1H), 8.06-8.01 (m, 1H), 7.38 (s, 1H), 6.29-6.24 (m, 1H), 4.40-4.36 (m, 2H), 3.91-3.89 (m, 3H), 2.67 (s, 3H), 1.49 (s, 9H).

Step 3: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (21A-3)

[1006] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (800 mg, 2.51 mmol, 1.0 eq) in a mixture of THF (10 mL) and MeOH (3.0 mL) was added NaOH (2 M in aqueous, 8.0 mL, 6.4 eq). The mixture was stirred at 20 C. for 1 h and then was stirred at 60 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and washed with MTBE (10 mL2). The aqueous was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with DCM (15 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (750 mg, 1.97 mmol, 78% yield) as a red solid, which was used in the next step without any further purification. MH.sup.=303.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.46-8.40 (m, 1H), 7.81-7.77 (m, 1H), 6.79-6.76 (m, 1H), 6.33-6.30 (m, 1H), 3.27-3.08 (m, 2H), 2.07-2.05 (m, 3H), 1.46-1.40 (m, 9H).

Step 4: (R)-tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (Compound 189)

[1007] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (186 mg, 1.08 mmol, 174 L, 1.1 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (300 mg, 986 mol, 1.0 eq) in DCM (8.0 mL) were added TEA (299 mg, 2.96 mmol, 412 L, 3.0 eq), EDCI (283 mg, 1.48 mmol, 1.5 eq) and HOBt (200 mg, 1.48 mmol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15040 mm, 10 m); flow rate: 30 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: 0.04% aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (280 mg, 612 mol, 62% yield) was obtained as a white solid. M+H.sup.+=458.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.89-8.82 (m, 1H), 8.32-8.26 (m, 1H), 7.92-7.87 (m, 1H), 7.85-7.81 (m, 1H), 7.62-7.45 (m, 4H), 7.34-7.28 (m, 2H), 6.22-6.12 (m, 2H), 6.04-5.98 (m, 1H), 5.07-5.00 (m, 1H), 4.35-4.30 (m, 2H), 2.53-2.50 (m, 3H), 1.84-1.79 (m, 3H), 1.48-1.44 (m, 9H).

Example 22: (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 148)

##STR00856##

Step 1: (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 148)

[1008] To a stirred solution of (R)-tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (220 mg, 481 mol, 1.0 eq) in DCM (8.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 112 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (150 mg, 420 mol, 87% yield, TFA salt) was obtained as a pink powder. M+H.sup.+=358.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.29 (d, J=8.6 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.46 (m, 2H), 7.38 (d, J=5.4 Hz, 2H), 6.51 (s, 1H), 6.14-6.01 (m, 1H), 4.26 (s, 2H), 2.42 (s, 3H), 1.73 (d, J=6.9 Hz, 3H).

Example 23: (R)-2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 156)

##STR00857##

Step 1: tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)azetidine-1-carboxylate (23A-1)

[1009] To a stirred solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq) in THF (6.0 mL) were added tert-butyl 3-ethynylazetidine-1-carboxylate (243 mg, 1.34 mmol, 1.3 eq), Pd(PPh.sub.3).sub.4 (23.8 mg, 20.6 mol, 0.02 eq), CuI (3.93 mg, 20.6 mol, 0.02 eq) and TEA (261 mg, 2.58 mmol, 358.63 L, 2.5 eq). Then the mixture was degassed and purged with N.sub.2 three times and stirred at 20 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.7). tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)azetidine-1-carboxylate (300 mg, 871 mol, 85% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.29 (s, 1H), 7.14 (s, 1H), 4.17-3.99 (m, 5H), 3.87 (s, 3H), 2.44 (s, 3H), 1.49-1.41 (m, 9H).

Step 2: Methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylate (23A-2)

[1010] To a solution of tert-butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl) azetidine-1-carboxylate (160 mg, 465 mol, 1.0 eq) in DCE (10 mL) was added Cu(OAc) 2 (169 mg, 929 mol, 2.0 eq). The mixture was stirred at 130 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylate (130 mg) as a brown oil, which was used in the next step without any further purification.

Step 3: 2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (23A-3)

[1011] To a solution of methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylate (80.0 mg, 42.1 mol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 2.0 mL, 24 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and washed with MTBE (3.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (80.0 mg) as a white oil, which was used in the next step without any further purification. M56+H.sup.+=275.2 (LCMS).

Step 4: (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)azetidine-1-carboxylate (23A-4)

[1012] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (100 mg, 303 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (57.0 mg, 333 mol, 53.3 L, 1.1 eq) in DCM (4.0 mL) were added EDCI (69.6 mg, 363 mol, 1.2 eq), HOBt (49.1 mg, 363 mol, 1.2 eq) and TEA (91.9 mg, 909 mol, 126 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.6). (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)azetidine-1-carboxylate (50.0 mg, 103 mol, 34% yield) was obtained as a white solid. M+H.sup.+=484.1 (LCMS).

Step 5: (R)-2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 156)

[1013] To a solution of (R)-tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-2-yl)azetidine-1-carboxylate (50.0 mg, 103 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (5.95 mg, 14.2 mol, 14% yield, HCl salt) was obtained as a white gum. M+H=384.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.28 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.62-7.43 (m, 3H), 7.34 (d, J=13.0 Hz, 2H), 6.46 (s, 1H), 6.07 (q, J=6.7 Hz, 1H), 4.48-4.23 (m, 5H), 2.42 (s, 3H), 1.73 (d, J=7.0 Hz, 3H).

Example 24: (R)-2-((Dimethylamino)methyl)-1-(hydroxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 192)

##STR00858##

Step 1: (R)-2-((Dimethylamino)methyl)-1-(hydroxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 192)

[1014] To a solution of (R)-2-(aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (90.0 mg, 252 mol, 1.0 eq) in MeOH (6.0 mL) was added TEA (50.0 L), followed by the addition of formaldehyde (2.94 g, 36.3 mmol, 2.70 mL, 37% purity in water, 144 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (134 mg, 2.13 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (20040 mm, 10 m); flow rate: 50 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (R)-2-((Dimethylamino)methyl)-1-(hydroxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (22.3 mg, 48.1 mol, 19% yield, FA salt) was obtained as a white solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.78-8.73 (m, 1H), 8.30-8.25 (m, 1H), 8.21-8.18 (m, 1H), 7.98-7.94 (m, 1H), 7.86-7.81 (m, 1H), 7.68-7.65 (m, 1H), 7.63-7.49 (m, 4H), 7.32-7.28 (m, 1H), 6.35-6.33 (m, 1H), 5.98-5.90 (m, 1H), 5.62-5.54 (m, 2H), 3.65-3.60 (m, 2H), 2.35-2.33 (m, 3H), 2.20-2.14 (m, 6H), 1.63-1.57 (m, 3H).

Example 25: (R)-5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 206)

##STR00859##

Step 1: Methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido)benzoate (25A-1)

[1015] To a stirred solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq) and TEA (125 mg, 1.24 mmol, 172 L, 1.2 eq) in THF (3.5 mL) was added dropwise a solution of TFAA (238 mg, 1.13 mmol, 158 L, 1.1 eq) in THF (1.0 mL) at 15 C. The mixture was stirred at the same temperature for 1 h then at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido)benzoate (400 mg) as a yellow solid which was used the next step without any further purification. MH.sup.=386.0 (LCMS).

Step 2: Methyl 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylate (25A-2)

[1016] To a mixture of CuI (4.92 mg, 25.8 mol, 0.04 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (2.27 mg, 3.23 mol, 0.005 eq) in DMF (4.5 mL) were added methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido)benzoate (250 mg, 646 mol, 1.0 eq), morpholine (113 mg, 1.29 mmol, 114 L, 2.0 eq), prop-2-yn-1-ol (54.3 mg, 969 mol, 57.2 L, 1.5 eq) and K.sub.2CO.sub.3 (179 mg, 1.29 mmol, 2.0 eq) followed by DMF (2.0 mL) under a N.sub.2 atmosphere. The mixture was stirred at 80 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was cooled to room temperature and diluted with MTBE (10 mL). The resulting mixture was washed with saturated aqueous NaHCO.sub.3 (5.0 mL2). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylate (170 mg, 85% yield) was obtained as a yellow oil.

Step 3: 5-Methyl-2-(morpholinomethyl)-1H-indole-6-carboxylic acid (25A-3)

[1017] To a solution of methyl 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylate (170 mg, 590 mol, 1.0 eq) in a mixture of THF (10 mL) and H.sub.2O (2.5 mL) was added NaOH (2 M aqueous, 7.37 mL, 25 eq). The mixture was stirred at 20 C. for 1 h then at 70 C. for 16 h. LCMS indicated that half of the starting material remained and another NaOH (2 M aqueous, 5.0 mL) aqueous was added, and the mixture was stirred another 5 h. The reaction mixture was allowed to cool to room temperature and washed with MTBE (10 mL). The aqueous was acidified to pH 5 with HCl (1 M aqueous) and extracted with DCM (5.0 mL5). The organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylic acid (175 mg, 90% purity) as a brown gum.

Step 4: (R)-5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (Compound 206)

[1018] To a mixture of 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylic acid (140 mg, 510 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (87.4 mg, 510 mol, 81.7 L, 1.0 eq) in DCM (2.0 mL) were added EDCI (147 mg, 766 mol, 1.5 eq) and HOBt (103 mg, 766 mol, 1.5 eq), followed by TEA (155 mg, 1.53 mmol, 213 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (R)-5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-6-carboxamide (18.4 mg, 43.0 mol, 8% yield, FA salt) was obtained as a white solid. M+H.sup.+=428.2 (LCMS); 1H NMR (400 MHZ, CDCl.sub.3) 9.43-9.32 (m, 1H), 8.41-8.37 (m, 1H), 8.32-8.25 (m, 1H), 7.93-7.87 (m, 1H), 7.86-7.79 (m, 1H), 7.63-7.44 (m, 4H), 7.37-7.31 (m, 2H), 6.35-6.27 (m, 1H), 6.22-6.12 (m, 1H), 6.07-5.96 (m, 1H), 3.84-3.69 (m, 6H), 2.63-2.49 (m, 7H), 1.82 (d, J=6.8 Hz, 3H).

Example 26: (R)N-(1-(Naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 125)

##STR00860##

Step 1: (R)N-(1-(Naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 125)

[1019] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (100 mg, 584 mol, 1.0 eq) and 1H-benzo[d]imidazole-6-carboxylic acid (94.7 mg, 584 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (118 mg, 1.17 mmol, 163 L, 2.0 eq), EDCI (134 mg, 701 mol, 1.2 eq) and HOBT (94.7 mg, 701 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (4.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)N-(1-(Naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (40.7 mg, 121 mol, 21% yield) was obtained as a white solid. M+H.sup.+=316.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.11-8.07 (m, 2H), 7.84-7.78 (m, 1H), 7.76 (s, 1H), 7.71-7.66 (m, 1H), 7.56-7.48 (m, 2H), 7.44-7.31 (m, 4H), 7.14-7.02 (m, 1H), 6.11-6.02 (m, 1H), 1.77-1.65 (m, 3H).

Example 27: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 102)

##STR00861##

Step 1: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 102)

[1020] To a mixture of (R)-1-(naphthalen-1-yl)ethanamine (40.3 mg, 235 mol, 37.6 L, 1.0 eq) and 5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (50.0 mg, 235 mol, 1.0 eq, HCl salt) in DCM (3.0 mL) were added EDCI (67.6 mg, 353 mol, 1.5 eq), HOBt (47.7 mg, 353 mol, 1.5 eq) and TEA (71.4 mg, 705 mol, 98.2 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (16.1 mg, 48.0 mol, 20% yield) as a white solid. M+H.sup.+=330.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 12.42 (s, 1H), 8.95-8.78 (m, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.23-8.17 (m, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.84 (br d, J=7.9 Hz, 1H), 7.69-7.49 (m, 4H), 7.47 (s, 1H), 7.34 (s, 1H), 6.00-5.86 (m, 1H), 2.44-2.36 (m, 3H), 1.60 (d, J=7.0 Hz, 3H).

Example 28: (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 128)

##STR00862##

Step 1: Methyl 2-methyl-4,5-dinitrobenzoate (28A-2)

[1021] To a solution of methyl 2-methyl-4-nitrobenzoate (1.00 g, 5.12 mmol, 1.0 eq) in H.sub.2SO.sub.4 (10 mL, 98% purity) was added KNO.sub.3 (596 mg, 5.89 mmol, 1.2 eq) at 0 C. The resulting mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into ice water (20 mL) and neutralized with saturated aqueous NaHCO.sub.3 to adjust the pH to 7. The product was extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 2-methyl-4,5-dinitrobenzoate (700 mg, 2.91 mmol, 57% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.54 (s, 1H), 8.26 (s, 1H), 3.98-3.84 (m, 3H), 2.73-2.58 (m, 3H).

Step 2: Methyl 4,5-diamino-2-methylbenzoate (28A-3)

[1022] To a solution of methyl 2-methyl-4,5-dinitrobenzoate (1.50 g, 6.25 mmol, 1.0 eq) and 10% palladium on carbon (100 mg) in a mixture of MeOH (20 mL) and dioxane (20 mL) was degassed and purged with H.sub.2 for three times. The mixture was stirred at 20 C. for 16 h under H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (2.0 mL3). The combined filtrates were concentrated under vacuum to give methyl 4,5-diamino-2-methylbenzoate (600 mg, 3.33 mmol, 53% yield) as a brown solid. M+H.sup.+=181.2 (LCMS).

Step 3: Methyl 4-amino-5-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (28A-4)

[1023] To a solution of methyl 4,5-diamino-2-methylbenzoate (170 mg, 943 mol, 1.0 eq) and 2-((tert-butoxycarbonyl)amino) acetic acid (165 mg, 943 mol, 1.0 eq) in THF (5.0 mL) was added DCC (389 mg, 1.89 mmol, 382 L, 2.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/50 to 1/5. Methyl 4-amino-5-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (200 mg, 593 mol, 63% yield) was obtained as a white solid. M+H.sup.+=338.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.09 (br s, 1H), 7.85-7.72 (m, 1H), 6.67-6.56 (m, 1H), 5.43 (br s, 1H), 4.01-3.91 (m, 2H), 3.84-3.73 (m, 3H), 2.56-2.37 (m, 3H), 1.54-1.43 (m, 9H).

Step 4: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (28A-5)

[1024] To a solution of methyl 4-amino-5-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (100 mg, 296 mol, 1.0 eq) in AcOH (1.0 mL). The resulting mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (90.0 mg) as a colorless oil, which was used in the next step without any further purification. M+H.sup.+=320.3 (LCMS).

Step 5: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (28A-6)

[1025] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (90.0 mg, 282 mol, 1.0 eq) in a mixture of THF (9.0 mL) and H.sub.2O (3.0 mL) was added NaOH (2 M aqueous, 423 L, 3.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10.0 mL) and washed with MTBE (5.0 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (90.0 mg) as a colorless oil, which was used in the next step without any further purification. M+H.sup.+=306.3 (LCMS).

Step 6: (R)-tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (28A-7)

[1026] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (33.7 mg, 197 mol, 31.5 L, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (60.0 mg, 197 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (59.7 mg, 590 mol, 82.1 L, 3.0 eq), EDCI (45.2 mg, 236 mol, 1.2 eq) and HOBt (31.9 mg, 236 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.5). (R)-tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (40.0 mg, 87.0 mol, 44% yield) was obtained as a white solid. M+H.sup.+=459.4 (LCMS).

Step 7: (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 128)

[1027] To a stirred solution of (R)-tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (40.0 mg, 87.0 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (9.70 mg, 20.5 mol, 24% yield, TFA salt) was obtained as a white solid. M+H.sup.+=359.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.32 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.69 (d, J=7.3 Hz, 1H), 7.65-7.50 (m, 4H), 7.47 (s, 1H), 6.12 (q, J=6.7 Hz, 1H), 4.42 (s, 2H), 2.50 (s, 3H), 1.77 (d, J=7.0 Hz, 3H).

Example 29: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 131)

##STR00863## ##STR00864##

Step 1: tert-Butyl 3-((2-amino-5-(methoxycarbonyl)-4-methylphenyl)carbamoyl)azetidine-1-carboxylate (29A-1)

[1028] To a solution of methyl 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (223 mg, 1.11 mmol, 1.0 eq) in DMF (1.5 mL) were added pyridine (1.5 mL) and CDI (185 mg, 1.11 mmol, 1.0 eq). The mixture was stirred at 45 C. for 30 min. Then to the mixture was added methyl 4,5-diamino-2-methyl-benzoate (200 mg, 1.11 mmol, 1.0 eq), the resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by lash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 3-((2-amino-5-(methoxycarbonyl)-4-methylphenyl)carbamoyl)azetidine-1-carboxylate (400 mg, 1.10 mmol, 50% yield) was obtained as a white solid. M100+H.sup.+=264.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14 (s, 1H), 7.86-7.69 (m, 1H), 6.54 (s, 1H), 5.64 (s, 2H), 3.96 (br s, 4H), 3.71 (s, 3H), 3.54-3.42 (m, 1H), 2.40 (s, 3H), 1.39 (s, 9H).

Step 2: Methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (29A-2)

[1029] To a solution of tert-butyl 3-((2-amino-5-(methoxycarbonyl)-4-methylphenyl) carbamoyl)azetidine-1-carboxylate (400 mg, 1.10 mmol, 1.0 eq) in AcOH (0.5 mL) was stirred at 70 C. for 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.4). Methyl 2-(1-(tert-butoxycarbonyl) azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole-6-carboxy late (350 mg, 1.01 mmol, 92% yield) was obtained as a yellow oil. M+H.sup.+=346.3 (LCMS).

Step 3: Methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylate (29A-3)

[1030] To a solution of methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (200 mg, 420 mol, 1.0 eq) in DMF (6.0 mL) was added sodium hydride (25.2 mg, 631 mol, 60% purity, 1.5 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. To the mixture was added SEM-Cl (105 mg, 631 mol, 112 L, 1.5 eq), the resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10:1, R.sub.f=0.5). Methyl 2-(1-(tert-butoxy carbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 315 mol, 75% yield) was obtained as a yellow oil. M+H.sup.+=476.3 (LCMS).

Step 4: 2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (29A-4)

[1031] To a solution of methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylate (80.0 mg, 42.1 mol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 2.0 mL, 24 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and washed with MTBE (3.0 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (80.0 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=462.4 (LCMS).

Step 5: (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (29A-5)

[1032] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (70.0 mg, 152 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (26.0 mg, 152 mol, 24.0 L, 1.0 eq) in DCM (4.0 mL) were added EDCI (34.9 mg, 182 mol, 1.2 eq), HOBt (24.6 mg, 182 mol, 1.2 eq) and TEA (46.0 mg, 455 mol, 63.0 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10:1, R.sub.f=0.7). (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (70.0 mg, 114 mol, 75% yield) was obtained as a yellow solid.

Step 6: (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (29A-6)

[1033] To a solution of (R)-tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (65.0 mg, 106 mol, 1.0 eq) in DMF (1.0 mL) were added ethane-1,2-diamine (28.6 mg, 476 mol, 31.84 L, 4.5 eq) and TBAF (1 M in THF, 317 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (2.0 mL) and extracted with EtOAc (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10:1, R.sub.f=0.6). (R)-tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl) carbamoyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (50.0 mg, 103 mol, 98% yield) was obtained as a yellow solid. M+H.sup.+=485.4 (LCMS).

Step 7: (R)-2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 131)

[1034] To a solution of (R)-tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (50.0 mg, 103 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (11.0 mg, 28.5 mol, 28% yield, TFA salt) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.93 (br d, J=7.9 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.66-7.43 (m, 6H), 6.18-5.96 (m, 1H), 4.55-4.41 (m, 5H), 2.48 (s, 3H), 1.74 (d, J=7.0 Hz, 3H).

Example 30: (R)N-(1-(naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (Compound 124)

##STR00865##

Step 1: (R)N-(1-(naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (Compound 124)

[1035] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (100 mg, 584 mol, 1.0 eq) and 1H-indazole-6-carboxylic acid (94.7 mg, 584 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (118 mg, 1.17 mmol, 163 L, 2.0 eq), T.sub.3P (2.23 g, 3.50 mmol, 2.08 mL, 50% in EtOAc, 6.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)N-(1-(Naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (28.2 mg, 89.4 mol, 15% yield) was obtained as a white solid. M+H.sup.+=316.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.21-8.19 (m, 1H), 8.15-8.09 (m, 1H), 8.03 (s, 1H), 7.93-7.84 (m, 2H), 7.78-7.75 (m, 1H), 7.64-7.61 (m, 1H), 7.55-7.43 (m, 4H), 6.48-6.46 (m, 1H), 6.22-6.14 (m, 1H), 1.84-1.83 (d, J=4, 3H),

Example 31: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (Compound 142)

##STR00866##

Step 1: Methyl 5-methyl-1H-indazole-6-carboxylate (31A-2)

[1036] To a solution of 6-bromo-5-methyl-1H-indazole (200 mg, 948 mol, 1.0 eq) in MeOH (3.0 mL) were added Pd(dppf)Cl.sub.2 (139 mg, 190 mol, 0.2 eq) and TEA (767 mg, 7.58 mmol, 1.10 mL, 8.0 eq) under a N.sub.2 atmosphere. The mixture was degassed and purged with CO three times. The resulting mixture was stirred at 70 C. for 16 h under a CO (50 psi) atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 5-methyl-1H-indazole-6-carboxylate (150 mg, 789 mol, 83% yield). M+H.sup.+=191.1 (LCMS).

Step 2: 5-Methyl-1H-indazole-6-carboxylic acid (31A-3)

[1037] To a solution of methyl 5-methyl-1H-indazole-6-carboxylate (100 mg, 526 mol, 1.0 eq) in a mixture of THF (3.0 mL) and H.sub.2O (1.0 mL) was added LiOH (66.2 mg, 1.58 mmol, 3.0 eq). The mixture was stirred at 20 C. for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. H.sub.2O (5.0 mL) was added and the mixture was washed with MTBE (2.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 5-methyl-1H-indazole-6-carboxylic acid (70.0 mg, 397 mol, 76% yield) as a white solid, which was used in the next step without any further purification. M+H.sup.+=177.2 (LCMS).

Step 3: (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (Compound 142)

[1038] To a solution of 5-methyl-1H-indazole-6-carboxylic acid (30.0 mg, 170 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (29.2 mg, 170 mol, 27.3 L, 1.0 eq) in DCM (2.0 mL) were added EDCI (39.2 mg, 204 mol, 1.2 eq), HOBt (27.6 mg, 204 mol, 1.2 eq) and TEA (34.5 mg, 341 mol, 47.4 L, 2.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10040 mm, 5 m); flow rate: 25 mL/min; gradient: 45%-90% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-5-Methyl-N-(1-(naphthalen-1-yl)ethyl)-1H-indazole-6-carboxamide (8.51 mg, 25.8 mol, 16% yield, TFA salt) was obtained as a white solid. M+H.sup.+=330.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.00 (br d, J=7.8 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.10 (br s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.63-7.46 (m, 5H), 6.09 (quin, J=7.1 Hz, 1H), 2.43 (s, 3H), 1.74 (d, J=7.0 Hz, 3H).

Example 32: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl) quinoline-7-carboxamide (Compound 150)

##STR00867##

Step 1: 7-Bromo-6-methylquinoline (32A-2)

[1039] To a mixture of 3-bromo-4-methyl-aniline (18.0 g, 96.8 mmol, 1.0 eq) and sodium 3-nitrobenzenesulfonate (26.1 g, 116 mmol, 1.2 eq) in H.sub.2SO.sub.4 (60 mL, 98% purity) and H.sub.2O (25 mL) was added propane-1,2,3-triol (26.7 g, 290 mmol, 21.7 mL, 3.0 eq). The mixture was stirred at 130 C. for 2 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and neutralized with K.sub.2CO.sub.3 to pH 8. The product was extracted with EtOAc (30 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7-Bromo-6-methylquinoline (10.4 g, 46.8 mmol, 48% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.87-8.85 (m, 1H), 8.63-8.56 (m, 1H), 8.01-7.96 (m, 1H), 7.62-7.58 (m, 1H), 7.41-7.35 (m, 1H), 2.60-2.56 (m, 3H).

Step 2: Methyl 6-methylquinoline-7-carboxylate (32A-3)

[1040] To a solution of 7-bromo-6-methylquinoline (6.00 g, 27.0 mmol, 1.0 eq) and TEA (10.9 g, 108 mmol, 15.0 mL, 4.0 eq) in MeOH (50 mL) was added Pd(dppf)Cl.sub.2 (1.98 g, 2.70 mmol, 0.1 eq). The mixture was stirred at 70 C. for 16 h under a CO (50 psi) atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 6-methylquinoline-7-carboxylate (6.00 g, 29.8 mmol, 37% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.98-8.89 (m, 1H), 8.72-8.64 (m, 1H), 8.14-8.06 (m, 1H), 7.71-7.63 (m, 1H), 7.49-7.39 (m, 1H), 4.16-3.89 (m, 3H), 2.85-2.68 (m, 3H).

Step 3: 6-Methylquinoline-7-carboxylic acid (32A-4)

[1041] To a solution of methyl 6-methylquinoline-7-carboxylate (300 mg, 1.49 mmol, 1.0 eq) in a mixture of THF (8.0 mL), H.sub.2O (4.0 mL) and MeOH (2.0 mL) was added LiOH.Math.H.sub.2O (125 mg, 2.98 mmol, 2.0 eq). The mixture was stirred at 20 C. for 30 min, then at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (8.0 mL) and washed with MTBE (8.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (8.0 mL6). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 6-methylquinoline-7-carboxylic acid (270 mg, 1.44 mmol, 97% yield) as a white solid, which was used in the next step without any further purification. MH.sup.=186.1 (LCMS).

Step 4: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)quinoline-7-carboxamide (Compound 150)

[1042] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (89.2 mg, 521 mol, 83.0 L, 1.5 eq) and 6-methylquinoline-7-carboxylic acid (65.0 mg, 347 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (70.3 mg, 694 mol, 96.7 L, 2.0 eq) and T.sub.3P (331 mg, 521 mol, 310 L, 50% purity in EtOAc, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl) quinoline-7-carboxamide (26.0 mg, 76.4 mol, 22% yield) was obtained as a white solid. M+H.sup.+=341.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.82 (br d, J=2.1 Hz, 1H), 8.32-8.23 (m, 1H), 8.12-7.98 (m, 2H), 7.90 (d, J=8.0 Hz, 1H), 7.86-7.79 (m, 1H), 7.67-7.57 (m, 3H), 7.57-7.44 (m, 2H), 7.44-7.36 (m, 1H), 6.36-6.14 (m, 2H), 2.69-2.59 (m, 3H), 1.90-1.80 (m, 3H).

Example 33: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7-carboxamide (Compound 167)

##STR00868##

Step 1: 7-(Methoxycarbonyl)-6-methylquinoline 1-oxide (33A-1)

[1043] To a mixture of methyl 6-methylquinoline-7-carboxylate (240 mg, 1.19 mmol, 1.0 eq) in DCM (5.0 mL) was added m-CPBA (308 mg, 1.43 mmol, 80% purity, 1.2 eq) at 0 C. The mixture was stirred at 20 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was poured into saturated aqueous Na.sub.2SO.sub.3 (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried and concentrated under vacuum to give 7-(methoxycarbonyl)-6-methylquinoline 1-oxide (300 mg, 968 mol, 81% yield) as a yellow solid. M+H.sup.+=218.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.33-9.23 (m, 1H), 8.56-8.46 (m, 1H), 7.80-7.70 (m, 1H), 7.69-7.60 (m, 1H), 7.38-7.30 (m, 1H), 4.04-3.91 (m, 3H), 2.82-2.70 (m, 3H).

Step 2: Methyl 2-chloro-6-methylquinoline-7-carboxylate (33A-2)

[1044] To a solution of 7-(methoxycarbonyl)-6-methylquinoline 1-oxide (230 mg, 1.06 mmol, 1.0 eq) in DCM (8.0 mL) was added POCl.sub.3 (244 mg, 1.59 mmol, 148 L, 1.5 eq) at 0 C., followed by DMF (39.0 mg, 529 mol, 40.7 L, 0.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. Saturated aqueous Na.sub.2CO.sub.3 solution was added to the reaction mixture slowly at 0 C. to adjust the pH to 8. The resulting mixture was separated and the aqueous phase was extracted with DCM (10 mL5). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated under vacuum to afford the crude product which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-chloro-6-methylquinoline-7-carboxylate (120 mg, 509 mol, 48% yield) was obtained as a white solid. M+H.sup.+=236.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.69-8.62 (m, 1H), 8.17-7.96 (m, 1H), 7.77-7.59 (m, 1H), 7.47 (d, J=8.5 Hz, 1H), 3.98 (s, 3H), 2.80-2.70 (m, 3H).

Step 3: 6-Methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid (33A-3)

[1045] To a solution of methyl 2-chloro-6-methylquinoline-7-carboxylate (120 mg, 509 mol, 1.0 eq) in dioxane (5.0 mL) was added HCl (6 M in aqueous, 962 L, 11 eq). The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, diluted with H.sub.2O (3.0 mL) and acidified to pH 5 with NaOH (2 M aqueous). The product was extracted with EtOAc (8.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product 6-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid (160 mg, 472 mol, 93% yield) as a white solid, which was used in the next step without any further purification. M+H.sup.+=204.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.83-11.74 (m, 1H), 7.91-7.83 (m, 1H), 7.81-7.76 (m, 1H), 7.58-7.54 (m, 1H), 6.63-6.52 (m, 1H), 1.25-1.20 (m, 3H).

Step 4: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7-carboxamide (Compound 167)

[1046] To a solution of (R)-1-(naphthalen-1-yl)ethanamine (75.8 mg, 443 mol, 70.9 L, 1.5 eq) and 6-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid (100 mg, 295 mol, 1.0 eq) in DCM (10 mL) were added TEA (89.6 mg, 886 mol, 123 L, 3.0 eq), EDCI (84.9 mg, 443 mol, 1.5 eq) and HOBt (59.9 mg, 442 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-65% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7-carboxamide (8.00 mg, 21.9 mol, 7% yield) was obtained as a white solid. M+H.sup.+=357.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.84-11.57 (m, 1H), 9.13-8.98 (m, 1H), 8.37-8.13 (m, 1H), 8.00-7.93 (m, 1H), 7.91-7.80 (m, 2H), 7.65-7.47 (m, 5H), 7.29-7.21 (m, 1H), 6.54-6.44 (m, 1H), 5.98-5.87 (m, 1H), 2.30-2.24 (m, 3H), 1.62-1.53 (m, 3H).

Example 34: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 145)

##STR00869##

Step 1: 6-Methylbenzo[d][1,3]dioxole-5-carbaldehyde (34A-2)

[1047] To a solution of 5-methylbenzo[d][1,3]dioxole (200 mg, 1.47 mmol, 175 L, 1.0 eq) in DCM (2.0 mL) was added dichloro(methoxy) methane (338 mg, 2.94 mmol, 260 L, 2.0 eq) at 0 C. The mixture was stirred at 0 C. for 15 min and a solution of TiCl.sub.4 (334 mg, 1.76 mmol, 1.2 eq) in DCM (2.0 mL) was added dropwise. The resulting mixture was stirred at 20 C. for 1 h. TLC indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (10 mL) and extracted with MTBE (10 mL2). The combined organic layers were dried and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/100 to 1/50. 6-Methylbenzo[d][1,3]dioxole-5-carbaldehyde (220 mg, 1.34 mmol, 91% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.24-10.05 (m, 1H), 7.29 (s, 1H), 6.70 (s, 1H), 6.03 (s, 2H), 2.62 (s, 3H).

Step 2: 6-Methylbenzo[d][1,3]dioxole-5-carboxylic acid (34A-3)

[1048] To a stirred solution of 6-methylbenzo[d][1,3]dioxole-5-carbaldehyde (200 mg, 1.22 mmol, 1.0 eq), NaH.sub.2PO.sub.4 (43.9 mg, 366 mol, 0.3 eq), and H.sub.2O.sub.2 (177 mg, 1.82 mmol, 150 L, 35% purity in H.sub.2O, 1.5 eq) in a mixture of acetonitrile (1.5 mL) and H.sub.2O (0.6 mL) was added a solution of NaClO.sub.2 (154 mg, 1.71 mmol, 1.4 eq) in H.sub.2O (2.0 mL) dropwise to maintain the temperature between 0 C. and 10 C. The resulting mixture was stirred at 20 C. for 1.5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous Na.sub.2SO.sub.3 (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude 6-methylbenzo[d][1,3]dioxole-5-carboxylic acid (220 mg) as a white solid.

Step 3: (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 145)

[1049] To a stirred solution of 6-methylbenzo[d][1,3]dioxole-5-carboxylic acid (61.0 mg, 339 mol, 1.0 eq) and (R)-1-(naphthalen-1-yl)ethanamine (63.8 mg, 372 mol, 59.6 L, 1.1 eq) in DCM (5.0 mL) were added TEA (103 mg, 1.02 mmol, 141 L, 3.0 eq) and T.sub.3P (323 mg, 508 mol, 302 L, 50% purity in EtOAc, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was poured into H.sub.2O (2.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.3). (R)-6-Methyl-N-(1-(naphthalen-1-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (37.5 mg, 106 mol, 31% yield) was obtained as a white solid. M+H.sup.+=334.0 (LCMS); 1H NMR (400 MHz, CDCl.sub.3) 8.30-8.18 (m, 1H), 7.92-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.63-7.44 (m, 4H), 6.81-6.75 (m, 1H), 6.68-6.60 (m, 1H), 6.17-6.05 (m, 1H), 5.94-5.84 (m, 3H), 2.41-2.32 (m, 3H), 1.83-1.74 (m, 3H).

Example 35: N-(5-Amino-2-methylphenyl)-2-(naphthalen-1-yl)propanamide (Compound 163)

##STR00870##

Step 1: Ethyl 2-(naphthalen-1-yl)propanoate (35A-2)

[1050] To a stirred solution of ethyl 2-(naphthalen-1-yl)acetate (500 mg, 2.33 mmol, 1.0 eq) in DMF (10 mL) was added sodium hydride (112 mg, 2.80 mmol, 60% purity, 1.2 eq) in portions at 0 C. The mixture was stirred at the same temperature for 15 min. Iodomethane (364 mg, 2.57 mmol, 160 L, 1.1 eq) was added dropwise. After the addition was complete, the resulting mixture was stirred at 0 C. for another 15 min. TLC indicated that that the starting material was completely consumed. The mixture was poured into H.sub.2O (20 mL) and extracted with MTBE (15 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give ethyl 2-(naphthalen-1-yl)propanoate (450 mg, 1.97 mmol, 84% yield) as a yellow oil, which was used in the next step without any further purification.

Step 2: 2-(Naphthalen-1-yl)propanoic acid (35A-3)

[1051] To a stirred solution of ethyl 2-(naphthalen-1-yl)propanoate (200 mg, 876 mol, 1.0 eq) in a mixture of EtOH (5.0 mL) and THF (5.0 mL) was added NaOH (2 M aqueous, 1.31 mL, 3.0 eq). The mixture was stirred at 20 C. for 1 h and then at 70 C. for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (20 mL) and washed with MTBE (15 mL3). The aqueous was acidified to pH 5 using HCl (1 M aqueous) and extracted with EtOAc (5 mL2). The combined organic layers were dried and concentrated in vacuum to give 2-(naphthalen-1-yl)propanoic acid (180 mg, 90% purity) as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.22-8.05 (m, 1H), 7.94-7.87 (m, 1H), 7.85-7.79 (m, 1H), 7.61-7.45 (m, 4H), 4.64-4.52 (m, 1H), 1.74-1.68 (m, 3H).

Step 3: N-(2-Methyl-5-nitrophenyl)-2-(naphthalen-1-yl)propanamide (35A-4)

[1052] To a stirred solution of 2-(naphthalen-1-yl)propanoic acid (100 mg, 499 mol, 1.0 eq) and 2-methyl-5-nitroaniline (83.6 mg, 549 mol, 209 L, 1.1 eq) in DCM (5.0 mL) was added TEA (152 mg, 1.50 mmol, 209 L, 3.0 eq), followed by T.sub.3P (636 mg, 999 mol, 594 L, 50% purity in EtOAc, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with MTBE (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.3). N-(2-Methyl-5-nitrophenyl)-2-(naphthalen-1-yl)propanamide (90.0 mg, 269 mol, 54% yield) was obtained as a yellow solid. M+H.sup.+=335.1 (LCMS).

Step 4: N-(5-Amino-2-methylphenyl)-2-(naphthalen-1-yl)propanamide (Compound 163)

[1053] To a stirred solution of N-(2-methyl-5-nitrophenyl)-2-(naphthalen-1-yl)propanamide (60.0 mg, 179 mol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) was added iron powder (50.1 mg, 897 mol, 5.0 eq), followed by NH.sub.4Cl (48.0 mg, 897 mol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 60 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(5-Amino-2-methylphenyl)-2-(naphthalen-1-yl)propanamide (8.11 mg, 26.4 mol, 15% yield) was obtained as a yellow solid. M+H.sup.+=305.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.32-8.20 (m, 1H), 7.93-7.88 (m, 1H), 7.85-7.79 (m, 1H), 7.66-7.62 (m, 1H), 7.61-7.54 (m, 1H), 7.54-7.46 (m, 2H), 6.90-6.84 (m, 1H), 6.75-6.70 (m, 1H), 6.53-6.47 (m, 1H), 4.73-4.62 (m, 1H), 1.87-1.82 (m, 3H), 1.77-1.63 (m, 3H).

Example 36: 5-Amino-N-(cyano(naphthalen-1-yl)methyl)-2-methylbenzamide (Compound 195)

##STR00871##

Step 1: 2-Amino-2-(naphthalen-1-yl) acetonitrile (36A-2)

[1054] To a solution of sodium cyanide (158 mg, 3.20 mmol, 1.0 eq) in MeOH (3.0 mL) was NH.sub.3.Math.H.sub.2O (1.82 g, 13.1 mmol, 2.00 mL, 25% purity, 4.1 eq), NH.sub.4Cl (171 mg, 3.20 mmol, 1.0 eq) and 1-naphthaldehyde (500 mg, 3.20 mmol, 435 L, 1.0 eq). The mixture was stirred at 20 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were concentrated under vacuum to give the crude product 2-amino-2-(naphthalen-1-yl) acetonitrile (450 mg), which was used in the next step without any further purification. M17+H.sup.+=166.1 (LCMS).

Step 2: N-(Cyano(naphthalen-1-yl)methyl)-2-methyl-5-nitrobenzamide (36A-3)

[1055] To a solution of 2-amino-2-(naphthalen-1-yl) acetonitrile (100 mg, 549 mol, 1.0 eq) and 2-methyl-5-nitrobenzoic acid (99.4 mg, 549 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (166 mg, 1.65 mmol, 229 L, 3.0 eq), EDCI (263 mg, 1.37 mmol, 2.5 eq) and HOBt (185 mg, 1.37 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) at 25 C. and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product N-(cyano(naphthalen-1-yl)methyl)-2-methyl-5-nitrobenzamide (170 mg), which was used in the next step without any further purification. M+H.sup.+=346.1 (LCMS).

Step 3: 5-Amino-N-(cyano(naphthalen-1-yl)methyl)-2-methylbenzamide (Compound 195)

[1056] To a solution of N-(cyano(naphthalen-1-yl)methyl)-2-methyl-5-nitrobenzamide (170 mg, 492 mol, 1.0 eq) in a mixture of MeOH (6.0 mL) and H.sub.2O (2.0 mL) were added iron powder (137 mg, 2.46 mmol, 5.0 eq) and NH.sub.4Cl (132 mg, 2.46 mmol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (8.0 mL) at 25 C. and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Amino-N-(cyano(naphthalen-1-yl)methyl)-2-methylbenzamide (33.3 mg, 102 mol, 21% yield, HCl salt) was obtained as a white solid. M+H.sup.+=316.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.73 (d, J=8.0 Hz, 1H), 8.09-8.01 (m, 3H), 7.85 (d, J=7.1 Hz, 1H), 7.69-7.57 (m, 2H), 7.56-7.49 (m, 1H), 7.70-7.46 (m, 1H), 7.15-7.02 (m, 2H), 6.97-6.86 (m, 2H), 2.24-2.17 (m, 3H).

Example 37: 5-Amino-N-(2-fluoro-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 200)

##STR00872##

Step 1: 2-Fluoro-1-(naphthalen-1-yl)ethanone (37A-2)

[1057] To a solution of iodosylbenzene (1.55 g, 7.05 mmol, 1.2 eq) and hydrogen fluoride (4.07 g, 23.5 mmol, 8.66 mL, 70% purity in TEA, 4.0 eq) in DCE (10 mL) was added 1-(naphthalen-1-yl)ethanone (1.00 g, 5.88 mmol, 1.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NaHCO.sub.3 (20 mL) and extracted with DCM (10 mL3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-1-(naphthalen-1-yl)ethanone (270 mg, 1.43 mmol, 24% yield) was obtained as a yellow solid. M+H.sup.+=189.1 (LCMS).

Step 2: 2-Fluoro-1-(naphthalen-1-yl)ethanamine (37A-3)

[1058] To a solution of 2-fluoro-1-(naphthalen-1-yl)ethenone (130 mg, 691 mol, 1.0 eq) in MeOH (15 mL) were added NH.sub.4OAc (1.28 g, 16.6 mmol, 24 eq) and NaBH.sub.3CN (347 mg, 5.53 mmol, 8.0 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.1). 2-Fluoro-1-(naphthalen-1-yl)ethanamine (150 mg, crude) was obtained as a yellow oil. M+H.sup.+=190.2 (LCMS).

Step 3: N-(2-Fluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (37A-4)

[1059] To a solution of 2-fluoro-1-(naphthalen-1-yl)ethanamine (273 mg, 1.44 mmol, 1.0 eq) and 2-methyl-5-nitrobenzoic acid (287 mg, 1.59 mmol, 1.1 eq) in DMF (10 mL) were added TEA (438 mg, 4.33 mmol, 602 L, 3.0 eq), EDCI (691 mg, 3.61 mmol, 2.5 eq) and HOBt (487 mg, 3.61 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. N-(2-Fluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (180 mg, 511 mol, 35% yield) was obtained as a brown solid. M+H.sup.+=353.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.23 (d, J=2.0 Hz, 1H), 8.21-8.09 (m, 2H), 7.90 (dd, J=8.1, 15.6 Hz, 2H), 7.67-7.60 (m, 2H), 7.57 (br d, J=7.7 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.51 (br d, J=8.2 Hz, 1H), 6.42-6.21 (m, 1H), 5.19-4.85 (m, 2H), 2.55 (s, 3H).

Step 4: 5-Amino-N-(2-fluoro-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 200)

[1060] To a solution of N-(2-fluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (100 mg, 284 mol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) were added iron powder (79.2 mg, 1.42 mmol, 5.0 eq) and NH.sub.4Cl (75.9 mg, 1.42 mmol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-N-(2-fluoro-1-(naphthalen-1-yl)ethyl)-2-methyl benzamide (26.8 mg, 83.0 mol, 29% yield) was obtained as a white solid. M+H.sup.+=323.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.18 (d, J=8.6 Hz, 1H), 7.89 (dd, J=8.1, 17.4 Hz, 2H), 7.67-7.45 (m, 4H), 6.99 (d, J=8.1 Hz, 1H), 6.71 (s, 1H), 6.65 (br d, J=7.7 Hz, 1H), 6.37-6.18 (m, 2H), 5.13-4.85 (m, 2H), 2.33 (s, 3H).

Example 38: 5-Amino-N-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 185)

##STR00873##

Step 1: (E)-2-Methyl-N-(naphthalen-1-ylmethylene) propane-2-sulfinamide (38A-1)

[1061] To a solution of 2-methylpropane-2-sulfinamide (1.55 g, 12.8 mmol, 1.0 eq) in DCM (25 mL) were added CuSO.sub.4 (4.09 g, 25.6 mmol, 3.93 mL, 2.0 eq) and 1-naphthaldehyde (2.00 g, 12.8 mmol, 1.74 mL, 1.0 eq). The mixture was stirred at 20 C. for 48 h. LCMS indicated that 53% of the starting material remained and 30% of the desired mass was detected. The reaction mixture was poured into H.sub.2O (25 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. (F)-2-Methyl-N-(naphthalen-1-ylmethylene) propane-2-sulfinamide (2.00 g, 3.01 mmol, 23% yield) was obtained as a yellow oil. M+H.sup.+=260.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.17 (s, 1H), 9.07-9.02 (m, 1H), 8.08-8.01 (m, 2H), 7.96-7.92 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.54 (m, 2H), 1.34 (s, 9H).

Step 2: N-(2,2-Difluoro-1-(naphthalen-1-yl)ethyl)-2-methylpropane-2-sulfinamide (38A-2)

[1062] To a solution of (E)-2-methyl-N-(naphthalen-1-ylmethylene) propane-2-sulfinamide (500 mg, 1.93 mmol, 1.0 eq) and (difluoromethyl)trimethylsilane (718 mg, 5.78 mmol, 3.0 eq) in THF (6.0 mL) was added 1-BuOK (1 M in THF, 5.78 mL, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times, stirred at 70 C. for 10 min, then stirred at 20 C. for another 30 min under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. N-(2,2-Difluoro-1-(naphthalen-1-yl)ethyl)-2-methylpropane-2-sulfinamide (270 mg, 819 mol, 43% yield) was obtained as a brown oil. M+H.sup.+=312.1 (LCMS).

Step 3: 2,2-Difluoro-1-(naphthalen-1-yl)ethanamine hydrochloride (38A-3)

[1063] To a solution of N-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 321 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 C. for 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product 2,2-difluoro-1-(naphthalen-1-yl)ethanamine hydrochloride (100 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=208.2 (LCMS).

Step 4: N-(2,2-Difluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (38A-4)

[1064] To a solution of 2,2-difluoro-1-(naphthalen-1-yl)ethanamine (100 mg, 410 mol, 1.0 eq, HCl salt) and 2-methyl-5-nitrobenzoic acid (81.8 mg, 451 mol, 1.1 eq) in DCM (5.0 mL) were added TEA (125 mg, 1.23 mmol, 171 L, 3.0 eq), EDCI (157 mg, 821 mol, 2.0 eq) and HOBt (111 mg, 821 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. N-(2,2-Difluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (60.0 mg, 1.62 mmol, 39% yield) was obtained as a white solid. M+H.sup.+=371.2 (LCMS).

Step 5: 5-Amino-N-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 185)

[1065] To a solution of N-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (50.0 mg, 135 mol, 1.0 eq) in MeOH (5.0 mL) were added H.sub.2O (1.0 mL), iron powder (37.7 mg, 675 mol, 5.0 eq) and NH.sub.4Cl (36.1 mg, 675 mol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (6.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Amino-N-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide was obtained as a white solid. M+H.sup.+=341.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.13-9.65 (m, 1H), 9.49 (br d, J=8.8 Hz, 1H), 8.31-8.23 (m, 1H), 8.04-7.94 (m, 2H), 7.80-7.74 (m, 1H), 7.69-7.53 (m, 3H), 7.34-7.19 (m, 2H), 7.15 (s, 1H), 6.71-6.66 (m, 1H), 6.59-6.52 (m, 1H), 2.29-2.19 (m, 3H).

Example 39: 5-Amino-2-methyl-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 183)

##STR00874##

Step 1: 2-Methyl-5-nitro-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (39A-2)

[1066] To a solution of 2-methyl-5-nitrobenzoic acid (88.5 mg, 488 mol, 1.1 eq), 2,2,2-trifluoro-1-(naphthalen-1-yl)ethanamine (100 mg, 444 mol, 1.0 eq) in DMF (10 mL) was added DIEA (172 mg, 1.33 mmol, 232 L, 3.0 eq). The mixture was stirred at 25 C. for 5 min then HATU (186 mg, 488 mol, 1.1 eq) was added. The resulting mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H.sub.2O (5.0 mL) and dried under vacuum to give 2-methyl-5-nitro-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (120 mg, 309 mol, 70% yield) as a white solid. M+H.sup.+=389.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.27-8.15 (m, 3H), 7.96 (t, J=6.9 Hz, 2H), 7.75-7.65 (m, 2H), 7.63-7.51 (m, 2H), 7.42 (d, J=8.1 Hz, 1H), 6.89-6.78 (m, 1H), 6.44 (br d, J=9.3 Hz, 1H), 2.54 (s, 3H).

Step 2: 5-Amino-2-methyl-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 183)

[1067] To a stirred solution of 2-methyl-5-nitro-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (110 mg, 283 mol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) was added iron powder (79.0 mg, 1.42 mmol, 5.0 eq), followed by NH.sub.4Cl (75.8 mg, 1.42 mmol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and the combined filtrates were poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 (10030 mm, 3 m); flow rate: 25 mL/min; gradient: 50%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give 5-amino-2-methyl-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (39.7 mg, 110 mol, 39% yield) as a white solid. M+H.sup.+=359.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.24 (d, J=8.6 Hz, 1H), 7.95-7.89 (m, 2H), 7.65 (dt, J=1.4, 8.6 Hz, 2H), 7.61-7.55 (m, 1H), 7.54-7.47 (m, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.88-6.73 (m, 1H), 6.69-6.58 (m, 2H), 6.36 (br d, J=9.5 Hz, 1H), 3.60 (br s, 2H), 2.29 (s, 3H).

Example 40: 5-Amino-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 191)

##STR00875##

Step 1: 2-Methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)propane-2-sulfinamide (40A-2)

[1068] To a solution of 1-bromonaphthalene (886 mg, 4.28 mmol, 595 L, 1.5 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 1.60 mL, 1.4 eq) dropwise at 78 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at 78 C. for 1 h, then a solution of 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (500 mg, 2.85 mmol, 1.0 eq) in THF (5.0 mL) was added dropwise at 78 C. The resulting mixture was stirred at 78 C. for 1 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (20 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-Methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)propane-2-sulfinamide (450 mg, 1.48 mmol, 52% yield) was obtained as a yellow gum.

Step 2: 3-(Naphthalen-1-yl)oxetan-3-amine (40A-3)

[1069] To a solution of 2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)propane-2-sulfinamide (250 mg, 824 mol, 1.0 eq) in MeOH (3.0 mL) was added HCl/dioxane (6 M, 1.0 mL) at 0 C. The resulting mixture was stirred at 0 C. for 10 min. LCMS indicated that the starting material was completely consumed, and the desired product was detected. The reaction mixture was concentrated under vacuum to give 3-(1-naphthyl)oxetan-3-amine (190 mg, 806 mol, 98% yield, HCl salt) as a white solid, which was used in the next step without any further purification.

Step 3: 2-Methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)-5-nitrobenzamide (40A-4)

[1070] To a solution of 2-methyl-5-nitrobenzoic acid (84.5 mg, 467 mol, 1.1 eq) and 3-(naphthalen-1-yl)oxetan-3-amine (100 mg, 424 mol, 1.0 eq, HCl salt) in DMF (10 mL) was added DIEA (164 mg, 1.27 mmol, 222 L, 3.0 eq). After stirring for 5 min, HATU (177 mg, 467 mol, 1.1 eq) was added. The resulting mixture was stirred at 25 C. for 3 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (20 mL), and a precipitate was formed. The mixture was filtered and the solid was washed H.sub.2O (5.0 mL) and dried under vacuum to give 2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)-5-nitrobenzamide (150 mg, 414 mol, 98% yield) as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.12 (br d, J=2.4 Hz, 2H), 8.01-7.93 (m, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.56 (s, 3H), 7.42 (br d, J=8.8 Hz, 1H), 7.33 (br d, J=9.1 Hz, 1H), 6.65 (br s, 1H), 5.61-5.42 (m, 4H), 2.37 (s, 3H).

Step 4: 5-Amino-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 191)

[1071] To a stirred solution of 2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)-5-nitrobenzamide (80.0 mg, 221 mol, 1.0 eq) in a mixture of MeOH (8.0 mL) and H.sub.2O (2.0 mL) was added iron powder (61.7 mg, 1.10 mmol, 5.0 eq), followed by NH.sub.4Cl (59.0 mg, 1.10 mmol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and filtrate was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give 5-amino-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (19.1 mg, 56.6 mol, 26% yield) as a white solid. M+H.sup.+=333.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.94 (dd, J=3.6, 5.9 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.1 Hz, 1H), 7.59-7.46 (m, 3H), 7.43-7.36 (m, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.69-6.53 (m, 3H), 5.50 (d, J=6.6 Hz, 2H), 5.46-5.39 (m, 2H), 2.14 (s, 3H).

Example 41: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 281)

##STR00876##

Step 1: 2-(Naphthalen-1-yl)propan-2-ol (41A-1)

[1072] A mixture of 1-(naphthalen-1-yl)ethanone (10.0 g, 58.8 mmol, 1.0 eq) in THF (100 mL) was degassed and purged with N.sub.2 three times. To this mixture was added methyl lithium (1.6 M in Et.sub.2O, 73.4 mL, 2.0 eq) dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 2 h and warmed to 25 C. stirring for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 2-(Naphthalen-1-yl)propan-2-ol (4.00 g, 21.3 mmol, 36% yield) was obtained as a white solid. M18+H.sup.+=169.1 (LCMS).

Step 2: 1-(2-Azidopropan-2-yl) naphthalene (41A-2)

[1073] A mixture of 2-(naphthalen-1-yl)propan-2-ol (1.00 g, 5.37 mmol, 1.0 eq), FeCl.sub.3 (87.1 mg, 537 mol, 0.1 eq) in DCM (10 mL) was degassed and purged with N.sub.2 three times. To the mixture was added TMSN.sub.3 (1.24 g, 10.7 mmol, 1.41 mL, 2.0 eq) dropwise at 0 C. The resulting mixture was stirred at 25 C. for 2 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was filtered to give a residue which was purified by column chromatography using a gradient of DCM. 1-(2-Azidopropan-2-yl) naphthalene (1.00 g, 4.73 mmol, 88% yield) was obtained as a colorless oil.

Step 3: 2-(Naphthalen-1-yl)propan-2-amine (41A-3)

[1074] To a solution of 1-(2-azidopropan-2-yl) naphthalene (1.00 g, 4.73 mmol, 1.0 eq) in trifluoroethanol (2.0 mL) was added 10% palladium on carbon (100 mg) at 25 C. in one portion. After degassing and purging with H.sub.2 three times, the mixture was stirred at 25 C. for 1 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrated was concentrated under vacuum to give the crude product 2-(naphthalen-1-yl)propan-2-amine (500 mg, 2.70 mmol, 63% yield), which was used in the next step without any further purification. M17+H.sup.+=169.1 (LCMS).

Step 4: tert-Butyl((5-methyl-6-((2-(naphthalen-1-yl)propan-2-yl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (41A-4)

[1075] To a solution of 2-(naphthalen-1-yl)propan-2-amine (100 mg, 540 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (197 mg, 648 mol, 1.2 eq) in DCM (3.0 mL) were added HATU (308 mg, 810 mol, 1.5 eq), DIEA (209 mg, 1.62 mmol, 3.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1:1, R.sub.f=0.3). tert-Butyl((5-methyl-6-((2-(naphthalen-1-yl)propan-2-yl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (100 mg, 212 mol, 39% yield) was obtained as a yellow oil. M+H.sup.+=472.2 (LCMS).

Step 5: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 281)

[1076] To a stirred solution of tert-butyl((5-methyl-6-((2-(naphthalen-1-yl)propan-2-yl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (100 mg, 212 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (45.3 mg, 119 mol, 56% yield, HCl salt) was obtained as a white solid. M+H.sup.+=372.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.25-11.07 (m, 1H), 8.83-8.75 (m, 2H), 8.49-8.23 (m, 3H), 7.94 (dd, J=3.1, 6.4 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.61 (d, J=7.1 Hz, 1H), 7.52-7.45 (m, 3H), 7.29 (d, J=5.0 Hz, 2H), 6.43 (s, 1H), 4.17 (br d, J=5.8 Hz, 2H), 2.14 (s, 3H), 1.89 (s, 6H).

Example 42: 2-(Aminomethyl)-5-methyl-N-(naphthalen-1-ylmethyl)-1H-indole-6-carboxamide (Compound 241)

##STR00877##

Step 1: tert-Butyl((5-methyl-6-((naphthalen-1-ylmethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (42A-1)

[1077] To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (120 mg, 394 mol, 1.0 eq) and 5 naphthalen-1-ylmethanamine (62.0 mg, 394 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (120 mg, 1.18 mmol, 165 L, 3.0 eq), EDCI (189 mg, 986 mol, 2.5 eq) and HOBt (133 mg, 986 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/100 to 1/1. tert-Butyl((5-methyl-6-((naphthalen-1-ylmethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (60.0 mg, 73.1 mol, 19% yield) was obtained as a yellow solid. M+H.sup.+=444.2 (LCMS).

Step 2: 2-(Aminomethyl)-5-methyl-N-(naphthalen-1-ylmethyl)-1H-indole-6-carboxamide (Compound 241)

[1078] To a stirred solution of tert-butyl((5-methyl-6-((naphthalen-1-ylmethyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (60.0 mg, 73.1 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(naphthalen-1-ylmethyl)-1H-indole-6-carboxamide (18.9 mg, 54.4 mol, 39% yield, HCl salt) was obtained as a white solid. M+H.sup.+=344.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 11.38 (s, 1H), 8.77 (t, J=5.8 Hz, 1H), 8.55 (br s, 3H), 8.24 (d, J=7.9 Hz, 1H), 8.01-7.94 (m, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.62-7.47 (m, 4H), 7.43 (s, 1H), 7.35 (s, 1H), 6.47 (s, 1H), 4.93 (d, J=5.8 Hz, 2H), 4.17 (q, J=5.7 Hz, 2H), 2.41 (s, 3H).

Example 43: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 147)

##STR00878##

Step 1: 1-(Naphthalen-1-yl)cyclopropanamine (43A-2)

[1079] A mixture of 1-naphthonitrile (30.0 g, 196 mmol, 1.0 eq) in anhydrous Et.sub.2O (1000 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (61.2 g, 215 mmol, 63.4 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 144 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (55.6 g, 392 mmol, 48.3 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (500 mL) and MTBE (500 mL), and extracted with MTBE (500 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (500 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(Naphthalen-1-yl)cyclopropanamine (15.0 g, 81.9 mmol, 21% yield) was obtained as a yellow oil. M+H.sup.+=184.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47-8.45 (br d, J=8.31 Hz, 1H), 7.91 (br d, J=8.19 Hz, 1H), 7.78 (br d, J=8.19 Hz, 1H), 7.67-7.57 (m, 1H), 7.56-7.50 (m, 2H), 7.46-7.38 (m, 1H), 1.25-1.18 (m, 2H), 1.09-1.00 (m, 2H).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-nitrobenzamide (43A-3)

[1080] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (70.0 mg, 382 mol, 1.0 eq) and 2-methyl-5-nitrobenzoic acid (76.1 mg, 420 mol, 1.1 eq) in DCM (2.0 mL) were added TEA (116 mg, 1.15 mmol, 160 L, 3.0 eq), EDCI (87.9 mg, 458 mol, 1.2 eq) and HOBt (61.9 mg, 458 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.7). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-nitrobenzamide (50.0 mg, 144 mol, 38% yield) was obtained as a white solid. M+H.sup.+=347.2 (LCMS).

Step 3: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 147)

[1081] To a solution of 2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-nitrobenzamide (30.0 mg, 86.7 mol, 1.0 eq) in a mixture of MeOH (2.0 mL) and H.sub.2O (0.5 mL) were added iron powder (24.2 mg, 433 mol, 5.0 eq) and NH.sub.4Cl (23.2 mg, 433 mol, 5.0 eq). The resulting mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (10.1 mg, 28.4 mol, 33% yield, HCl salt) was obtained as a white solid. M+H.sup.+=317.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.33 (s, 1H), 8.56 (d, J=8.3 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.60-7.42 (m, 3H), 7.30-7.26 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 2.20-1.92 (m, 3H), 1.55-1.39 (m, 2H), 1.38-1.25 (m, 2H).

Example 44: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclobutyl)benzamide (Compound 219)

##STR00879##

Step 1: 1-(Naphthalen-1-yl)cyclobutanol (44A-2)

[1082] A test tube with magnesium (572 mg, 23.5 mmol, 1.65 eq) was flame dried under vacuum. After cooling to 25 C. under argon, I.sub.2 (36.2 mg, 143 mol, 0.01 eq) and THF (21 mL) were added, followed by a solution of 1-bromonaphthalene (4.43 g, 21.4 mmol, 10.7 mL, 1.5 eq) in THF (10 mL) in portions at 25 C. The reaction mixture was then stirred at 70 C. for 1.5 h. The mixture was cooled to 0 C. and cyclobutanone (1.00 g, 14.3 mmol, 1.10 mL, 1.0 eq) was added dropwise. The resulting mixture was stirred for 16 h at 25 C. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(Naphthalen-1-yl)cyclobutanol (2.40 g, 12.1 mmol, 8% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.36-8.25 (m, 1H), 7.93-7.86 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.57-7.48 (m, 3H), 7.47-7.41 (m, 1H), 2.88 (ddd, J=5.9, 8.8, 12.3 Hz, 2H), 2.64 (ddd, J=6.7, 9.3, 12.3 Hz, 2H), 2.32-2.22 (m, 1H), 2.17 (dddd, J=3.4, 5.6, 9.2, 11.2 Hz, 1H), 1.79-1.64 (m, 1H).

Step 2: 1-(1-Azidocyclobutyl) naphthalene (44A-3)

[1083] To a solution of 1-(naphthalen-1-yl)cyclobutanol (500 mg, 2.52 mmol, 1.0 eq) and azidotrimethylsilane (349 mg, 3.03 mmol, 1.2 eq) in DCM (13 mL) was added FeCl.sub.3 (8.18 mg, 50.4 mol, 0.02 eq) at 0 C. under a N.sub.2 atmosphere. Then the reaction mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by H.sub.2O (30 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 1-(1-azidocyclobutyl) naphthalene (560 mg) as a yellow gum, which was used in the next step without any further purification.

Step 3: 1-(Naphthalen-1-yl)cyclobutanamine (44A-4)

[1084] To a solution of 1-(1-azidocyclobutyl) naphthalene (100 mg, 448 mol, 1.0 eq) in THF (4.0 mL) was added LiAlH.sub.4 (17.9 mg, 470 mol, 1.0 eq) at 0 C. under a N.sub.2 atmosphere. Then the reaction mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by the addition of saturated aqueous NH.sub.4Cl (10 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 1-(naphthalen-1-yl)cyclobutanamine as a yellow gum, which was used in the next step without any further purification. M+H.sup.+=198.1 (LCMS).

Step 4: 2-Methyl-N-(1-(naphthalen-1-yl)cyclobutyl)-5-nitrobenzamide (44A-5)

[1085] To a solution of 2-methyl-5-nitrobenzoic acid (70.7 mg, 390 mol, 1.1 eq) and 1-(naphthalen-1-yl)cyclobutanamine (70.0 mg, 355 mol, 1.0 eq) in DMF (4 mL) was added DIEA (138 mg, 1.06 mmol, 185 L, 3.0 eq). After stirring 5 min, HATU (148 mg, 390 mol, 1.1 eq) was added. The resulting mixture was stirred at 25 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL), and then extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.4). 2-Methyl-N-(1-(naphthalen-1-yl)cyclobutyl)-5-nitrobenzamide (100 mg, 277 mol, 78% yield) was obtained as a white solid.

Step 5: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclobutyl)benzamide (Compound 219)

[1086] To a stirred solution of 2-methyl-N-(1-(naphthalen-1-yl)cyclobutyl)-5-nitrobenzamide (100 mg, 277 mol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) was added iron powder (77.5 mg, 1.39 mmol, 5.0 eq), followed by NH.sub.4Cl (74.2 mg, 1.39 mmol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and the filtrate were poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 35%-65% B over 10 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclobutyl)benzamide (35.9 mg, 107 mol, 39% yield) was obtained as a white solid. M+H.sup.+=331.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.03-7.96 (m, 1H), 7.95-7.89 (m, 1H), 7.80 (d, J=7.4 Hz, 2H), 7.56-7.42 (m, 3H), 6.90 (d, J=8.0 Hz, 1H), 6.62-6.50 (m, 2H), 6.27 (br s, 1H), 3.67-3.38 (m, 2H), 3.25 (ddd, J=6.1, 9.3, 12.6 Hz, 2H), 3.03-2.88 (m, 2H), 2.37-2.26 (m, 1H), 2.19 (s, 3H), 1.95-1.82 (m, 1H).

Example 45: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 177)

##STR00880##

Step 1: tert-Butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (45A-1)

[1087] To a solution of 1-(1-naphthyl)cyclopropanamine (39.5 mg, 215 mol, 1.1 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (60.0 mg, 196 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (59.5 mg, 588 mol, 81.8 L, 3.0 eq), EDCI (113 mg, 588 mol, 3.0 eq) and HOBt (79.4 mg, 588 mol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (100 mg), which was used in the next step without any further purification. M+H.sup.+=472.3 (LCMS).

Step 2: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 177)

[1088] To a solution of tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (100 mg, 212 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (21.7 mg, 58.4 mol, 28% yield, HCl salt) was obtained as a white solid. M+H.sup.+=372.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.02-8.88 (m, 3H), 8.68-8.62 (m, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.76 (m, 2H), 7.62-7.50 (m, 2H), 7.49-7.43 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.41 (dd, J=2.5, 8.1 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 4.29-4.20 (m, 1H), 4.31-4.20 (m, 2H), 4.19-4.10 (m, 2H), 1.99-1.83 (m, 3H), 1.39-1.28 (m, 2H), 1.19-1.07 (m, 2H).

Example 46: 5-(Cyanomethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 313)

##STR00881##

Step 1: 5-(Hydroxymethyl)-2-methylbenzoic acid (46A-2)

[1089] To a solution of (3-bromo-4-methylphenyl) methanol (1.00 g, 4.97 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 4.97 mL, 2.5 eq) at 78 C. The mixture was stirred at the same temperature for 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (10 mL) and acidified to pH 6 using HCl (1 M, aqueous). The product was extracted with EtOAc (5.0 mL3). The organic layer was washed with brine (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc/petroleum ether=1/5, then filtered. 5-(Hydroxymethyl)-2-methylbenzoic acid (280 mg, 1.68 mmol, 29% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 13.67-12.06 (m, 1H), 7.98 (d, J=0.6 Hz, 1H), 8.04-7.93 (m, 1H), 7.55 (dd, J=1.4, 7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 4.68 (s, 2H), 2.68 (s, 3H).

Step 2: 5-(Hydroxymethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (46A-3)

[1090] To a solution of 5-(hydroxymethyl)-2-methylbenzoic acid (280 mg, 1.68 mmol, 1.0 eq), 1-(1-naphthyl)cyclopropanamine (309 mg, 1.68 mmol, 1.0 eq) in DMF (10 mL) were added TEA (511 mg, 5.05 mmol, 704 L, 3.0 eq), EDCI (323 mg, 1.68 mmol, 1.0 eq) and HOBt (228 mg, 1.68 mmol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H.sub.2O (5.0 mL) and dried under vacuum to give the crude product 5-(hydroxymethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (570 mg) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.66 (d, J=8.2 Hz, 1H), 7.96-7.91 (m, 1H), 7.83 (d, J=7.7 Hz, 2H), 7.60-7.43 (m, 3H), 7.17 (br d, J=7.7 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 5.14 (s, 1H), 4.39 (d, J=5.5 Hz, 2H), 2.01 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Step 3: 5-(Chloromethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (46A-4)

[1091] To a solution of 5-(hydroxymethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (400 mg, 1.21 mmol, 1.0 eq) in DCM (20 mL) was added TEA (122 mg, 1.21 mmol, 168 L, 1.0 eq), followed by MsCl (138 mg, 1.21 mmol, 93.0 L, 1.0 eq). The mixture was stirred at 0 C. for 3 h and then at 20 C. for 9 h. LCMS indicated that the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/10. 5-(Chloromethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 858 mol, 71% yield) was obtained as a white solid. M+H.sup.+=350.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.48 (d, J=8.4 Hz, 1H), 7.93 (dd, J=7.6, 16.7 Hz, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.45 (m, 2H), 7.25 (s, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.50 (br s, 1H), 4.47 (s, 2H), 2.17 (s, 3H), 1.55-1.55 (m, 1H), 1.63-1.55 (m, 1H), 1.45-1.38 (m, 2H).

Step 4: 5-(Cyanomethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 313)

[1092] To a solution of 5-(chloromethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 858 mol, 1.0 eq) in THF (9.0 mL) were added NaHCO.sub.3 (1 M aqueous, 15.0 mL), KI (285 mg, 1.72 mmol, 2.0 eq), NaCN (510 mg, 10.4 mmol, 12.0 eq) and H.sub.2O (9.0 mL). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to warm to room temperature and concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-80% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(Cyanomethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (31.9 mg, 89.0 mol, 10% yield, FA salt) was obtained as a white solid. M+H.sup.+=341.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18 (s, 1H), 8.63 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.83 (dd, J=4.0, 7.6 Hz, 2H), 7.60-7.42 (m, 3H), 7.25-7.19 (m, 1H), 7.18-7.13 (m, 1H), 7.03 (d, J=1.3 Hz, 1H), 3.93 (s, 2H), 1.99 (s, 3H), 1.35 (s, 2H), 1.18 (br s, 2H).

Example 47: 5-(2-Aminoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 378)

##STR00882##

Step 1: 5-(2-Aminoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 378)

[1093] To a solution of 5-(cyanomethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 206 mol, 1.0 eq) in THF (10 mL) were added Raney-Ni (17.6 mg, 206 mol, 1.0 eq) and NH.sub.3.Math.H.sub.2O (26.7 mg, 206 mol, 29.3 L, 27% purity, 1.0 eq) under a N.sub.2 atmosphere. The mixture reaction was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (50 psi) at 30 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The combined organic layers were filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-Aminoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (17.6 mg, 44.4 mol, 22% yield, FA salt) was obtained as as a white solid. M+H.sup.+=345.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14 (s, 1H), 8.66 (br d, J=8.2 Hz, 1H), 8.42 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.83 (dd, J=2.9, 7.6 Hz, 2H), 7.61-7.44 (m, 3H), 7.13-7.03 (m, 2H), 6.92 (s, 1H), 2.82 (br d, J=6.4 Hz, 2H), 2.68 (br d, J=7.1 Hz, 2H), 2.00 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 48: 6-Methyl-N.SUP.1.-(1-(naphthalen-1-yl)cyclopropyl) isophthalamide (Compound 257)

##STR00883##

Step 1: 5-Cyano-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (48A-2)

[1094] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (114 mg, 621 mol, 1.0 eq) and 5-cyano-2-methylbenzoic acid (100 mg, 621 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 283 L, 3.0 eq), EDCI (297 mg, 1.55 mmol, 2.5 eq) and HOBt (210 mg, 1.55 mmol, 2.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. 5-Cyano-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 460 mol, 74% yield) was obtained as a yellow oil. M+H.sup.+=327.2 (LCMS).

Step 2: 6-Methyl-N.SUP.1.-(1-(naphthalen-1-yl)cyclopropyl) isophthalamide (Compound 257)

[1095] A mixture of 5-cyano-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 434 mol, 1.0 eq) in H.sub.2SO.sub.4 (3.0 mL) was stirred at 70 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 35%-55% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 6-Methyl-N.sup.1-(1-(naphthalen-1-yl)cyclopropyl) isophthalamide (16.0 mg, 43.2 mol, 14% yield, HCl salt) was obtained as a white solid. M+H.sup.+=345.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 8.64 (s, 1H), 7.98-7.88 (m, 2H), 7.84 (d, J=7.9 Hz, 2H), 7.74 (br d, J=7.9 Hz, 1H), 7.64-7.43 (m, 4H), 7.27 (br s, 1H), 7.21 (d, J=8.0 Hz, 1H), 2.06 (s, 3H), 1.38 (s, 2H), 1.19 (br s, 2H).

Example 49: 5-(2-Amino-2-oxoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 312)

##STR00884##

Step 1: 5-(2-Amino-2-oxoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 312)

[1096] To a solution of 5-(cyanomethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 294 mol, 1.0 eq) in a mixture of DMSO (1.0 mL) and EtOH (3.0 mL) were added H.sub.2O.sub.2 (99.9 mg, 881 mol, 84.7 L, 30% purity, 3.0 eq) and NaOH (2 M aqueous, 441 L, 3.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NaSO.sub.3 (20 mL) and extracted with EtOAc (15 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc/petroleum ether=1/5, then filtered. 5-(2-Amino-2-oxoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (35.2 mg, 89.7 mol, 31% yield) was obtained as a white solid. M+H.sup.+=359.0 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11 (s, 1H), 8.64 (br d, J=8.4 Hz, 1H), 7.93 (br d, J=7.9 Hz, 1H), 7.83 (br d, J=7.7 Hz, 2H), 7.60-7.44 (m, 3H), 7.38 (br s, 1H), 7.13 (br d, J=7.6 Hz, 1H), 7.07-7.02 (m, 1H), 6.95 (s, 1H), 6.81 (br s, 1H), 3.25 (s, 2H), 1.96 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 50: 5-(2,5-Dihydro-1H-pyrrol-3-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 398)

##STR00885##

Step 1: 5-Bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (50A-1)

[1097] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (155 mg, 846 mol, 1.0 eq) and 5-bromo-2-methylbenzoic acid (200 mg, 930 mol, 1.1 eq) in DMF (2.0 mL) were added TEA (257 mg, 2.54 mmol, 353 L, 3.0 eq), EDCI (243 mg, 1.27 mmol, 1.5 eq) and HOBt (171 mg, 1.27 mmol, 1.5 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.7). 5-Bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (260 mg, 684 mol, 81% yield) was obtained as a white solid. M+H.sup.+=380.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.25 (s, 1H), 8.63 (d, J=8.2 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.82 (dd, J=7.8, 11.1 Hz, 2H), 7.62-7.50 (m, 2H), 7.48-7.39 (m, 2H), 7.21 (d, J=1.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 1.97 (s, 3H), 1.37 (br s, 2H), 1.17 (br s, 2H).

Step 2: tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (50A-2)

[1098] To a stirred solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (60.0 mg, 158 mol, 1.0 eq) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (55.9 mg, 189 mol, 1.2 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (0.3 mL) were added Pd(dppf)Cl.sub.2 (11.5 mg, 15.8 mol, 0.1 eq), K.sub.2CO.sub.3 (65.4 mg, 473 mol, 3.0 eq) in one portion. The mixture was degassed and purged with N.sub.2 three times and then was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.4). tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (70.0 mg, 149 mol, 95% yield) was obtained as a white solid. M+H.sup.+=469.2 (LCMS).

Step 3: 5-(2,5-Dihydro-1H-pyrrol-3-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 398)

[1099] To a stirred solution of tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (70.0 mg, 149 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2,5-Dihydro-1H-pyrrol-3-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (25.3 mg, 68.7 mol, 46% yield, HCl salt) was obtained as a white solid. M+H.sup.+=369.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.45 (br s, 2H), 9.16 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.86-7.79 (m, 2H), 7.62-7.55 (m, 1H), 7.54 (br d, J=1.4 Hz, 1H), 7.49-7.40 (m, 2H), 7.21-7.12 (m, 2H), 6.34 (t, J=1.8 Hz, 1H), 4.25 (br d, J=1.8 Hz, 2H), 4.10 (br s, 2H), 2.03 (s, 3H), 1.42-1.34 (m, 2H), 1.24-1.15 (m, 2H).

Example 51: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (Compound 399)

##STR00886##

Step 1: tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (51A-1)

[1100] To a stirred solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (60.0 mg, 158 mol, 1.0 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (58.5 mg, 189 mol, 1.2 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (0.3 mL) was added Pd(dppf)Cl.sub.2 (11.5 mg, 15.8 mol, 0.1 eq), K.sub.2CO.sub.3 (65.4 mg, 473 mol, 3.0 eq) in one portion. The mixture was degassed and purged with N.sub.2 three times and then was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.4). tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (70.0 mg, 145 mol, 92% yield) was obtained as a white solid. M+H.sup.+=483.2 (LCMS).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (Compound 399)

[1101] To a stirred solution of tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (70.0 mg, 145 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (50.0 mg, 131 mol, 90% yield, HCl salt) was obtained as a white solid. M+H.sup.+=383.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.17 (s, 1H), 9.11 (br s, 2H), 8.66 (d, J=8.3 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.83 (t, J=7.1 Hz, 2H), 7.61-7.55 (m, 1H), 7.55-7.49 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.36 (dd, J=1.8, 8.1 Hz, 1H), 7.19-7.09 (m, 2H), 6.10 (br s, 1H), 3.70 (br s, 2H), 3.27 (br s, 2H), 2.58 (br s, 2H), 2.03 (s, 3H), 1.42-1.33 (m, 2H), 1.24-1.14 (m, 2H).

Example 52: (E)-Methyl 4-(2-(3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoyl) hydrazinyl)-4-oxobut-2-enoate (Compound 373)

##STR00887##

Step 1: 2-(3-Methoxy-3-oxopropyl)benzoic acid (52A-2)

[1102] To a solution of 2-(2-carboxyethyl)benzoic acid (2.00 g, 10.0 mmol, 1.0 eq) in MeOH (30 mL) was added H.sub.2SO.sub.4 (1.00 g, 10.0 mmol, 500 L, 1.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 2-(3-Methoxy-3-oxo-propyl)benzoic acid (1.50 g, 7.00 mmol, 70% yield) was obtained as a white solid. M+H.sup.+=209.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.93 (d, 1H), 7.44-7.50 (m, 1H), 7.28-7.35 (m, 2H), 3.65 (s, 3H), 3.28-3.34 (m, 2H), 2.66 (t, 2H).

Step 2: Methyl 3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoate (52A-3)

[1103] To a solution of 2-(3-methoxy-3-oxo-propyl)benzoic acid (300 mg, 1.44 mmol, 1.0 eq) and 1-(1-naphthyl)cyclopropanamine (264 mg, 1.44 mmol, 1.0 eq) in DCM (10 mL) were added TEA (437 mg, 4.32 mmol, 601 L, 3.0 eq), HOBt (292 mg, 2.16 mmol, 1.5 eq) and EDCI (414 Mg, 2.16 mmol, 1.5 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). Methyl 3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoate (109 mg, 300 mol, 20% yield) was obtained a white solid. M+H.sup.+=374.2 (LCMS).

Step 3: 2-(3-Hydrazinyl-3-oxopropyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (52A-4)

[1104] To a mixture of methyl 3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoate (90.0 mg, 200 mol, 1.0 eq) in EtOH (3.0 mL) was added NH.sub.2NH.sub.2.Math.H.sub.2O (120 mg, 2.00 mmol, 100 L, 10 eq) at 25 C. The reaction mixture was stirred at 80 C. for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give the crude product 2-(3-hydrazino-3-oxo-propyl)-N-[1-(1-naphthyl)cyclopropyl]benzamide (90.0 mg), which was used in the next step without any further purification. M+H.sup.+=374.2 (LCMS).

Step 4: (E)-Methyl 4-(2-(3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoyl)hydrazinyl)-4-oxobut-2-enoate (Compound 373)

[1105] To a mixture of (E)-4-methoxy-4-oxo-but-2-enoic acid (200 mg, 1.54 mmol, 1.0 eq) and DMF (11.2 mg, 154 mol, 11.8 L, 0.1 eq) in DCM (1.0 mL) was added (COCl).sub.2 (390 mg, 3.07 mmol, 269 L, 2.0 eq) at 0 C. The reaction mixture was stirred at 0 C. for 15 min. The reaction mixture was concentrated under vacuum to give a residue which was diluted with DCM (500 L). The solution was added to a mixture of 2-(3-hydrazino-3-oxo-propyl)-N-[1-(1-naphthyl)cyclopropyl]benzamide (90.0 mg, 241 mol, 1.0 eq) and DIEA (156 mg, 1.20 mmol, 210 L, 5.0 eq) in DCM (1.0 mL) at 0 C. The reaction mixture was stirred at 25 C. for 15 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (E)-Methyl 4-(2-(3-(2-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoyl) hydrazinyl)-4-oxobut-2-enoate (11.9 mg, 23.8 mol, 11% yield) was obtained as a white solid. M+H.sup.+=486.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22 (s, 1H), 8.66 (br d, J=8.4 Hz, 1H), 7.93 (br d, J=7.8 Hz, 1H), 7.82 (br dd, J=2.4, 7.6 Hz, 2H), 7.62-7.42 (m, 3H), 7.32-7.18 (m, 2H), 7.17-6.96 (m, 3H), 6.69 (d, J=15.6 Hz, 1H), 3.75 (s, 3H), 2.78 (br t, J=7.8 Hz, 2H), 2.38 (br t, J=7.8 Hz, 2H), 1.39 (br s, 2H), 1.17 (br s, 2H).

Example 53: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 215)

##STR00888##

Step 1: tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (53A-1)

[1106] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (124 mg, 677 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (200 mg, 677 mol, 1.0 eq) in DCM (10 mL) were added TEA (206 mg, 2.03 mmol, 283 L, 3.0 eq), EDCI (325 mg, 1.69 mmol, 2.5 eq) and HOBt (229 mg, 1.69 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (300 mg, 651 mol, 96% yield) was obtained as a yellow gum. M+H.sup.+=461.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47 (br d, J=8.3 Hz, 1H), 7.93 (br dd, J=7.6, 17.4 Hz, 2H), 7.81 (br d, J=8.2 Hz, 1H), 7.62-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.00 (br d, J=8.6 Hz, 1H), 6.78-6.72 (m, 1H), 6.69 (br s, 1H), 6.50 (br s, 1H), 3.95-3.83 (m, 2H), 3.46 (br d, J=4.8 Hz, 2H), 1.50-1.36 (m, 13H).

Step 2: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 215)

[1107] To a stirred solution of tert-butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (200 mg, 434 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (140 mg, 334 mol, 77% yield, HCl salt) as a white solid. M+H.sup.+=361.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.13 (br s, 3H), 7.93 (d, J=7.5 Hz, 1H), 7.86-7.78 (m, 2H), 7.62-7.42 (m, 3H), 7.07 (d, J=8.5 Hz, 1H), 6.88 (dd, J=2.6, 8.4 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 4.09 (t, J=5.1 Hz, 2H), 3.17-3.08 (m, 2H), 1.97 (s, 3H), 1.39-1.33 (m, 2H), 1.21-1.13 (m, 2H).

Example 54: 5-(2-Aminoethoxy)-N,2-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 211)

##STR00889##

Step 1: tert-Butyl(2-(4-methyl-3-(methyl(1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (54A-1)

[1108] To a solution of tert-butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (50.0 mg, 109 mol, 1.0 eq) in THF (3.0 mL) was added sodium hydride (8.68 mg, 217 mol, 60% purity, 2.0 eq) and the mixture was stirred at 0 C. for 30 min. Mel (7.70 mg, 54.3 mol, 3.38 L, 0.5 eq) was added at 0 C. and was stirred at 20 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 50%-80% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). tert-Butyl(2-(4-methyl-3-(methyl(1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (50.0 mg, 105 mol, 97% yield, HCl salt) was obtained as a white solid. M+H.sup.+=475.1. Step 2: 5-(2-Aminoethoxy)-N,2-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 211)

[1109] To a solution of tert-butyl(2-(4-methyl-3-(methyl(1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (50.0 mg, 105 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.91 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give 5-(2-aminoethoxy)-N,2-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (38.0 mg, 84.2 mol, 76% yield, HCl salt) as a white solid. M+H.sup.+=375.1; 1H NMR (400 MHZ, DMSO-d.sub.6) 9.20-9.07 (m, 1H), 8.08 (br s, 2H), 8.14-8.01 (m, 1H), 7.99-7.85 (m, 3H), 7.64-7.47 (m, 3H), 7.13-7.07 (m, 1H), 6.90-6.82 (m, 1H), 6.62-6.54 (m, 1H), 4.15-4.06 (m, 2H), 3.16-3.09 (m, 2H), 2.78-2.71 (m, 3H), 1.86-1.81 (m, 5H), 1.37 (br s, 2H).

Example 55: 5-(3-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 316)

##STR00890##

Step 1: 5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (55A-2)

[1110] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (4.82 g, 26.3 mmol, 0.8 eq) and 5-hydroxy-2-methylbenzoic acid (5.00 g, 32.9 mmol, 1.0 eq) in DMF (100 mL) were added TEA (3.33 g, 32.7 mmol, 4.57 mL, 1.0 eq), EDCI (6.61 g, 34.5 mmol, 1.1 eq) and HOBt (888 mg, 6.57 mmol, 0.2 eq). The mixture was stirred at 25 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (100 mL) and extracted with EtOAc (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was triturated from a mixture of EtOAc (10 mL) and petroleum ether (30 mL) and stirred at room temperature for 10 min. 5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (5.00 g, 15.8 mmol, 48% yield) was obtained as a white solid. M+H.sup.+=318.1 (LCMS).

Step 2: tert-Butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) propyl)carbamate (55A-3)

[1111] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) and tert-butyl(3-hydroxypropyl)carbamate (55.2 mg, 315 mol, 54.1 L, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added CMBP (114 mg, 473 mol, 1.5 eq) dropwise at 20 C. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) propyl) carbamate (70.0 mg, 148 mol, 47% yield, HCl salt) was obtained as a white solid. M+H.sup.+=475.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.79 (m, 2H), 7.60-7.43 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.88-6.78 (m, 2H), 6.60 (d, J=2.6 Hz, 1H), 3.86 (t, J=6.3 Hz, 2H), 3.02 (q, J=6.5 Hz, 2H), 1.95 (s, 3H), 1.76 (q, J=6.5 Hz, 2H), 1.35 (s, 11H), 1.19-1.16 (m, 2H).

Step 3: 5-(3-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 316)

[1112] To a stirred solution of tert-butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy) propyl)carbamate (70.0 mg, 148 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(3-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (53.7 mg, 131 mol, 87% yield, HCl salt) was obtained as a white solid. M+H.sup.+=375.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.98-7.85 (m, 4H), 7.85-7.80 (m, 2H), 7.60-7.49 (m, 2H), 7.46 (dd, J=7.3, 8.1 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 3.96 (t, J=6.2 Hz, 2H), 2.94-2.83 (m, 2H), 1.99-1.91 (m, 5H), 1.38-1.32 (m, 2H), 1.21-1.12 (m, 2H).

Example 56: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 233)

##STR00891##

Step 1: Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoate (56A-1)

[1113] To a solution of methyl 5-hydroxy-2-methylbenzoate (1.00 g, 6.02 mmol, 1.0 eq) and tert-butyl(2-hydroxyethyl)(methyl)carbamate (1.58 g, 9.03 mmol, 1.5 eq) in toluene (30 mL) were added TMAD (3.11 g, 18.1 mmol, 3.0 eq) and PPh.sub.3 (4.74 g, 18.1 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times, and then stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoate (600 mg, 1.86 mmol, 31% yield) was obtained as a yellow oil. M56+H.sup.+=268.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.43 (br s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.95 (dd, J=2.4, 8.3 Hz, 1H), 4.16-4.04 (m, 2H), 3.89 (s, 3H), 3.60 (br s, 2H), 2.98 (s, 3H), 2.52 (s, 3H), 1.46 (s, 9H).

Step 2: 5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (56A-2)

[1114] To a solution of methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoate (550 mg, 1.70 mmol, 1.0 eq) in a mixture of MeOH (16 mL) and THF (8.0 mL) was added NaOH (2 M aqueous, 3.40 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and the mixture was washed with MTBE (15 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (470 mg), which was used in the next step without any further purification. M56+H.sup.+=254.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.58 (br d, J=1.9 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.01 (dd, J=2.8, 8.4 Hz, 1H), 4.12 (br s, 2H), 3.62 (br s, 2H), 3.00 (s, 3H), 2.58 (s, 3H), 1.47 (s, 9H).

Step 3: tert-Butyl methyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (56A-3)

[1115] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (90.6 mg, 495 mol, 0.9 eq), 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (170 mg, 550 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (111 mg, 1.10 mmol, 153 L, 2.0 eq), EDCI (126 mg, 659 mol, 1.2 eq) and HOBt (89.1 mg, 659 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl methyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (90.0 mg, 190 mol, 35% yield) was obtained as a yellow oil.

Step 4: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 233)

[1116] To a solution of tert-butyl methyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (90.0 mg, 190 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (71.0 mg, 173 mol, 91% yield, HCl salt) was obtained as a white solid. M+H.sup.+=375.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.16 (s, 1H), 9.02 (br s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.78 (m, 2H), 7.62-7.39 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (dd, J=2.6, 8.4 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 4.16 (t, J=4.9 Hz, 2H), 3.29-3.17 (m, 2H), 2.56 (t, J=5.3 Hz, 3H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 57: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N((S)-2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 386)

##STR00892##

Step 1: tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (57A-1)

[1117] To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (592 mg, 3.16 mmol, 1.1 eq) in toluene (15 mL) were added TMAD (1.55 g, 9.03 mmol, 3.0 eq) and PPh.sub.3 (2.37 g, 9.03 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M56+H.sup.+=280.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.50-7.47 (m, 1H), 7.17-7.12 (m, 1H), 7.03-6.97 (m, 1H), 4.56-4.45 (m, 1H), 4.34-4.24 (m, 1H), 4.13 (br d, J=4.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.95 (br s, 4H), 2.55-2.51 (m, 3H), 2.42-2.20 (m, 2H), 1.47-1.40 (m, 9H).

Step 2: Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (57A-2)

[1118] To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (800 mg, 2.39 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.26 g, 28.6 mmol, 2.12 mL, 12 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (800 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification as a yellow oil. M+H.sup.+=236.1 (LCMS).

Step 3: Methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (57A-3)

[1119] To a solution of (methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (400 mg, 1.03 mmol, 1.0 eq, TFA salt) in MeOH (8.0 mL) was added TEA (80.0 L), followed by the addition of formaldehyde (335 mg, 4.12 mmol, 307 L, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (518 mg, 8.25 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product methyl 2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=250.1 (LCMS).

Step 4: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (57A-4)

[1120] A solution of methyl 2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzoate (300 mg, 1.20 mmol, 1.0 eq) in HCl (2 M aqueous 9.00 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H.sub.2O (10 mL) and washed with MTBE (20 mL2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (10 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to give the crude product 2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzoic acid (220 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=236.1 (LCMS).

Step 5: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N((S)-2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 386)

[1121] To a solution of(S)-2,2,2-trifluoro-1-(naphthalen-1-yl)ethanamine (47.9 mg, 213 mol, 1.0 eq) in acetonitrile (2.0 mL) was added 2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzoic acid (50.0 mg, 213 mol, 1.0 eq), followed by TCFH (71.6 mg, 255 mol, 1.2 eq) and 1-methylimidazole (61.1 mg, 744 mol, 59.3 L, 3.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5 mL) and extracted with EtOAc (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 10 m); flow rate: 25 mL/min; gradient: 5%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methyl phenoxy)methyl)azetidine-1-carboxylate (46.1 mg, 93.6 mol, 44% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=443.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.36-9.75 (m, 1H), 8.31-8.24 (m, 1H), 8.07-7.99 (m, 2H), 7.96-7.88 (m, 1H), 7.73-7.55 (m, 3H), 7.24-7.18 (m, 1H), 7.06-6.98 (m, 1H), 6.91-6.79 (m, 2H), 4.70-4.57 (m, 1H), 4.32-4.24 (m, 2H), 4.09-3.98 (m, 1H), 3.92-3.81 (m, 1H), 2.88-2.81 (m, 3H), 2.44-2.30 (m, 2H), 2.23-2.14 (m, 3H).

Example 58: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 214)

##STR00893##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 214)

[1122] To a solution of 5-(2-aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (130 mg, 361 mol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (58.5 mg, 721 mol, 53.7 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (45.3 mg, 721 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (61.0 mg, 157 mol, 43% yield, HCl salt) as a white solid. M+H.sup.+=389.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.43 (br s, 1H), 9.14 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.85-7.80 (m, 2H), 7.61-7.43 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 4.26 (t, J=5.1 Hz, 2H), 3.45-3.41 (m, 2H), 2.78 (d, J=4.6 Hz, 6H), 1.96 (s, 3H), 1.39-1.33 (m, 2H), 1.20-1.15 (m, 2H).

Example 59: 5-(2-(Ethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 351)

##STR00894##

Step 1: 5-(2-Bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (59A-1)

[1123] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (1.00 g, 3.15 mmol, 1.0 eq) and 1,2-dibromoethane (5.92 g, 31.5 mmol, 2.38 mL, 10 eq) in acetone (30 mL) were added potassium carbonate (1.00 g, 7.25 mmol, 2.3 eq) and 18-crown-6 (41.6 mg, 158 mol, 0.05 eq). The mixture was stirred at 60 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 100/1. 5-(2-Bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (800 mg, 1.89 mmol, 60% yield) was obtained as a colorless oil. M+H.sup.+=424.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.79 (m, 2H), 7.61-7.42 (m, 3H), 7.04 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.8, 8.4 Hz, 1H), 6.64 (d, J=2.8 Hz, 1H), 4.26-4.20 (m, 2H), 3.77-3.72 (m, 2H), 1.96 (s, 3H), 1.39-1.34 (m, 2H), 1.19 (s, 2H).

Step 2: 5-(2-(Ethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 351)

[1124] To a solution of 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 165 mol, 1.0 eq) in acetonitrile (3.0 mL) was added ethanamine (8.18 mg, 181 mol, 11.9 L, 1.1 eq), followed by KI (5.48 mg, 33.0 mol, 0.2 eq) and K.sub.2CO.sub.3 (45.6 mg, 330 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Ethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (33.0 mg, 77.7 mol, 47% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=389.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14-9.11 (m, 1H), 8.67-8.61 (m, 1H), 7.96-7.90 (m, 1H), 7.85-7.79 (m, 2H), 7.61-7.43 (m, 3H), 7.10-7.04 (m, 1H), 6.93-6.85 (m, 1H), 6.68-6.64 (m, 1H), 4.18-4.10 (m, 2H), 3.29-3.21 (m, 2H), 3.02-2.92 (m, 2H), 1.99-1.93 (m, 3H), 1.38-1.32 (m, 2H), 1.22-1.14 (m, 5H).

Example 60: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzamide (Compound 247)

##STR00895##

Step 1: Methyl 5-(2-aminoethoxy)-2-methylbenzoate (60A-1)

[1125] To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (500 mg, 1.62 mmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give the crude product methyl 5-(2-aminoethoxy)-2-methylbenzoate (400 mg, HCl salt), which was used in the next step without any further purification. M+H.sup.+=210.1 (LCMS).

Step 2: Methyl 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoate (60A-2)

[1126] To a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (333 mg, 1.43 mmol, 1.0 eq) and methyl 5-(2-aminoethoxy)-2-methylbenzoate (300 mg, 1.43 mmol, 1.0 eq) in THF (6.0 mL) was added TEA (435 mg, 4.30 mmol, 599 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 2/1. Methyl 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoate (300 mg, 954 mol, 67% yield) was obtained as a yellow oil. M+H.sup.+=292.0 (LCMS).

Step 3: 2-Methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (60A-3)

[1127] To a solution of methyl 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoate (300 mg, 1.03 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and THF (4.0 mL) was added NaOH (2 M aqueous, 2.16 mL). The mixture was stirred at 20 C. for 16 h. LCMS indicated that 14% of the starting material remained and the 80% of desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and washed with MTBE (3.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (280 mg), which was used in the next step without any further purification. M+H.sup.+=278.0 (LCMS).

Step 4: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzamide (Compound 247)

[1128] To a solution of 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (80.0 mg, 289 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (52.9 mg, 289 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (58.4 mg, 577 mol, 80.3 L, 2.0 eq), EDCI (66.4 mg, 346 mol, 1.2 eq) and HOBt (46.8 mg, 346 mol, 1.2 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzamide (52.4 mg, 115 mol, 40% yield, HCl salt) was obtained as a yellow oil. M+H.sup.+=443.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.46 (d, J=8.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.63-7.43 (m, 3H), 7.01 (d, J=8.4 Hz, 1H), 6.77 (dd, J=2.6, 8.4 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.68-6.66 (m, 1H), 3.95 (t, J=5.1 Hz, 2H), 3.23 (d, J=9.4 Hz, 2H), 3.05 (t, J=4.9 Hz, 2H), 2.11 (s, 3H), 1.43-1.37 (m, 2H), 1.27 (s, 2H).

Example 61: 5-(2-(Isopropylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 362)

##STR00896##

Step 1: 5-(2-(Isopropylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 362)

[1129] To a solution of propan-2-amine (10.7 mg, 181 mol, 15.6 L, 1.1 eq) in ACN (5.0 mL) were added 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 165 mol, 1.0 eq), KI (2.74 mg, 16.5 mol, 0.1 eq) and K.sub.2CO.sub.3 (45.6 mg, 330 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Isopropylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (21.9 mg, 49.6 mol, 30% yield, HCl salt) was obtained as a white solid. M+H.sup.+=403.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18-9.08 (m, 1H), 8.74-8.69 (m, 1H), 8.68-8.63 (m, 1H), 7.97-7.91 (m, 1H), 7.86-7.80 (m, 2H), 7.61-7.43 (m, 3H), 7.12-7.05 (m, 1H), 6.93-6.86 (m, 1H), 6.70-6.65 (m, 1H), 4.19-4.13 (m, 2H), 3.26 (br s, 3H), 1.97 (s, 3H), 1.40-1.33 (m, 2H), 1.23 (d, J=6.5 Hz, 6H), 1.20-1.16 (m, 2H).

Example 62: 5-(2-((Cyclopropylmethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 361)

##STR00897##

Step 1: 5-(2-((Cyclopropylmethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 361)

[1130] To a solution of cyclopropylmethanamine (12.9 mg, 181 mol, 1.1 eq) in ACN (5.0 mL) were added 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 165 mol, 1.0 eq), KI (2.74 mg, 16.5 mol, 0.1 eq) and K.sub.2CO.sub.3 (45.6 mg, 330 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-((Cyclopropylmethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (18.9 mg, 41.6 mol, 25% yield, HCl salt) was obtained as a white solid. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 9.01-8.80 (m, 2H), 8.72-8.61 (m, 1H), 7.98-7.91 (m, 1H), 7.82 (br d, J=5.9 Hz, 2H), 7.62-7.42 (m, 3H), 7.13-7.03 (m, 1H), 6.95-6.86 (m, 1H), 6.72-6.63 (m, 1H), 4.23-4.12 (m, 2H), 3.29 (br d, J=4.9 Hz, 2H), 2.93-2.79 (m, 2H), 1.97 (s, 3H), 1.45-1.30 (m, 2H), 1.24-1.14 (m, 2H), 1.11-0.99 (m, 1H), 0.63-0.50 (m, 2H), 0.35 (br s, 2H).

Example 63: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(phenylamino)ethoxy)benzamide (Compound 315)

##STR00898##

Step 1: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(phenylamino)ethoxy)benzamide (Compound 315)

[1131] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) and 2-(phenylamino) ethanol (43.2 mg, 315 mol, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added CMBP (114 mg, 473 mol, 1.5 eq) dropwise at 20 C. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(phenylamino)ethoxy)benzamide (55.9 mg, 113 mol, 95% yield, HCl salt) was obtained as a white solid. M+H.sup.+=437.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.96-7.90 (m, 1H), 7.85-7.78 (m, 2H), 7.58-7.42 (m, 3H), 7.13 (t, J=7.8 Hz, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.85 (dd, J=2.6, 8.4 Hz, 1H), 6.77-6.60 (m, 4H), 4.02 (t, J=5.5 Hz, 2H), 3.41 (br s, 2H), 1.96 (s, 3H), 1.39-1.32 (m, 2H), 1.20-1.13 (m, 2H).

Example 64: 5-(2-(Benzylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 360)

##STR00899##

Step 1: 5-(2-(Benzylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 360)

[1132] To a solution of 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (50.0 mg, 118 mol, 1.0 eq) and phenylmethanamine (13.9 mg, 130 mol, 14.1 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (1.96 mg, 11.8 mol, 0.1 eq) and potassium carbonate (32.6 mg, 236 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Benzylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (64.6 mg, 132 mol, 28% yield, HCl salt) was obtained as a white solid. M+H.sup.+=451.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.26 (br s, 2H), 9.12 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.87-7.79 (m, 2H), 7.61-7.38 (m, 8H), 7.07 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.7, 8.4 Hz, 1H), 6.66 (d, J=2.8 Hz, 1H), 4.26-4.10 (m, 4H), 3.25 (br s, 2H), 1.97 (s, 3H), 1.40-1.31 (m, 2H), 1.20-1.15 (m, 2H).

Example 65: 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 359)

##STR00900##

Step 1: 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 359)

[1133] To a solution of 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 165 mol, 1.0 eq) and 2-aminoethanol (11.1 mg, 181 mol, 11.0 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (2.74 mg, 16.5 mol, 0.1 eq) and potassium carbonate (45.6 mg, 330 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (16.1 mg, 36.5 mol, 22% yield, HCl salt) was obtained as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.72 (br d, J=2.9 Hz, 2H), 8.65 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.83 (t, J=6.5 Hz, 2H), 7.61-7.43 (m, 3H), 7.08 (d, J=8.5 Hz, 1H), 6.88 (dd, J=2.6, 8.4 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 5.31-5.13 (m, 1H), 4.17 (t, J=5.1 Hz, 2H), 3.65 (t, J=5.3 Hz, 2H), 3.35-3.25 (m, 2H), 3.09-2.99 (m, 2H), 1.97 (s, 3H), 1.40-1.31 (m, 2H), 1.21-1.16 (m, 2H).

Example 66: 5-(2-((2-Methoxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 358)

##STR00901##

Step 1: 5-(2-((2-Methoxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 358)

[1134] To a solution of 5-(2-bromoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (50.0 mg, 118 mol, 1.0 eq) and 2-methoxyethanamine (9.74 mg, 130 mol, 11.3 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (1.96 mg, 11.8 mol, 0.1 eq) and potassium carbonate (32.6 mg, 236 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-((2-Methoxyethyl)amino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (19.0 mg, 41.6 mol, 18% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.79 (br d, J=1.4 Hz, 2H), 8.65 (d, J=8.1 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.87-7.80 (m, 2H), 7.61-7.43 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.7, 8.3 Hz, 1H), 6.66 (d, J=2.6 Hz, 1H), 4.16 (br t, J=5.1 Hz, 2H), 3.58 (t, J=5.1 Hz, 2H), 3.28 (s, 5H), 3.16 (quin, J=5.3 Hz, 2H), 1.97 (s, 3H), 1.35 (s, 2H), 1.21-1.15 (m, 2H).

Example 67: 5-(2-(3-Fluoroazetidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 300)

##STR00902##

Step 1: 2-(3-Fluoroazetidin-1-yl)ethanol (67A-2)

[1135] To a solution of 3-fluoroazetidine (300 mg, 2.69 mmol, 1.0 eq, HCl salt) in acetonitrile (6.0 mL) was added K.sub.2CO.sub.3 (1.12 g, 8.07 mmol, 3.0 eq). The mixture was stirred at 20 C. for 30 min, then 2-bromoethanol (336 mg, 2.69 mmol, 191 L, 1.0 eq) was added. The mixture was stirred at 80 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.5). 2-(3-Fluoroazetidin-1-yl)ethanol (80.0 mg, 672 mol, 25% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 3.89-3.83 (m, 1H), 3.75 (dd, J=1.7, 5.2 Hz, 1H), 3.72-3.67 (m, 4H), 3.66-3.59 (m, 2H), 2.84-2.73 (m, 2H).

Step 2: 5-(2-(3-Fluoroazetidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 300)

[1136] To a solution of 2-(3-fluoroazetidin-1-yl)ethanol (18.8 mg, 158 mol, 1.0 eq) and 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (50.0 mg, 158 mol, 1.0 eq) in toluene (2.0 mL) was added CMBP (38.0 mg, 158 mol, 1.0 eq). The resulting mixture was degassed and purged with N.sub.2 three times and then the mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (2.0 mL) and extracted with EtOAc (1.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(3-Fluoroazetidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (8.20 mg, 19.6 mol, 12% yield, FA salt) was obtained as a white solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.81 (dd, J=7.9, 10.0 Hz, 2H), 7.60-7.41 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.80 (dd, J=2.7, 8.3 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 5.27-4.97 (m, 1H), 3.84 (t, J=5.4 Hz, 2H), 3.62-3.49 (m, 2H), 3.20-3.05 (m, 2H), 2.73 (t, J=5.4 Hz, 2H), 1.95 (s, 3H), 1.35 (s, 2H), 1.19-1.12 (m, 2H).

Example 68: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(piperidin-1-yl)ethoxy)benzamide (Compound 254)

##STR00903##

Step 1: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(piperidin-1-yl)ethoxy)benzamide (Compound 254)

[1137] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 221 mol, 1.0 eq), 2-(piperidin-1-yl)ethanol (28.5 mg, 221 mol, 29.3 L, 1.0 eq) and CMBP (79.9 mg, 331 mol, 1.5 eq) in toluene (3.5 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(2-(piperidin-1-yl)ethoxy)benzamide (60.1 mg, 140 mol, 64% yield) was obtained as a yellow solid. M+H.sup.+=429.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.66 (d, J=8.1 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.86-7.77 (m, 2H), 7.61-7.42 (m, 3H), 7.02 (d, J=8.6 Hz, 1H), 6.83 (dd, J=2.7, 8.4 Hz, 1H), 6.61 (d, J=2.7 Hz, 1H), 3.96 (t, J=5.9 Hz, 2H), 2.65-2.57 (m, 3H), 2.39 (br s, 3H), 1.95 (s, 3H), 1.47 (quin, J=5.5 Hz, 4H), 1.40-1.29 (m, 4H), 1.22-1.11 (m, 2H).

Example 69: 5-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 284)

##STR00904##

Step 1: 2-(4,4-Difluoropiperidin-1-yl)ethanol (69A-2)

[1138] To a solution of 4,4-difluoropiperidine (500 mg, 4.13 mmol, 1.0 eq) in ACN (20 mL) were added K.sub.2CO.sub.3 (1.71 g, 12.4 mmol, 3.0 eq) and 2-bromoethanol (2.58 g, 20.6 mmol, 1.47 mL, 5.0 eq). The mixture was stirred at 90 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (7.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(4,4-Difluoropiperidin-1-yl)ethanol (330 mg, 2.00 mmol, 48% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 3.62 (t, J=5.4 Hz, 2H), 2.68-2.54 (m, 6H), 2.16-1.85 (m, 4H).

Step 2: 5-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 284)

[1139] To a solution of 2-(4,4-difluoropiperidin-1-yl)ethanol (52.0 mg, 315 mol, 1.0 eq), 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) in toluene (2.5 mL) was added CMBP (76.1 mg, 315 mol, 1.0 eq). The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (67.8 mg, 143 mol, 45% yield, FA salt) was obtained as a white solid. M+H.sup.+=465.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.87-7.78 (m, 2H), 7.61-7.41 (m, 3H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.7, 8.3 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 3.98 (t, J=5.7 Hz, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.57 (br t, J=5.4 Hz, 4H), 1.96 (s, 7H), 1.36 (br d, J=1.6 Hz, 2H), 1.23-1.12 (m, 2H).

Example 70: 2-Methyl-5-(2-morpholinoethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 209)

##STR00905##

Step 1: Methyl 2-methyl-5-(2-morpholinoethoxy)benzoate (70A-1)

[1140] To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and 4-(2-chloroethyl) morpholine (804 mg, 3.61 mmol, 1.2 eq) in acetone (20 mL) was added K.sub.2CO.sub.3 (1.66 g, 12.0 mmol, 4.0 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 2-methyl-5-(2-morpholinoethoxy)benzoate (300 mg, 1.07 mmol, 36% yield) was obtained as a colorless oil. M+H.sup.+=280.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.46 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.97 (dd, J=2.8, 8.4 Hz, 1H), 4.12 (t, J=5.7 Hz, 2H), 3.89 (s, 3H), 3.77-3.71 (m, 4H), 2.80 (t, J=5.7 Hz, 2H), 2.61-2.55 (m, 4H), 2.51 (s, 3H).

Step 2: 2-Methyl-5-(2-morpholinoethoxy)benzoic acid (70A-2)

[1141] To a solution of methyl 2-methyl-5-(2-morpholinoethoxy)benzoate (200 mg, 716 mol, 1.0 eq) in a mixture of MeOH (4.0 mL), H.sub.2O (2.0 mL) and THF (8.0 mL) was added LiOH.Math.H.sub.2O (60.1 mg, 1.43 mmol, 2.0 eq). The mixture was stirred at 25 C. for 1 h, then the mixture was stirred at 70 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (5.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with dimethyltetrahydrofuran (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(2-morpholinoethoxy)benzoic acid (80.0 mg), which was used in the next step without any further purification. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.33 (d, J=2.6 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.04 (dd, J=2.6, 8.4 Hz, 1H), 4.09 (br t, J=5.6 Hz, 2H), 3.60-3.56 (m, 4H), 2.71 (br s, 2H), 2.54-2.51 (m, 4H), 2.42 (s, 3H).

Step 3: 2-Methyl-5-(2-morpholinoethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 209)

[1142] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (50.0 mg, 273 mol, 1.0 eq) and 2-methyl-5-(2-morpholinoethoxy)benzoic acid (72.4 mg, 273 mol, 1.0 eq) in DCM (10 mL) were added TEA (82.8 mg, 819 mol, 114 L, 3.0 eq), EDCI (105 mg, 546 mol, 3.0 eq) and HOBt (73.7 mg, 546 mol, 2.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-(2-morpholinoethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (45.4 mg, 102 mol, 38% yield) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.45 (d, J=8.4 Hz, 1H), 7.92 (dd, J=7.8, 15.8 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.61-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.78 (dd, J=2.7, 8.4 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 3.99 (t, J=5.6 Hz, 2H), 3.76-3.67 (m, 4H), 2.72 (t, J=5.6 Hz, 2H), 2.56-2.49 (m, 4H), 2.11 (s, 3H), 1.57 (br s, 2H), 1.42-1.37 (m, 2H).

Example 71: 5-(2-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 324)

##STR00906##

Step 1: tert-Butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (71A-1)

[1143] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq), tert-butyl(1-hydroxypropan-2-yl)carbamate (55.2 mg, 315 mol, 1.0 eq) and CMBP (114 mg, 473 mol, 1.5 eq) in toluene (5.0 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was used without further purification. tert-Butyl(1-(4-methyl-3-((1-(naphthalene-1-yl)cyclopropyl)carbamoyl)phenoxy) propan-2-yl)carbamate (90.0 mg, 190 mol, 60% yield) was obtained as a white solid.

Step 2: 5-(2-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 324)

[1144] To a stirred solution of tert-butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy) propan-2-yl)carbamate (80.0 mg, 169 mol, 1.0 eq) in EtOAc (8.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Aminopropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (50.9 mg, 124 mol, 73% yield, HCl salt) was obtained as a white solid. M+H.sup.+=375.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18-9.06 (m, 1H), 8.69-8.61 (m, 1H), 7.94 (br d, J=7.9 Hz, 4H), 7.83 (t, J=7.4 Hz, 2H), 7.60-7.44 (m, 3H), 7.11-7.05 (m, 1H), 6.92-6.86 (m, 1H), 6.69-6.63 (m, 1H), 4.08-3.97 (m, 1H), 3.89-3.80 (m, 1H), 3.60-3.49 (m, 1H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.27-1.16 (m, 5H).

Example 72: 5-(2-Amino-3,3-dimethylbutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 343)

##STR00907##

Step 1: tert-Butyl(1-hydroxy-3,3-dimethylbutan-2-yl)carbamate (72A-2)

[1145] To a mixture of 2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (500 mg, 2.16 mmol, 1.0 eq) and NMM (219 mg, 2.16 mmol, 238 L, 1.0 eq) in THF (4.0 mL) was added isobutyl carbonochloridate (295 mg, 2.16 mmol, 284 L, 1.0 eq) at 10 C., the reaction mixture was stirred at 10 C. for 30 min. TLC indicated that the starting material was completely consumed. Then the reaction mixture was filtered. To the filtrate was added NaBH.sub.4 (123 mg, 3.24 mmol, 1.5 eq) in portions at 10 C. The resulting reaction mixture was stirred at the same temperature for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (30 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.2). tert-Butyl(1-hydroxy-3,3-dimethylbutan-2-yl)carbamate (220 mg, 1.01 mmol, 47% yield) was obtained as a white solid.

Step 2: tert-Butyl(3,3-dimethyl-1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy) butan-2-yl)carbamate (72A-3)

[1146] A mixture of 5-hydroxy-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (150 mg, 472 mol, 1.0 eq), tert-butyl N-[1-(hydroxymethyl)-2,2-dimethyl-propyl]carbamate (205 mg, 945 mol, 2.0 eq) and CMBP (171 mg, 709 mol, 1.5 eq) in toluene (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.3). tert-Butyl(3,3-dimethyl-1-(4-methyl-3-((1-(naphthalene-1-yl)cyclopropyl)carbamoyl). phenoxy)butan-2-yl)carbamate (45 mg, 87.1 mol, 18% yield) was obtained as a white solid. M+H.sup.+=517.3 (LCMS)

Step 3: 5-(2-Amino-3,3-dimethylbutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 343)

[1147] To a mixture of tert-butyl N-[2,2-dimethyl-1-[4-methyl-3-[1-(1-naphthyl)cyclopropyl]carbamoyl]phenoxy]methyl]propyl]carbamate (45.0 mg, 87.1 mol, 1.0 eq) in EtOAc (500 L) was added HCl/EtOAc (4 M, 1.0 mL). The reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Amino-3,3-dimethyl-butoxy)-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (18.0 mg, 45.0 mol, 47% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.02-7.76 (m, 6H), 7.64-7.40 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.93 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 4.16 (dd, J=3.2, 10.4 Hz, 1H), 3.91 (br t, J=9.6 Hz, 1H), 3.26-3.09 (m, 1H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H), 1.00 (s, 9H).

Example 73: 5-(2-Amino-3-methoxypropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 400)

##STR00908##

Step 1: 2-((tert-Butoxycarbonyl)amino)-3-methoxypropanoic acid (73A-2)

[1148] To a mixture of 2-amino-3-methoxy-propanoic acid (500 mg, 4.20 mmol, 1.0 eq) and NaOH (336 mg, 8.39 mmol, 2.0 eq) in a mixture of THF (4.0 mL) and H.sub.2O (2.0 mL) was added tert-butoxycarbonyl tert-butyl carbonate (1.01 g, 4.62 mmol, 1.1 eq) at 0 C. The reaction mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.3). 2-((tert-Butoxycarbonyl)amino)-3-methoxy-propanoic acid (320 mg, 1.46 mmol, 35% yield) was obtained as white oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.38-9.92 (m, 1H), 5.76 (br s, 1H), 4.19 (br s, 1H), 3.62-3.76 (m, 1H), 3.50 (br s, 1H), 3.26 (s, 3H), 1.35 (s, 9H).

Step 2: tert-Butyl(1-hydroxy-3-methoxypropan-2-yl)carbamate (73A-3)

[1149] To a mixture of 2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (220 mg, 1.00 mmol, 1.0 eq) and NMM (101 mg, 1.00 mmol, 1.0 eq) in THF (2.0 mL) was added isobutyl carbonochloridate (137 mg, 1.00 mmol, 1.0 eq) at 10 C. The reaction mixture was stirred at 10 C. for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was filtered. To the filtrate was added NaBH.sub.4 (57.0 mg, 1.51 mmol, 1.5 eq) at 10 C., the reaction mixture was stirred at 10 C. for 30 min. TLC indicated that the intermediate was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (30 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.1). tert-Butyl(1-hydroxy-3-methoxypropan-2-yl)carbamate (100 mg, 487 mol, 49% yield) was obtained as a colorless oil.

Step 3: tert-Butyl(1-methoxy-3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (73A-4)

[1150] A mixture of 5-hydroxy-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (150 mg, 473 mol, 1.0 eq), tert-butyl N-[1-(hydroxymethyl)-2-methoxy-ethyl]carbamate (97.0 mg, 473 mol, 1.0 eq) and CMBP (114 mg, 473 mol, 1.0 eq) in toluene (4.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.7). tert-Butyl(1-methoxy-3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) propan-2-yl)carbamate (140 mg, 277 mol, 59% yield) was obtained as a white solid. M+H.sup.+=505.2 (LCMS).

Step 4: 5-(2-Amino-3-methoxypropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 400)

[1151] To a solution of tert-butyl(1-methoxy-3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy) propan-2-yl)carbamate (140 mg, 277 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-amino-3-methoxy-propoxy)-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (92.7 mg, 210 mol, 74% yield, HCl salt) was obtained as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.19 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.94-7.76 (m, 3H), 7.60-7.38 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.8 Hz, 1H), 4.15-3.99 (m, 2H), 3.74-3.57 (m, 3H), 3.41 (s, 3H), 2.00 (s, 3H), 1.51-1.40 (m, 2H), 1.34-1.28 (m, 2H).

Example 74: 5-(2-Amino-2-phenylethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 367)

##STR00909##

Step 1: tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)-1-phenylethyl)carbamate (74A-1)

[1152] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 630 mol, 1.0 eq) and tert-butyl(2-hydroxy-1-phenylethyl)carbamate (141 mg, 630 mol, 1.0 eq) in toluene (10 mL) was degassed and purged with N.sub.2 three times. To the mixture were added TMAD (326 mg, 1.89 mmol, 3.0 eq), PPh.sub.3 (496 mg, 1.89 mmol, 3.0 eq), and the mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)-1-phenylethyl)carbamate (150 mg, 280 mol, 44% yield) was obtained as a yellow oil. M+H.sup.+=537.4 (LCMS).

Step 2: 5-(2-Amino-2-phenylethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 367)

[1153] To a solution of tert-butyl(2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)-1-phenylethyl)carbamate (150 mg, 280 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Amino-2-phenylethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (73.2 mg, 155 mol, 55% yield, HCl salt) was obtained as a white solid. M+H.sup.+=437.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.63 (br s, 4H), 7.98-7.90 (m, 1H), 7.82 (t, J=8.3 Hz, 2H), 7.59-7.41 (m, 8H), 7.06 (d, J=8.6 Hz, 1H), 6.90 (dd, J=2.4, 8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 4.74-4.65 (m, 1H), 4.26-4.12 (m, 2H), 1.96 (s, 3H), 1.34 (br s, 2H), 1.17 (br s, 2H).

Example 75: 5-(2-Amino-3-phenylpropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 322)

##STR00910##

Step 1: tert-Butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)-3-phenylpropan-2-yl)carbamate (75A-1)

[1154] A mixture of 5-hydroxy-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (80.0 mg, 252 mol, 1.0 eq), tert-butyl N-(1-benzyl-2-hydroxy-ethyl)carbamate (63.3 mg, 252 mol, 1.0 eq) and CMBP (91.2 mg, 378 mol, 1.5 eq) in toluene (4.0 mL) was degassed and purged with N.sub.2 atmosphere, and then the mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.4). tert-Butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)-3-phenylpropan-2-yl)carbamate (80.0 mg, 145 mol, 58% yield) was obtained as a white solid. M+H.sup.+=551.2 (LCMS).

Step 2: 5-(2-Amino-3-phenylpropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 322)

[1155] To a mixture of tert-butyl N-[1-benzyl-2-[4-methyl-3-[1-(1-naphthyl)cyclopropyl]carbamoyl]phenoxy]ethyl]carbamate (70.0 mg, 127 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Amino-3-phenyl-propoxy)-2-methyl-N-[1-(1-naphthyl)cyclopropyl]benzamide (25.0 mg, 51.7 mol, 41% yield, HCl salt) was obtained as a white solid. M+H.sup.+=451.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.64 (br d, J=8.4 Hz, 1H), 8.25 (br s, 3H), 7.94 (br d, J=7.8 Hz, 1H), 7.83 (br t, J=7.8 Hz, 2H), 7.60-7.40 (m, 3H), 7.36-7.17 (m, 5H), 7.05 (br d, J=8.4 Hz, 1H), 6.88-6.78 (m, 1H), 6.63 (br s, 1H), 4.00-3.61 (m, 3H), 3.14-2.88 (m, 2H), 1.95 (s, 3H), 1.43-1.04 (m, 4H).

Example 76: 5-(2-Amino-2-methylpropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 352)

##STR00911##

Step 1: tert-Butyl(2-methyl-1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)propan-2-yl)carbamate (76A-1)

[1156] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) in DMF (5.0 mL) was added sodium hydride (18.9 mg, 473 mol, 60% purity, 1.5 eq) under a N.sub.2 atmosphere, the mixture was stirred at 0 C. for 30 min, then tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (119 mg, 473 mol, 1.5 eq) was added. The resulting mixture was stirred at 70 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.7). tert-Butyl(2-methyl-1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) propan-2-yl)carbamate (140 mg, 287 mol, 91% yield) was obtained as a yellow solid. 1H NMR (400 MHZ, CDCl.sub.3) 8.48 (d, J=8.6 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.54-7.45 (m, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.79 (dd, J=2.6, 8.3 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 6.48 (br s, 1H), 3.84 (s, 2H), 2.10 (s, 3H), 1.46-1.38 (m, 13H), 1.35 (s, 6H).

Step 2: 5-(2-Amino-2-methylpropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 352)

[1157] To a solution of tert-butyl(2-methyl-1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy) propan-2-yl)carbamate (80.0 mg, 164 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-(2-amino-2-methylpropoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (38.6 mg, 90.7 mol, 55% yield) as a brown solid. M+H.sup.+=389.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.18 (br d, J=1.9 Hz, 3H), 7.93 (d, J=8.0 Hz, 1H), 7.86-7.77 (m, 2H), 7.64-7.39 (m, 3H), 7.07 (d, J=8.5 Hz, 1H), 6.89 (dd, J=2.6, 8.3 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 3.87 (s, 2H), 1.96 (s, 3H), 1.36 (s, 2H), 1.29 (s, 6H), 1.22-1.12 (m, 2H).

Example 77: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 256)

##STR00912##

Step 1: tert-Butyl(1-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)cyclopropyl)carbamate (77A-1)

[1158] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 586 mol, 1.0 eq) and tert-butyl(1-(hydroxymethyl)cyclopropyl)carbamate (165 mg, 879 mol, 1.5 eq) in toluene (2.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added CMBP (212 mg, 879 mol, 1.5 eq) in portions at 25 C. The resulting mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl(1-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)cyclopropyl)carbamate (150 mg, 308 mol, 53% yield) was obtained as a yellow oil. M+H.sup.+=487.2 (LCMS).

Step 2: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 256)

[1159] To a stirred solution of tert-butyl(1-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)cyclopropyl)carbamate (150 mg, 308 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (69.2 mg, 179 mol, 68% yield, HCl salt) was obtained as a white solid. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.71 (br s, 3H), 8.59 (br d, J=8.3 Hz, 1H), 7.95 (d, J=7.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.51-7.41 (m, 3H), 7.37 (br s, 1H), 6.82-6.72 (m, 2H), 6.68 (br d, J=7.2 Hz, 1H), 3.80 (s, 2H), 1.99 (s, 3H), 1.53 (br s, 2H), 1.34 (br s, 2H), 1.19 (s, 2H), 0.68 (br s, 2H).

Example 78: 5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 274)

##STR00913##

Step 1: tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (78A-1)

[1160] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 945 mol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (177 mg, 945 mol, 1.0 eq) in toluene (15 mL) was added CMBP (342 mg, 1.42 mmol, 1.5 eq). The mixture was degassed and purged with N.sub.2 three times and then the mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (300 mg, 617 mol, 65% yield) was obtained as a colorless oil. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.50 (d, J=8.4 Hz, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.82 (dd, J=2.6, 8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.64 (s, 1H), 4.43 (br dd, J=2.9, 5.1 Hz, 1H), 4.22-4.15 (m, 1H), 4.04-3.96 (m, 1H), 3.87 (t, J=7.6 Hz, 2H), 2.12 (s, 3H), 2.06 (s, 2H), 1.57 (s, 2H), 1.40 (br s, 2H), 1.36 (s, 9H).

Step 2: 5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 274)

[1161] To a solution of tert-butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (100 mg, 206 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.00 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (30.1 mg, 71.2 mol, 35% yield, HCl salt) was obtained as a white solid. M+H.sup.+=387.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.37 (s, 1H), 9.15 (m, 2H), 8.67 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.86-7.78 (m, 2H), 7.62-7.42 (m, 3H), 7.08 (d, J=8.6 Hz, 1H), 6.90 (dd, J=2.7, 8.4 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 4.63 (br d, J=6.0 Hz, 1H), 4.29 (dd, J=7.5, 11.2 Hz, 1H), 4.13 (dd, J=3.2, 11.1 Hz, 1H), 3.95-3.76 (m, 2H), 2.47-2.26 (m, 2H), 1.97 (s, 3H), 1.36 (s, 2H), 1.23-1.13 (m, 2H).

Example 79: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 310)

##STR00914##

Step 1: (S)-tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (79A-1)

[1162] To a mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) and(S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (59.0 mg, 315 mol, 1.0 eq) in toluene (5.0 mL) was added CMBP (114 mg, 473 mol, 1.5 eq). The resulting mixture was degassed and purged with N.sub.2 three times and then was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). (S)-tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine-1-carboxylate (130 mg, 267 mol, 85% yield) was obtained as a yellow solid. M+H.sup.+=487.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.50 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.64-7.43 (m, 3H), 7.05-6.95 (m, 1H), 6.88-6.73 (m, 2H), 6.64 (br s, 1H), 4.48-4.38 (m, 1H), 4.22-4.15 (m, 1H), 4.03-3.96 (m, 1H), 3.87 (br t, J=7.2 Hz, 2H), 2.38-2.17 (m, 2H), 2.12 (s, 3H), 1.57-1.53 (m, 2H), 1.46-1.31 (m, 11H).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (79A-2)

[1163] To a solution of(S)-tert-butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (130 mg, 267 mol, 1.0 eq) in DCM (10 mL) was added TFA (2.5 mL). The resulting mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give crude product(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 199 mol, 78% yield, TFA salt) as a yellow gum, which was used in the next step without any further purification. M+H.sup.+=387.2 (LCMS).

Step 3: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 310)

[1164] To a stirred solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 259 mol, 1.0 eq, TFA salt) in MeOH (5.0 mL) were added TEA (26.2 mg, 259 mol, 36.0 L, 1.0 eq) and formaldehyde (42.0 mg, 517 mol, 38.5 L, 37% purity in aqueous, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6, and then NaBH.sub.3CN (32.5 mg, 517 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (44.3 mg, 110 mol, 43% yield) as a white solid. M+H.sup.+=401.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.66 (br d, J=8.4 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.82 (t, J=7.6 Hz, 2H), 7.61-7.41 (m, 3H), 7.02 (d, J=8.5 Hz, 1H), 6.82 (dd, J=2.5, 8.3 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 3.85 (d, J=5.4 Hz, 2H), 3.27-3.15 (m, 2H), 2.79-2.67 (m, 1H), 2.21 (s, 3H), 2.04-1.90 (m, 4H), 1.89-1.77 (m, 1H), 1.36 (br s, 2H), 1.17 (br s, 2H).

Example 80: (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 309)

##STR00915##

Step 1: (R)-tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (80A-1)

[1165] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) and (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (59.0 mg, 315 mol, 3.97 L, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added CMBP (114 mg, 473 mol, 1.5 eq) at 20 C. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (R)-tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (280 mg, 575 mol, 91% yield) was obtained as a white solid. M+H.sup.+=487.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.86-7.79 (m, 2H), 7.60-7.42 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.6, 8.4 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 4.43-4.33 (m, 1H), 4.13 (dd, J=4.9, 10.3 Hz, 1H), 3.98 (dd, J=2.9, 10.3 Hz, 1H), 3.72 (br d, J=6.6 Hz, 2H), 2.31-2.21 (m, 1H), 2.12-2.01 (m, 1H), 1.95 (s, 3H), 1.38-1.35 (m, 2H), 1.35-1.26 (m, 9H), 1.17 (s, 2H).

Step 2: (R)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (80A-2)

[1166] To a stirred solution of (R)-tert-butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (280 mg, 575 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (5.6 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product (R)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (280 mg, crude, TFA salt) as a white solid. M+H.sup.+==387.1 (LCMS).

Step 3: (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 309)

[1167] To a solution of (R)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (140 mg, 280 mol, 1.0 eq, TFA salt) in MeOH (6.0 mL) was added TEA (39.0 L), followed by the addition of formaldehyde (45.4 mg, 559 mol, 41.7 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (35.2 mg, 559 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (30.3 mg, 75.7 mol, 27% yield) was obtained as a colorless oil. M+H.sup.+=401.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.95-7.89 (m, 1H), 7.85-7.78 (m, 2H), 7.59-7.42 (m, 3H), 7.01 (d, J=8.5 Hz, 1H), 6.82 (dd, J=2.8, 8.4 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 3.85 (d, J=5.5 Hz, 2H), 3.27-3.16 (m, 2H), 2.75-2.68 (m, 1H), 2.20 (s, 3H), 1.98-1.90 (m, 4H), 1.89-1.78 (m, 1H), 1.38-1.33 (m, 2H), 1.19-1.13 (m, 2H).

Example 81: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 387)

##STR00916##

Step 1: tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (81A-1)

[1168] To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (592 mg, 3.16 mmol, 1.1 eq) in toluene (15 mL) were added TMAD (1.55 g, 9.03 mmol, 3.0 eq) and PPh.sub.3 (2.37 g, 9.03 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M56+H.sup.+=280.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.50-7.47 (m, 1H), 7.17-7.12 (m, 1H), 7.03-6.97 (m, 1H), 4.56-4.45 (m, 1H), 4.34-4.24 (m, 1H), 4.13 (br d, J=4.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.95 (br s, 4H), 2.55-2.51 (m, 3H), 2.42-2.20 (m, 2H), 1.47-1.40 (m, 9H).

Step 2: Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (81A-2)

[1169] To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (800 mg, 2.39 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.26 g, 28.6 mmol, 2.12 mL, 12 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (800 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification as a yellow oil. M+H.sup.+=236.1 (LCMS).

Step 3: Methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (81A-3)

[1170] To a solution of (methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (400 mg, 1.03 mmol, 1.0 eq, TFA salt) in MeOH (8.0 mL) was added TEA (80.0 L), followed by formaldehyde (335 mg, 4.12 mmol, 307 L, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (518 mg, 8.25 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=250.1 (LCMS).

Step 4: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (81A-4)

[1171] A solution of methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (300 mg, 1.20 mmol, 1.0 eq) in HCl (2 M aqueous, 9.00 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H.sub.2O (10 mL) and washed with MTBE (20 mL2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (10 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to give the crude product 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (220 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=236.1 (LCMS).

Step 5: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 387)

[1172] To a solution of 2-methyl-5-[(1-methylazetidin-2-yl)methoxy]benzoic acid (50.0 mg, 212 mol, 1.0 eq) in DMF (2.0 mL) was added 3-(1-naphthyl)oxetan-3-amine (42.3 mg, 213 mol, 1.0 eq), followed by HATU (88.9 mg, 234 mol, 1.1 eq) and DIEA (82.4 mg, 638 mol, 111 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15040 mm, 10 m); flow rate: 60 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (23.6 mg, 56.3 mol, 27% yield) was obtained as a yellow solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.69 (s, 1H), 8.01-7.95 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (br d, J=6.8 Hz, 2H), 7.57-7.47 (m, 3H), 7.04 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.8, 8.4 Hz, 1H), 6.66 (d, J=2.8 Hz, 1H), 5.30-5.18 (m, 4H), 3.86 (d, J=5.4 Hz, 2H), 3.28-3.17 (m, 2H), 2.75-2.68 (m, 1H), 2.21 (s, 3H), 1.94 (s, 4H), 1.89-1.79 (m, 1H).

Example 82: (S)-2-Methyl-5-(2-(methylamino)ethoxy)-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 349)

##STR00917##

Step 1: (S)-tert-Butyl methyl(2-(4-methyl-3-((2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (82A-1)

[1173] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (100 mg, 323 mol, 1.0 eq), (S)-2,2,2-trifluoro-1-(naphthalen-1-yl)ethanamine (72.8 mg, 323 mol, 1.0 eq) in ACN (5.0 mL) were added TCFH (109 mg, 388 mol, 1.2 eq) and 1-methylimidazole (92.9 mg, 1.13 mmol, 90.2 L, 3.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. (S)-tert-Butyl methyl(2-(4-methyl-3-((2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)ethyl) carbamate (90.0 mg, 174 mol, 54% yield) was obtained as a colorless oil.

Step 2: (S)-2-Methyl-5-(2-(methylamino)ethoxy)-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (Compound 349)

[1174] To a solution of(S)-tert-butyl methyl(2-(4-methyl-3-((2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (90.0 mg, 174 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-(2-(methylamino)ethoxy)-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)benzamide (43.6 mg, 96.2 mol, 55% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.82 (d, J=9.3 Hz, 1H), 8.98 (br s, 2H), 8.28 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.93 (d, J=7.3 Hz, 1H), 7.72-7.66 (m, 1H), 7.65-7.58 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 7.01 (dd, J=2.7, 8.4 Hz, 1H), 6.90-6.79 (m, 2H), 4.22 (t, J=5.0 Hz, 2H), 3.28 (t, J=4.9 Hz, 2H), 2.59 (s, 3H), 2.20 (s, 3H).

Example 83: 5-((1-Ethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 314)

##STR00918##

Step 1: 5-((1-Ethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 314)

[1175] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 259 mol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of acetaldehyde (57.0 mg, 517 mol, 72.6 L, 40% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (32.5 mg, 517 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((1-Ethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (23.7 mg, 51.5 mol, 35% yield, FA salt) was obtained as a white solid. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.10 (s, 1H), 8.63 (d, J=8.3 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.81 (dd, J=7.8, 10.1 Hz, 2H), 7.60-7.40 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.82 (dd, J=2.8, 8.4 Hz, 1H), 6.59 (d, J=2.7 Hz, 1H), 3.98-3.85 (m, 2H), 3.61-3.55 (m, 1H), 3.39 (dt, J=2.4, 8.0 Hz, 1H), 2.92 (br d, J=8.1 Hz, 1H), 2.72-2.66 (m, 1H), 2.46-2.39 (m, 1H), 2.09-1.99 (m, 1H), 1.94 (s, 4H), 1.34 (br s, 2H), 1.16 (br s, 2H), 0.87 (t, J=7.2 Hz, 3H).

Example 84: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-(2,2,2-trifluoroethyl)azetidin-2-yl)methoxy)benzamide (Compound 396)

##STR00919##

Step 1: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-(2,2,2-trifluoroethyl)azetidin-2-yl)methoxy)benzamide (Compound 396)

[1176] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 259 mol, 1.0 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (60.0 mg, 259 mol, 1.0 eq) in DMF (10 mL) was added TEA (157 mg, 1.55 mmol, 216 L, 6.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified preparative HPLC (Phenomenex C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-(2,2,2-trifluoroethyl)azetidin-2-yl)methoxy)benzamide (14.2 mg, 29.9 mol, 12% yield) was obtained as a white solid. M+H.sup.+=469.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.65 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.82 (t, J=8.3 Hz, 2H), 7.63-7.40 (m, 3H), 7.02 (d, J=8.6 Hz, 1H), 6.83 (dd, J=2.7, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.73-3.62 (m, 1H), 3.44-3.35 (m, 2H), 3.22-3.04 (m, 2H), 2.10-1.96 (m, 2H), 1.94 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 85: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-phenylazetidin-2-yl)methoxy)benzamide (Compound 331)

##STR00920##

Step 1: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-phenylazetidin-2-yl)methoxy)benzamide (Compound 331)

[1177] To a mixture of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 300 mol, 1.0 eq, TFA salt), phenylboronic acid (43.9 mg, 360 mol, 1.2 eq) in DCE (10 mL) were added Cu(OAc) 2 (60.0 mg, 330 mol, 1.1 eq), TEA (121 mg, 1.20 mmol, 167 L, 4.0 eq), and 4 molecular sieve (70.0 mg, 1.20 mmol, 4.0 eq). The mixture was degassed and purged with O.sub.2 three times and then it was stirred at 80 C. for 16 h under an O.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (20040 mm, 3 m); flow rate: 25 mL/min; gradient: 65%-98% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-((1-phenylazetidin-2-yl)methoxy)benzamide (140 mg, 334 mol, 77% yield) as a white solid. M+H.sup.+=463.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.14 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.82 (t, J=7.4 Hz, 2H), 7.60-7.42 (m, 3H), 7.13 (t, J=7.9 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.89 (dd, J=2.6, 8.3 Hz, 1H), 6.73-6.64 (m, 2H), 6.60 (d, J=7.9 Hz, 2H), 4.26 (br t, J=6.2 Hz, 1H), 4.12 (d, J=5.0 Hz, 2H), 3.93-3.86 (m, 1H), 3.55 (q, J=7.8 Hz, 1H), 2.40-2.30 (m, 1H), 2.29-2.18 (m, 1H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.17 (br s, 2H).

Example 86: 5-((1-Benzylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 330)

##STR00921##

Step 1: 5-((1-Benzylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 330)

[1178] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 200 mol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of benzaldehyde (21.2 mg, 200 mol, 158 L, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-((1-Benzylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (33.0 mg, 69.2 mol, 35% yield) was obtained as a white solid. M+H.sup.+=477.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.66 (br d, J=8.4 Hz, 1H), 7.92 (br d, J=7.8 Hz, 1H), 7.82 (br t, J=6.4 Hz, 2H), 7.59-7.43 (m, 3H), 7.25-7.18 (m, 4H), 7.18-7.11 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.76 (dd, J=2.5, 8.3 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 3.87-3.71 (m, 3H), 3.54-3.40 (m, 2H), 3.17 (br t, J=6.2 Hz, 1H), 2.79 (q, J=7.9 Hz, 1H), 2.01 (br d, J=8.4 Hz, 1H), 1.95 (s, 3H), 1.92-1.83 (m, 1H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 87: 5-((1-Isopropylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 323)

##STR00922##

Step 1: 5-((1-Isopropylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 323)

[1179] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 99.9 mol, 50% purity, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of acetone (11.6 mg, 200 mol, 14.7 L, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (12.6 mg, 200 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((1-Isopropylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (18.5 mg, 43.1 mol, 43% yield) was obtained as a white solid. M+H.sup.+=429.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.54 (d, J=8.4 Hz, 1H), 7.96 (dd, J=0.9, 7.0 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.63-7.55 (m, 1H), 7.54-7.44 (m, 2H), 7.02-6.97 (m, 1H), 6.95-6.84 (m, 1H), 6.73 (s, 2H), 4.47-4.28 (m, 1H), 4.17-3.74 (m, 3H), 3.45-3.29 (m, 1H), 3.04-2.88 (m, 1H), 2.31 (br d, J=2.1 Hz, 2H), 2.12 (s, 3H), 1.62-1.53 (m, 2H), 1.45-1.35 (m, 2H), 1.29-1.13 (m, 6H).

Example 88: 5-((1-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 332)

##STR00923##

Step 1: 5-((1-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 332)

[1180] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 200 mol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 L), followed by the addition of cyclopropanecarbaldehyde (28.0 mg, 400 mol, 30.0 L, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, and then NaBH.sub.3CN (25.1 mg, 400 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((1-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalene-1-yl)cyclopropyl)benzamide (13.3 mg, 30.2 mol, 15% yield, FA salt) was obtained as a white solid. M+H.sup.+=441.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.79 (m, 1H), 9.10 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.83 (t, J=7.9 Hz, 2H), 7.61-7.40 (m, 3H), 7.08 (d, J=8.3 Hz, 1H), 6.90 (dd, J=2.6, 8.4 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.70 (br s, 1H), 4.33-4.15 (m, 2H), 4.06-3.89 (m, 2H), 3.23-3.12 (m, 1H), 3.02-2.87 (m, 1H), 2.43-2.25 (m, 2H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.19 (br s, 2H), 0.95 (br s, 1H), 0.52 (td, J=4.3, 8.6 Hz, 2H), 0.41-0.19 (m, 2H).

Example 89: 5-((1-(2-Methoxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 348)

##STR00924##

Step 1: 5-((1-(2-Methoxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 348)

[1181] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 388 mol, 1.0 eq) in ACN (6.0 mL) was added K.sub.2CO.sub.3 (161 mg, 1.16 mmol, 3.0 eq). The mixture was stirred at 20 C. for 30 min, then 1-bromo-2-methoxyethane (80.9 mg, 582 mol, 54.7 L, 1.5 eq) was added. The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-((1-(2-Methoxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (27.4 mg, 54.8 mol, 14% yield, HCl salt) was obtained as a white solid. M+H.sup.+=445.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.53 (br d, J=3.8 Hz, 1H), 9.15 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.2 Hz, 2H), 7.60-7.43 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (dd, J=2.5, 8.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 4.78-4.63 (m, 1H), 4.38 (dd, J=8.3, 11.1 Hz, 1H), 4.16 (dd, J=3.2, 11.2 Hz, 1H), 3.96-3.89 (m, 2H), 3.62-3.55 (m, 1H), 3.54-3.46 (m, 1H), 3.43-3.32 (m, 2H), 3.18 (s, 3H), 2.42-2.22 (m, 2H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 90: 5-((1-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 341)

##STR00925##

Step 1: 5-((1-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 341)

[1182] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 517 mol, 1.0 eq) and 2-bromoethanol (64.7 mg, 517 mol, 36.7 L, 1.0 eq) in ACN (5.0 mL) was added K.sub.2CO.sub.3 (215 mg, 1.55 mmol, 3.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((1-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (32.9 mg, 68.5 mol, 13% yield, FA salt) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.67 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.87-7.79 (m, 2H), 7.62-7.42 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.7, 8.3 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.95-3.84 (m, 2H), 3.44 (br d, J=3.4 Hz, 1H), 3.39-3.29 (m, 3H), 2.88 (br d, J=8.1 Hz, 1H), 2.69 (td, J=6.1, 11.9 Hz, 1H), 2.45 (br dd, J=6.1, 11.8 Hz, 1H), 2.06-1.85 (m, 5H), 1.37 (s, 2H), 1.22-1.11 (m, 2H).

Example 91: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 394)

##STR00926##

Step 1: tert-Butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (91A-1)

[1183] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 945 mol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)-2-methylazetidine-1-carboxylate (190 mg, 945 mol, 1.0 eq) in toluene (18 mL) were added TMAD (488 mg, 2.84 mmol, 3.0 eq), PPh.sub.3 (744 mg, 2.84 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (370 mg, 246 mol, 26% yield) was obtained as a yellow solid. M+H.sup.+=501.3 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.53 (br s, 1H), 8.00-7.93 (m, 1H), 7.90 (br d, J=8.1 Hz, 1H), 7.79 (s, 1H), 7.62-7.54 (m, 1H), 7.54-7.44 (m, 2H), 7.05-6.94 (m, 1H), 6.85-6.62 (m, 3H), 4.13-4.02 (m, 1H), 3.90-3.67 (m, 3H), 2.44-2.31 (m, 1H), 2.19-2.08 (m, 3H), 1.99-1.89 (m, 1H), 1.58 (br d, J=17.9 Hz, 3H), 1.52-1.40 (m, 4H), 1.36-1.22 (m, 9H).

Step 2: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 394)

[1184] To a stirred solution of tert-butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (180 mg, 360 mol, 1.0 eq) in DCM (9.0 mL) was added TFA (3.6 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (13.5 mg, 25.9 mol, 7% yield, HCl salt) was obtained as a brown solid. M+H.sup.+=401.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 9.02-8.85 (m, 1H), 8.82-8.58 (m, 2H), 7.97-7.90 (m, 1H), 7.87-7.80 (m, 2H), 7.61-7.42 (m, 3H), 7.14-7.05 (m, 1H), 6.96-6.89 (m, 1H), 6.75-6.69 (m, 1H), 4.21-4.13 (m, 1H), 4.01-3.94 (m, 1H), 3.88-3.73 (m, 2H), 2.46 (br d, J=10.8 Hz, 1H), 2.26 (br s, 1H), 2.01-1.93 (m, 3H), 1.61-1.52 (m, 3H), 1.41-1.33 (m, 2H), 1.22-1.13 (m, 2H).

Example 92: 5-(2-Hydroxyethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 393)

##STR00927##

Step 1: 5-(2-Hydroxyethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 393)

[1185] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 221 mol, 1.0 eq) and 1,3-dioxolan-2-one (38.9 mg, 441 mol, 2.0 eq) in toluene (3.5 mL) was added K.sub.2CO.sub.3 (61.0 mg, 441 mol, 2.0 eq), the mixture was degassed and purged with N.sub.2 three times and stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Welch Ultimate XB SIO.sub.2 (10030 mm, 10 m); flow rate: 40 mL/min; gradient: 5%-95% B over 10 min; mobile phase A: heptane, mobile phase B: EtOH). 5-(2-Hydroxyethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (30.9 mg, 81.9 mol, 37% yield) was obtained as a brown solid. M+H.sup.+=362.0 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.14-9.02 (m, 1H), 8.70-8.62 (m, 1H), 7.98-7.89 (m, 1H), 7.86-7.78 (m, 2H), 7.61-7.41 (m, 3H), 7.06-6.99 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.58 (m, 1H), 4.83-4.76 (m, 1H), 3.92-3.84 (m, 2H), 3.69-3.60 (m, 2H), 2.01-1.92 (m, 3H), 1.40-1.31 (m, 2H), 1.21-1.12 (m, 2H).

Example 93: 5-(2-Amino-2-oxoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 285)

##STR00928##

Step 1: 5-(2-Amino-2-oxoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 285)

[1186] To a solution of 2-iodoacetamide (61.2 mg, 331 mol, 1.5 eq) in acetone (10 mL) was added K.sub.2CO.sub.3 (91.5 mg, 662 mol, 3.0 eq). The mixture was stirred at 20 C. for 30 min. 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 221 mol, 1.0 eq) was added. The mixture was stirred at 90 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-Amino-2-oxoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (37.2 mg, 99.4 mol, 45% yield) was obtained as a white solid. M+H.sup.+=375.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.82 (dd, J=3.1, 7.6 Hz, 2H), 7.60-7.42 (m, 4H), 7.33 (br s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.34 (s, 2H), 1.95 (s, 3H), 1.35 (s, 2H), 1.17 (s, 2H).

Example 94: 5-(Azetidin-3-yloxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 171)

##STR00929##

Step 1: tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) azetidine-1-carboxylate (94A-1)

[1187] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (59.7 mg, 326 mol, 1.0 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-2-methylbenzoic acid (100 mg, 326 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (98.8 mg, 978 mol, 136 L, 3.0 eq), EDCI (62.4 mg, 489 mol, 1.5 eq) and HOBt (43.8 mg, 489 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (20 mL) and extracted with DCM (15 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.4). tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)azetidine-1-carboxylate (90.0 mg, 190 mol, 65% yield) was obtained as a brown solid. M+H.sup.+=473.2 (LCMS).

Step 2: 5-(Azetidin-3-yloxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 171)

[1188] To a solution of tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)azetidine-1-carboxylate (80.0 mg, 169 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 319 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-yloxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 82.2 mol, 49% yield, TFA salt) was obtained as a white solid. M+H.sup.+=373.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.24-9.20 (m, 1H), 8.60-8.56 (m, 1H), 7.93-7.89 (m, 2H), 7.84-7.81 (m, 1H), 7.62-7.43 (m, 3H), 7.12-7.08 (m, 1H), 6.80-6.76 (m, 1H), 6.54-6.51 (m, 1H), 5.06-5.00 (m, 1H), 4.46-4.41 (m, 2H), 4.07 (br s, 2H), 2.00 (s, 3H), 1.47-1.43 (m, 2H), 1.33-1.31 (m, 2H).

Example 95: 5-(3-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 265)

##STR00930##

Step 1: tert-Butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)cyclobutyl)carbamate (95A-1)

[1189] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 630 mol, 1.0 eq) and tert-butyl(3-hydroxycyclobutyl)carbamate (177 mg, 945 mol, 1.5 eq) in toluene (3.0 mL) was added CMBP (228 mg, 945 mol, 1.5 eq) at 25 C. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)cyclobutyl)carbamate (300 mg), which was used in the next step without any further purification. M+H.sup.+=431.1 (LCMS).

Step 2: 5-(3-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 265)

[1190] To a mixture of tert-butyl(3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)cyclobutyl)carbamate (300 mg, 617 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(3-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (96.3 mg, 249 mol, 40% yield, HCl salt) was obtained as a white solid. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (d, J=4.4 Hz, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.35 (br d, J=10.9 Hz, 3H), 7.93 (d, J=8.2 Hz, 1H), 7.86-7.76 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.50 (m, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.08-6.98 (m, 1H), 6.77-6.67 (m, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.97-4.40 (m, 1H), 3.77-3.31 (m, 1H), 2.77-2.65 (m, 1H), 2.60-2.52 (m, 1H), 2.38-2.28 (m, 1H), 2.20-2.09 (m, 1H), 1.96 (d, J=3.7 Hz, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 96: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 263)

##STR00931##

Step 1: tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (96A-1)

[1191] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 473 mol, 1.0 eq), tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate (95.1 mg, 473 mol, 1.0 eq) and CMBP (171 mg, 709 mol, 1.5 eq) in toluene (8.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (200 mg, 400 mol, 85% yield) was obtained as a yellow oil. M+H.sup.+=429.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.53-8.46 (m, 1H), 7.98-7.93 (m, 1H), 7.92-7.87 (m, 1H), 7.83-7.77 (m, 1H), 7.60-7.45 (m, 3H), 7.02-6.96 (m, 1H), 6.67 (br s, 3H), 4.09-4.00 (m, 1H), 3.82-3.65 (m, 1H), 3.46-3.28 (m, 2H), 2.12 (s, 3H), 2.01-1.82 (m, 4H), 1.60 (s, 7H), 1.49-1.43 (m, 6H).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 263)

[1192] To a stirred solution of tert-butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl) pyrrolidine-1-carboxylate (100 mg, 200 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 10 mL) at 0 C. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-65% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)benzamide (51.3 mg, 117 mol, 59% yield, HCl salt) was obtained as a white solid. M+H.sup.+=401.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.53-9.36 (m, 1H), 9.12 (s, 1H), 8.88 (br dd, J=1.7, 3.6 Hz, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.86-7.80 (m, 2H), 7.61-7.44 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.6, 8.4 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 4.18-4.11 (m, 1H), 4.08-4.00 (m, 1H), 3.82 (br d, J=2.9 Hz, 1H), 3.16 (br s, 2H), 2.14-2.01 (m, 1H), 1.97 (s, 3H), 1.95-1.81 (m, 2H), 1.73-1.63 (m, 1H), 1.36 (s, 2H), 1.21-1.15 (m, 2H).

Example 97: 2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 283)

##STR00932##

Step 1: 2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 283)

[1193] To a solution of 2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)benzamide (160 mg, 200 mol, 1.0 eq) in MeOH (4 mL) was added TEA (200 L), followed by the addition of formaldehyde (32.4 mg, 400 mol, 29.8 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (25.1 mg, 400 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give 2-methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (35.9 mg, 86.6 mol, 43% yield) as a yellow gum. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.65 (s, 1H), 7.96-7.90 (m, 1H), 7.85-7.79 (m, 2H), 7.59-7.42 (m, 3H), 7.04-6.99 (m, 1H), 6.82 (dd, J=2.8, 8.4 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 3.91-3.68 (m, 2H), 2.92 (td, J=4.3, 9.1 Hz, 1H), 2.53-2.52 (m, 1H), 2.30 (s, 3H), 2.15 (d, J=8.5 Hz, 1H), 2.07-1.73 (m, 4H), 1.72-1.59 (m, 2H), 1.57-1.45 (m, 1H), 1.40-1.32 (m, 2H), 1.22-1.10 (m, 2H).

Example 98: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-3-yloxy)benzamide (Compound 268)

##STR00933##

Step 1: tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) piperidine-1-carboxylate (98A-1)

[1194] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 630 mol, 1.0 eq) and tert-butyl 3-hydroxypiperidine-1-carboxylate (190 mg, 945 mol, 1.5 eq) in toluene (3.0 mL) was added CMBP (228 mg, 945 mol, 1.5 eq) at 25 C. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) piperidine-1-carboxylate (125 mg), which was used in the next step without any further purification. M+H.sup.+=445.2 (LCMS).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-3-yloxy)benzamide (Compound 268)

[1195] To a mixture of tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy) piperidine-1-carboxylate (125 mg, 250 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-3-yloxy)benzamide (42.4 mg, 106 mol, 42% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=401.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d) 9.32-9.20 (m, 1H), 9.14 (s, 1H), 8.65 (br d, J=8.3 Hz, 2H), 7.93 (d, J=7.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.61-7.49 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.62 (br s, 1H), 3.28-3.16 (m, 1H), 3.15-3.04 (m, 1H), 3.00 (br s, 2H), 1.95 (s, 3H), 1.87-1.77 (m, 2H), 1.77-1.69 (m, 1H), 1.62 (br t, J=10.4 Hz, 1H), 1.36 (s, 2H), 1.23-1.12 (m, 2H).

Example 99: 2-Methyl-5-((1-methylpiperidin-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 289)

##STR00934##

Step 1: 2-Methyl-5-((1-methylpiperidin-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 289)

[1196] To a solution of 2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-3-yloxy)benzamide (15.0 mg, 37.5 mol, 1.0 eq) in MeOH (1.0 mL) was added TEA (300 L), followed by the addition of formaldehyde (2.25 mg, 74.9 mol, 2.06 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (4.71 mg, 74.9 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were washed with brine (3.0 mL3), dried over Na.sub.2SO.sub.4, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylpiperidin-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (4.70 mg, 11.3 mol, 30% yield) was obtained as a white solid. M+H.sup.+=415.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.97-7.74 (m, 3H), 7.61-7.43 (m, 3H), 7.01 (d, J=8.4 Hz, 1H), 6.86-6.81 (m, 1H), 6.59 (d, J=2.5 Hz, 1H), 4.27-4.20 (m, 1H), 2.75 (br d, J=8.4 Hz, 1H), 2.14 (s, 3H), 2.03-1.60 (m, 8H), 1.56-1.42 (m, 1H), 1.35 (br s, 2H), 1.25 (br d, J=11.0 Hz, 1H), 1.17 (br s, 2H).

Example 100: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-2-ylmethoxy)benzamide (Compound 339)

##STR00935##

Step 1: tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)piperidine-1-carboxylate (100A-1)

[1197] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (450 mg, 1.42 mmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl) piperidine-1-carboxylate (915 mg, 4.26 mmol, 3.0 eq) in toluene (15 mL) were added TMAD (732 mg, 4.26 mmol, 3.0 eq) and PPh.sub.3 (1.12 g, 4.26 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (12 mL) and extracted with EtOAc (9.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl) piperidine-1-carboxylate (113 mg, 15% yield) was obtained as a white solid. M+H.sup.+=515.3 (LCMS).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-2-ylmethoxy)benzamide (Compound 339)

[1198] To a solution of tert-butyl 2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl) piperidine-1-carboxylate (113 mg, 220 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-2-ylmethoxy)benzamide (15.7 mg, 34.8 mol, 16% yield, HCl salt) was obtained as a white solid. M+H.sup.+=415.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 9.15-9.09 (m, 1H), 8.65 (d, J=8.6 Hz, 1H), 7.98-7.91 (m, 1H), 7.86-7.80 (m, 2H), 7.60-7.44 (m, 3H), 7.11-7.06 (m, 1H), 6.93-6.87 (m, 1H), 6.69-6.65 (m, 1H), 4.13-4.02 (m, 1H), 3.98-3.87 (m, 1H), 3.49-3.41 (m, 1H), 3.23 (br d, J=14.1 Hz, 1H), 2.98-2.83 (m, 1H), 1.97 (s, 3H), 1.87-1.68 (m, 3H), 1.59-1.44 (m, 3H), 1.39-1.33 (m, 2H), 1.20-1.17 (m, 2H).

Example 101: 2-Methyl-5-((1-methylpiperidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 288) and 2-methyl-5-((1-methylazepan-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 293)

##STR00936##

Step 1: 2-Methyl-5-((1-methylpiperidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 288) and 2-methyl-5-((1-methylazepan-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 293)

[1199] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 221 mol, 1.0 eq) and (1-methylpiperidin-2-yl) methanol (28.5 mg, 221 mol, 29.0 L, 1.0 eq) in toluene (3.5 mL) was added CMBP (80.0 mg, 331 mol, 1.5 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylpiperidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (12.3 mg, 28.7 mol, 13% yield) was obtained as a yellow solid. M+H.sup.+=429.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.68-8.63 (m, 1H), 7.96-7.90 (m, 1H), 7.87-7.78 (m, 2H), 7.62-7.42 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.7, 8.3 Hz, 1H), 6.62-6.57 (m, 1H), 3.93 (br d, J=4.5 Hz, 1H), 3.78 (br d, J=4.9 Hz, 1H), 2.76-2.68 (m, 1H), 2.19-2.08 (m, 4H), 1.95 (s, 4H), 1.66 (br d, J=10.0 Hz, 2H), 1.57-1.47 (m, 1H), 1.45-1.10 (m, 7H). 2-Methyl-5-((1-methylazepan-3-yl)oxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (17.6 mg, 41.1 mol, 19% yield) was obtained as a white solid. M+H.sup.+=429.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.74-8.58 (m, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.8, 11.7 Hz, 2H), 7.61-7.41 (m, 3H), 7.11-6.95 (m, 1H), 6.79 (dd, J=2.8, 8.4 Hz, 1H), 6.54 (d, J=2.6 Hz, 1H), 4.49-4.27 (m, 1H), 2.79-2.63 (m, 2H), 2.61-2.56 (m, 1H), 2.47-2.35 (m, 1H), 2.26-2.17 (m, 3H), 2.02-1.93 (m, 3H), 1.92-1.83 (m, 1H), 1.69-1.52 (m, 4H), 1.48-1.40 (m, 1H), 1.38-1.30 (m, 2H), 1.20-1.09 (m, 2H).

Example 102: 2-Methyl-5-(morpholin-3-ylmethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 286)

##STR00937##

Step 1: tert-Butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)morpholine-4-carboxylate (102A-1)

[1200] To a solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq) and tert-butyl 3-(hydroxymethyl) morpholine-4-carboxylate (68.5 mg, 315 mol, 1.0 eq) in toluene (5.0 mL) was added CMBP (114 mg, 473 mol, 1.5 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). tert-Butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl) morpholine-4-carboxylate (40.0 mg, 77.4 mol, 25% yield) was obtained as a yellow oil. M+H.sup.+=517.2 (LCMS).

Step 2: 2-Methyl-5-(morpholin-3-ylmethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 286)

[1201] To a solution of tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenoxy)methyl) morpholine-4-carboxylate (40.0 mg, 77.4 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(morpholin-3-ylmethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (22.9 mg, 49.9 mol, 65% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.56-9.41 (m, 1H), 9.40-9.24 (m, 1H), 9.13 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.83 (dd, J=4.1, 7.6 Hz, 2H), 7.64-7.42 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.6, 8.4 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.18-3.87 (m, 4H), 3.75-3.56 (m, 3H), 3.26-3.07 (m, 2H), 1.96 (s, 3H), 1.40-1.34 (m, 2H), 1.21-1.15 (m, 2H).

Example 103: 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 302)

##STR00938##

Step 1: 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 302)

[1202] To a solution of 2-methyl-5-(morpholin-3-ylmethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 96.0 mol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (15.6 mg, 192 mol, 14.3 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (12.1 mg, 192 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclo propyl)benzamide (22.9 mg, 52.1 mol, 54% yield, FA salt) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.82 (t, J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.7 Hz, 1H), 4.00 (dd, J=4.2, 10.3 Hz, 1H), 3.81-3.73 (m, 2H), 3.71-3.63 (m, 1H), 3.48 (dt, J=2.4, 10.7 Hz, 1H), 3.28 (dd, J=9.5, 10.9 Hz, 1H), 2.68-2.59 (m, 1H), 2.37-2.30 (m, 1H), 2.26-2.13 (m, 4H), 1.95 (s, 3H), 1.35 (s, 2H), 1.21-1.12 (m, 2H).

Example 105: 5-((Hexahydro-1H-pyrrolizin-7a-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 376)

##STR00939##

Step 1: 5-((Hexahydro-1H-pyrrolizin-7a-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 376)

[1203] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (70.0 mg, 221 mol, 1.0 eq), (hexahydro-1H-pyrrolizin-7a-yl) methanol (62.3 mg, 441 mol, 2.0 eq) TMAD (114 mg, 662 mol, 3.0 eq) and PPh.sub.3 (174 mg, 662 mol, 3.0 eq) in toluene (5.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give 5-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclo propyl)benzamide (17.1 mg, 38.6 mol, 18% yield) as a yellow solid. M+H.sup.+=441.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.67 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.88-7.75 (m, 2H), 7.61-7.40 (m, 3H), 6.98-6.95 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.81 (dd, J=2.7, 8.3 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 3.51 (s, 2H), 2.95-2.83 (m, 2H), 2.56-2.51 (m, 2H), 1.95 (s, 3H), 1.87-1.63 (m, 6H), 1.60-1.46 (m, 2H), 1.41-1.31 (m, 2H), 1.23-1.11 (m, 2H).

Example 106: 5-(2-(Dimethylamino)ethoxy)-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 303)

##STR00940##

Step 1: 5-Hydroxy-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (106A-2)

[1204] To a solution of 5-hydroxy-2-methoxybenzoic acid (100 mg, 595 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (109 mg, 595 mol, 1.0 eq) in DMF (3.0 mL) was added TEA (60.2 mg, 595 mol, 82.8 L, 1.0 eq), followed by EDCI (120 mg, 625 mol, 1.1 eq) and HOBt (16.1 mg, 119 mol, 0.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.5). 5-Hydroxy-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (120 mg) was obtained as a yellow oil. M+H.sup.+=334.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 303)

[1205] To a solution of 5-hydroxy-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (120 mg, 360 mol, 1.0 eq) and 2-(dimethylamino) ethanol (35.3 mg, 396 mol, 39.7 L, 1.1 eq) in toluene (4.0 mL) was added CMBP (95.6 mg, 396 mol, 1.1 eq). The mixture was degassed and purged with N.sub.2 three times, and then was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (81.0 mg, 181 mol, 50% yield) was obtained as a brown solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.98-8.92 (m, 1H), 8.63-8.55 (m, 1H), 7.97-7.90 (m, 1H), 7.86-7.76 (m, 2H), 7.67-7.59 (m, 1H), 7.57-7.38 (m, 2H), 7.09-7.03 (m, 1H), 6.99-6.91 (m, 2H), 3.97-3.89 (m, 2H), 3.74-3.65 (m, 3H), 2.56-2.54 (m, 2H), 2.24-2.10 (m, 6H), 1.42-1.35 (m, 2H), 1.24-1.15 (m, 2H).

Example 107: 2-Bromo-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 269)

##STR00941##

Step 1: Methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (107A-2)

[1206] To a solution of 2-chloro-N,N-dimethylethanamine (1.25 g, 8.66 mmol, 1.0 eq, HCl salt) in DMF (10 mL) was added K.sub.2CO.sub.3 (5.98 g, 43.3 mmol, 5.0 eq). The mixture was stirred at 25 C. for 30 min, then 18-crown-6 (3.62 g, 13.7 mmol, 1.6 eq), KI (2.41 g, 14.5 mmol, 1.7 eq) and methyl 2-bromo-5-hydroxybenzoate (2.00 g, 8.66 mmol, 1.0 eq) were added. The mixture was stirred at 70 C. for 5 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) at 25 C. and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (570 mg, 1.32 mmol, 22% yield) was obtained as a white solid. M+H.sup.+=302.0 (LCMS).

Step 2: 2-Bromo-5-(2-(dimethylamino)ethoxy)benzoic acid (107A-3)

[1207] A mixture of methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (570 mg, 1.89 mmol, 1.0 eq) in HCl (2 M aqueous, 15 mL) was stirred at 100 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with DCM/MeOH (V/V=10/1, 15 mL) then filtered. The filter cake was washed with DCM/MeOH (15 mL2) to ensure that all product was washed from the solids. The combined organic layers were concentrated under vacuum to give the crude product 2-bromo-5-(2-(dimethylamino)ethoxy)benzoic acid (500 mg), which was used in the next step without any further purification. M+H.sup.+=288.1 (LCMS).

Step 3: 2-Bromo-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 269)

[1208] To a solution of 2-bromo-5-(2-(dimethylamino)ethoxy)benzoic acid (100 mg, 292 mol, 1.2 eq) in DCM (1.0 mL) were added 1-(naphthalen-1-yl)cyclopropanamine (44.5 mg, 243 mol, 1.0 eq), EDCI (69.9 mg, 364 mol, 1.5 eq), HOBt (49.2 mg, 364 mol, 1.5 eq) and TEA (73.8 mg, 729 mol, 101 L, 3.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) at 25 C. and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Bromo-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (17.2 mg, 37.9 mol, 16% yield, HCl salt) was obtained as a white solid. M+H.sup.+=453.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.45-10.29 (m, 1H), 9.31 (s, 1H), 8.62 (d, J=8.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.58-7.44 (m, 4H), 6.98-6.93 (m, 1H), 6.74 (d, J=3.1 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.45-3.39 (m, 2H), 2.76 (d, J=4.8 Hz, 6H), 1.40 (s, 2H), 1.21-1.14 (m, 2H).

Example 108: 5-(2-(Dimethylamino)ethoxy)-2-ethynyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 337)

##STR00942##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-2-((trimethylsilyl)ethynyl)benzamide (108A-1)

[1209] To a solution of 2-bromo-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 408 mol, 1.0 eq, HCl salt) in a mixture of toluene (16 mL) and H.sub.2O (4.0 mL) were added ethynyltrimethylsilane (80.2 mg, 816 mol, 113 L, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (28.7 mg, 40.8 mol, 0.1 eq), CuI (7.78 mg, 40.8 mol, 0.1 eq) and TEA (207 mg, 2.04 mmol, 284 L, 5.0 eq) under a N.sub.2 atmosphere. The resulting mixture was stirred at 80 C. for 16 h. LCMS indicated that 48% of the starting material remained and 32% of desired product was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 70%-98% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-2-((trimethylsilyl)ethynyl)benzamide (50.0 mg, 106 mol, 26% yield) was obtained as a white solid. M+H.sup.+=471.2 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-ethynyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 337)

[1210] To a solution of 5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-2-((tri methylsilyl)ethynyl)benzamide (40.0 mg, 84.9 mol, 1.0 eq) in MeOH (2.0 mL) was added Cs.sub.2CO.sub.3 (138 mg, 425 mol, 5.0 eq). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-ethynyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (9.70 mg, 20.6 mol, 24% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=399.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.39 (br s, 1H), 9.19 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.86-7.79 (m, 2H), 7.60-7.41 (m, 4H), 7.01 (dd, J=2.6, 8.6 Hz, 1H), 6.81 (d, J=2.6 Hz, 1H), 4.32 (t, J=4.9 Hz, 2H), 3.89 (s, 1H), 3.43 (br d, J=4.6 Hz, 2H), 2.77 (d, J=4.5 Hz, 6H), 1.44-1.39 (m, 2H), 1.21-1.15 (m, 2H).

Example 109: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 353)

##STR00943##

Step 1: Methyl 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoate (109A-1)

[1211] To a solution of methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (200 mg, 662 mol, 1.0 eq) and cyclopropylboronic acid (171 mg, 1.99 mmol, 3.0 eq) in a mixture of toluene (10 mL) and H.sub.2O (1.0 mL) were added K.sub.3PO.sub.4 (422 mg, 1.99 mmol, 3.0 eq), PCy.sub.3 (9.28 mg, 33.1 mol, 10.7 L, 0.05 eq) and Pd(OAc) 2 (7.43 mg, 33.1 mol, 0.05 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.4). Methyl 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoate (100 mg, 380 mol, 57% yield) was obtained as a yellow oil. M+H.sup.+=264.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.35 (s, 1H), 6.98 (s, 2H), 4.07 (br t, J=4.9 Hz, 2H), 3.92 (s, 3H), 2.74 (br t, J=4.9 Hz, 2H), 2.58-2.46 (m, 1H), 2.35 (s, 6H), 0.93 (br d, J=8.4 Hz, 2H), 0.61 (br d, J=5.5 Hz, 2H).

Step 2: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoic acid (109A-2)

[1212] To a solution of methyl 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoate (90.0 mg, 342 mol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (2.5 mL) was added NaOH (2 M in aqueous, 684 L, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and acidified to pH 6 using HCl (1 M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. Then the slurry was treated with DCM/MeOH (V/V=10/1, 10 mL) and stirred for 10 min. The mixture was filtered, and the filter cake was washed with DCM/MeOH=10/1 (5.0 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give crude 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoic acid (85 mg) as a yellow gum. M+H.sup.+=250.1 (LCMS).

Step 3: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 353)

[1213] To a solution of 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoic acid (70.0 mg, 281 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (51.5 mg, 281 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (85.2 mg, 842 mol, 117 L, 3.0 eq), EDCI (64.6 mg, 337 mol, 1.2 eq) and HOBt (45.5 mg, 337 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (27.6 mg, 60.5 mol, 22% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.21-9.75 (m, 1H), 9.14 (s, 1H), 8.65 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.86-7.76 (m, 2H), 7.60-7.38 (m, 3H), 6.90-6.78 (m, 2H), 6.63 (d, J=2.1 Hz, 1H), 4.23 (br s, 2H), 3.43 (q, J=4.7 Hz, 2H), 2.79 (d, J=4.6 Hz, 6H), 1.78-1.61 (m, 1H), 1.37 (br s, 2H), 1.19 (br s, 2H), 0.39-0.20 (m, 4H).

Example 110:3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 311)

##STR00944##

Step 1: 6-Bromo-2-fluoro-3-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (110A-2)

[1214] To a solution of 6-bromo-2-fluoro-3-methoxybenzoic acid (200 mg, 803 mol, 1.2 eq) and 1-(naphthalen-1-yl)cyclopropanamine (123 mg, 669 mol, 1.0 eq) in DMF (3.0 mL) were added TEA (203 mg, 2.01 mmol, 279 L, 3.0 eq), EDCI (154 mg, 803 mol, 2.5 eq) and HOBt (109 mg, 803 mol, 1.2 eq). The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 6-Bromo-2-fluoro-3-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (220 mg, 531 mol, 79% yield) was obtained as a yellow oil. M+H.sup.+=414.1 (LCMS).

Step 2: 2-Fluoro-3-methoxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (110A-3)

[1215] To a solution of 6-bromo-2-fluoro-3-methoxy-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (180 mg, 435 mol, 1.0 eq) in DMF (3.0 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (131 mg, 521 mol, 146 L, 50% purity in THF, 1.2 eq), Cs.sub.2CO.sub.3 (467 mg, 1.43 mmol, 3.3 eq), and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (355 mg, 435 mol, 1.0 eq). The reaction mixture was degassed and purged with N.sub.2 three times and then stirred at 115 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-3-methoxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (220 mg, 531 mol, 79% yield) was obtained as a yellow oil. M+H.sup.+=350.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.44 (d, J=8.4 Hz, 1H), 7.95-7.87 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.62-7.41 (m, 6H), 3.80 (s, 3H), 1.95 (s, 3H), 1.61 (br d, J=1.9 Hz, 2H), 1.42-1.36 (m, 2H).

Step 3: 2-Fluoro-3-hydroxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (110A-4)

[1216] To a solution of 2-fluoro-3-methoxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (90.0 mg, 258 mol, 1.0 eq) in DCM (5.0 mL) was added a solution of BBr.sub.3 (968 mg, 3.86 mmol, 372 L, 15 eq) in DCM (1.0 mL) dropwise at 78 C. The resulting mixture was stirred at the same temperature for 1 h, warmed to 20 C. and stirred for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-3-hydroxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 119 mol, 46% yield) was obtained as a yellow oil. M+H.sup.+=336.1 (LCMS).

Step 4:3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 311)

[1217] To a solution of 2-fluoro-3-hydroxy-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (30.0 mg, 890 mol, 1.0 eq) in DMF (3.0 mL) was added K.sub.2CO.sub.3 (61.8 mg, 447 mol, 5.0 eq). The mixture was stirred at 20 C. for 30 min. To the reaction mixture were added 2-chloro-N,N-dimethylethanamine (12.9 mg, 89.5 mol, 1.0 eq, HCl salt), 18-crown-6 (37.8 mg, 143 mol, 1.6 eq) and KI (25.2 mg, 152 mol, 1.7 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (4.10 mg, 8.67 mol, 10% yield, FA salt) was obtained as a white solid. M+H.sup.+=407.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.35 (s, 1H), 8.56 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.96-7.89 (m, 1H), 7.87-7.76 (m, 2H), 7.62-7.40 (m, 3H), 7.02 (t, J=8.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.03 (t, J=5.7 Hz, 2H), 2.57 (t, J=5.7 Hz, 2H), 2.18 (s, 6H), 1.78 (s, 3H), 1.31 (br s, 2H), 1.21-1.14 (m, 2H).

Example 111: 5-Amino-4-iodo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 216)

##STR00945##

Step 1: 5-Amino-4-iodo-2-methylbenzoic acid (111A-1)

[1218] To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (200 mg, 687 mol, 1.0 eq) in MeOH (10 mL) was added NaOH (2 M in aqueous, 1.03 mL, 3.0 eq). The mixture was stirred at 25 C. for 2 h and then was stirred another 2 h at 70 C. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and acidified to pH 6 with HCl (1 M aqueous), and a precipitate was formed. The mixture was filtered and the solid was washed with H.sub.2O (5.0 mL), dried under vacuum to give 5-amino-4-iodo-2-methylbenzoic acid (180 mg, 650 mol, 95% yield) as a white solid, which was used in the next step without any further purification. M+H.sup.+=278.0 (LCMS).

Step 2: 5-Amino-4-iodo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 216)

[1219] To a solution of 5-amino-4-iodo-2-methylbenzoic acid (130 mg, 469 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (86.0 mg, 469 mol, 1.0 eq) in DMF (7.0 mL) were added TEA (142 mg, 1.41 mmol, 196 L, 3.0 eq), EDCI (180 mg, 938 mol, 2.0 eq) and HOBt (127 mg, 938 mol, 2.0 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H.sub.2O (5.0 mL), dried under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-4-iodo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (28.4 mg, 64.2 mol, 20% yield) was obtained as a white solid. M+H.sup.+=442.9 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.44 (d, J=8.4 Hz, 1H), 8.00-7.87 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.65-7.44 (m, 3H), 7.39 (s, 1H), 6.49 (s, 1H), 6.44 (br s, 1H), 3.91 (br s, 2H), 2.03 (s, 3H), 1.56-1.52 (m, 2H), 1.42-1.34 (m, 2H).

Example 112:4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 369)

##STR00946##

Step 1: Methyl 4-bromo-5-hydroxy-2-methylbenzoate (112A-1)

[1220] To a solution of methyl 5-hydroxy-2-methylbenzoate (200 mg, 1.20 mmol, 1.0 eq) in DCM (2.0 mL) was added K.sub.2CO.sub.3 (175 mg, 1.26 mmol, 1.05 eq) at 25 C. The mixture was degassed and purged with N.sub.2 three times. To this mixture was added a solution of Br.sub.2 (192 mg, 1.20 mmol, 62.0 L, 1.0 eq) in DCM (4.0 mL) at 15 C. dropwise. After the addition was completed, the mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with DCM (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.6). Methyl 4-bromo-5-hydroxy-2-methylbenzoate (160 mg, 54% yield) was obtained as a yellow solid.

Step 2: Methyl 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (112A-2)

[1221] To a solution of 2-chloro-N,N-dimethylethanamine (188 mg, 1.31 mmol, 4.0 eq) in DMF (5.0 mL) was added K.sub.2CO.sub.3 (902 mg, 6.53 mmol, 20 eq) and the reaction mixture was stirred at 20 C. for 30 min. Methyl 4-bromo-5-hydroxy-2-methylbenzoate (80.0 mg, 326 mol, 1.0 eq), 18-crown-6 (545 mg, 2.06 mmol, 6.3 eq) and KI (364 mg, 2.19 mmol, 6.7 eq) were added in sequence. The resulting mixture was stirred at 70 C. for 11 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Water Xbridge BEH C18 (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). Methyl 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (88.0 mg, 273 mol, 84% yield) was obtained as a yellow solid. M+H.sup.+=316.0 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38 (s, 1H), 7.37 (s, 1H), 4.09 (s, 2H), 3.82 (s, 3H), 2.76 (s, 2H), 2.43 (s, 3H), 2.33 (s, 6H).

Step 3:4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (112A-3)

[1222] To a solution of methyl 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (68.0 mg, 215 mol, 1.0 eq) in a mixture of MeOH (2.7 mL) and THF (1.4 mL) was added NaOH (2 M aqueous, 1.4 mL, 12.7 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with MTBE (2.0 mL2). The aqueous layer was acidified to pH 6 using HCl (1 M aqueous). The mixture was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (60.0 mg, 199 mol, 92% yield) as a yellow solid. M+H.sup.+=302.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.53 (s, 1H), 7.38 (s, 1H), 4.52-4.38 (m, 2H), 3.36-3.24 (m, 2H), 2.78 (s, 6H), 2.53 (s, 3H).

Step 4:4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 369)

[1223] To a solution of 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 165 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (24.3 mg, 132 mol, 0.8 eq) in DMF (2.5 mL) were added TEA (33.5 mg, 331 mol, 46.1 L, 2.0 eq), EDCI (47.6 mg, 248 mol, 1.5 eq) and HOBt (33.5 mg, 331 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (15.6 mg, 30.9 mol, 19% yield, HCl salt) was obtained as a white solid. M+H.sup.+=467.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 13.08-12.84 (m, 1H), 8.67-8.57 (m, 1H), 8.01-7.92 (m, 1H), 7.92-7.86 (m, 1H), 7.83-7.76 (m, 1H), 7.67-7.58 (m, 1H), 7.54-7.43 (m, 2H), 7.01 (s, 1H), 6.87 (br s, 1H), 4.51 (br d, J=1.4 Hz, 2H), 3.59-3.24 (m, 2H), 2.95 (br s, 6H), 2.10 (s, 3H), 1.64-1.55 (m, 2H), 1.45-1.35 (m, 2H).

Example 113: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 366)

##STR00947##

Step 1: 2-((4-Iodo-5-methylpyridin-2-yl)oxy)-N,N-dimethylethanamine (113A-2)

[1224] To a solution of 2-(dimethylamino) ethanol (1.69 g, 19.0 mmol, 3.0 eq) in NMP (10 mL) was added NaH (759 mg, 19.0 mmol, 60% purity, 3.0 eq) at 0 C., the reaction mixture was stirred at 25 C. for 30 min. 2-Fluoro-4-iodo-5-methyl-pyridine (1.50 g, 6.33 mmol, 1.0 eq) was added to the solution, and the reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-75% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give 2-((4-iodo-5-methylpyridin-2-yl)oxy)-N,N-dimethylethanamine (600 mg, 2.00 mmol, 31% yield) as a white oil. M+H.sup.+=307.0 (LCMS).

Step 2: Methyl 2-(2-(dimethylamino)ethoxy)-5-methylisonicotinate (113A-3)

[1225] A mixture of 2-[(4-iodo-5-methyl-2-pyridyl)oxy]-N,N-dimethyl-ethanamine (400 mg, 1.31 mmol, 1.0 eq), Pd(OAc) 2 (29.3 mg, 131 mol, 0.1 eq), DPPF (72.4 mg, 131 mol, 0.1 eq) and TEA (661 mg, 6.53 mmol, 909 L, 5.0 eq) in MeOH (10 mL) was stirred at 80 C. for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under vacuum to give a residue which was purified by preparative TLC ((EtOAc/petroleum ether=1/1, R.sub.f=0.4). Methyl 2-[2-(dimethylamino)ethoxy]-5-methyl-pyridine-4-carboxylate (300 mg, 1.00 mmol, 96% yield) was obtained as a brown oil. M+H.sup.+=239.1 (LCMS).

Step 3: 2-(2-(Dimethylamino)ethoxy)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl) isonicotinamide (Compound 366)

[1226] To a mixture of methyl 2-[2-(dimethylamino)ethoxy]-5-methyl-pyridine-4-carboxylate (100 mg, 400 mol, 1.0 eq) and 1-(1-naphthyl)cyclopropanamine (76.9 mg, 400 mol, 1.0 eq) in toluene (2.0 mL) was added AlMe.sub.3 (2 M in toluene, 600 L, 3.0 eq) at 0 C. The reaction mixture was stirred at 100 C. for 1 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (100 L) and TFA (100 L), then the reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-[2-(Dimethylamino)ethoxy]-5-methyl-N-[1-(1-naphthyl)cyclopropyl]pyridine-4-carboxamide (48.8 mg, 69.7 mol, 23% yield, TFA salt) was obtained as a white solid. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.52 (br d, J=4.0 Hz, 1H), 9.35 (s, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.01-7.90 (m, 2H), 7.83 (dd, J=7.6, 15.6 Hz, 2H), 7.62-7.40 (m, 3H), 6.52 (s, 1H), 4.55-4.35 (m, 2H), 3.44 (br s, 2H), 2.81 (br s, 6H), 1.93 (s, 3H), 1.39-1.15 (m, 4H).

Example 114: 2-(2-(Dimethylamino)ethoxy)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (Compound 350)

##STR00948##

Step 1: 2-Chloro-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (114A-2)

[1227] To a solution of 2-chloro-5-methylpyrimidine-4-carboxylic acid (150 mg, 869 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (143 mg, 782 mol, 0.8 eq) in DCM (5.0 mL) were added TEA (264 mg, 2.61 mmol, 363 L, 3.0 eq), EDCI (200 mg, 1.04 mmol, 1.2 eq) and HOBt (141 mg, 1.04 mmol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.8). 2-Chloro-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (60.0 mg, 178 mol, 20% yield) was obtained as a yellow oil. M+H.sup.+=338.1 (LCMS).

Step 2: 2-(2-(Dimethylamino)ethoxy)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (Compound 350)

[1228] To a solution of 2-chloro-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (100 mg, 296 mol, 1.0 eq) and 2-(dimethylamino) ethanol (26.4 mg, 210 mol, 29.7 L, 0.7 eq, HCl salt) in DMF (5.0 mL) were added 18-crown-6 (124 mg, 468 mol, 1.6 eq), K.sub.2CO.sub.3 (205 mg, 1.48 mmol, 5.0 eq) and KI (82.6 mg, 497 mol, 1.7 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-(2-(Dimethylamino)ethoxy)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)pyrimidine-4-carboxamide (29.1 mg, 74.0 mol, 25% yield, FA salt) was obtained as a white solid. M+H.sup.+=391.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.45 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.47 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.87-7.80 (m, 2H), 7.62-7.43 (m, 3H), 4.33 (t, J=5.7 Hz, 2H), 2.54 (s, 2H), 2.16-2.11 (m, 9H), 1.41 (s, 2H), 1.21 (br s, 2H).

Example 115: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl) nicotinamide (Compound 275)

##STR00949##

Step 1: Ethyl 5-(2-(dimethylamino)ethoxy)-2-methylnicotinate (115A-2)

[1229] A mixture of ethyl 5-hydroxy-2-methylnicotinate (300 mg, 1.66 mmol, 1.0 eq) and 2-bromo-N,N-dimethylethanamine (262 mg, 1.82 mmol, 1.1 eq, HCl) in DMF (10 mL) was degassed and purged with N.sub.2 three times. To the mixture were added 18-crown-6 (691 mg, 2.62 mmol, 1.6 eq), KI (462 mg, 2.78 mmol, 1.7 eq) and K.sub.2CO.sub.3 (1.1 g, 8.28 mmol, 5.0 eq). The resulting mixture was stirred at 70 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 200/1 to 10/1. Ethyl 5-(2-(dimethylamino)ethoxy)-2-methylnicotinate (200 mg, 380 mol, 48% yield) was obtained as a white solid. M+H.sup.+=253.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.35 (d, J=3.0 Hz, 1H), 7.74 (d, J=3.0 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.22-4.12 (m, 2H), 2.76 (s, 3H), 2.42 (br s, 6H), 1.41 (t, J=7.1 Hz, 3H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylnicotinic acid (115A-3)

[1230] A solution of ethyl 5-(2-(dimethylamino)ethoxy)-2-methylnicotinate (160 mg, 634 mol, 1.0 eq) in HCl (2 M aqueous, 5.0 mL) was stirred at 100 C. for 14 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-2-methylnicotinic acid (160 mg), which was used in the next step without any further purification. M+H.sup.+=225.2 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl) nicotinamide (Compound 275)

[1231] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylnicotinic acid (100 mg, 446 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (82.0 mg, 446 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (135 mg, 1.34 mmol, 186 L, 3.0 eq), EDCI (128 mg, 669 mol, 1.5 eq) and HOBt (90.0 mg, 669 mol, 1.5 eq). The mixture was stirred at 20 C. for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl) nicotinamide (60.0 mg, 155 mol, 35% yield, FA salt) was obtained as a white solid. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.04 (d, J=2.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.73 (t, J=7.3 Hz, 2H), 7.51-7.32 (m, 3H), 6.97 (d, J=3.0 Hz, 1H), 3.94 (t, J=5.7 Hz, 2H), 2.43-2.37 (m, 3H), 2.08 (s, 6H), 2.02 (s, 3H), 1.33-1.24 (m, 2H), 1.13-1.05 (m, 2H).

Example 116: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 199)

##STR00950##

Step 1: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 199)

[1232] To a solution of 5-methyl-1H-indole-6-carboxylic acid (140 mg, 800 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (146 mg, 799 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (243 mg, 2.40 mmol, 300 L, 3.0 eq), EDCI (383 mg, 2.00 mmol, 2.5 eq) and HOBt (267 mg, 2.00 mmol, 2.5 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (200 mg, 512 mol, 64% yield. HCl salt) was obtained as a white solid. M+H.sup.+=341.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.20-10.85 (m, 1H), 9.02 (s, 1H), 8.82-8.61 (m, 1H), 7.99-7.90 (m, 1H), 7.87-7.80 (m, 2H), 7.64-7.42 (m, 3H), 7.34-7.29 (m, 1H), 7.26-7.23 (m, 1H), 7.11 (s, 1H), 6.29 (br s, 1H), 2.22-2.10 (m, 3H), 1.44-1.31 (m, 2H), 1.23-1.10 (m, 2H).

Example 117: 2-(Methoxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 240)

##STR00951##

Step 1: Methyl 5-amino-4-(3-methoxyprop-1-yn-1-yl)-2-methylbenzoate (117A-1)

[1233] To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq) in TEA (10 mL) were added 3-methoxyprop-1-yne (120 mg, 1.72 mmol, 1.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (120 mg, 172 mol, 0.1 eq) and CuI (16.4 mg, 85.9 mol, 0.1 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5-amino-4-(3-methoxyprop-1-yn-1-yl)-2-methylbenzoate (400 mg, 1.54 mmol, 90% yield) was obtained as a yellow oil. M+H.sup.+=234.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.36-7.34 (m, 1H), 7.23 (s, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 3.53 (s, 3H), 2.53-2.48 (m, 3H).

Step 2: Methyl 2-(methoxymethyl)-5-methyl-1H-indole-6-carboxylate (117A-2)

[1234] To a solution of methyl 5-amino-4-(3-methoxyprop-1-yn-1-yl)-2-methylbenzoate (350 mg, 1.50 mmol, 1.0 eq) in DCE (6.0 mL) was added Cu(OAc) 2 (545 mg, 3.00 mmol, 2.0 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 130 C. for 2 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, filtered and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). Methyl 2-(methoxymethyl)-5-methyl-1H-indole-6-carboxylate (180 mg, 772 mol, 51% yield) was obtained as a yellow oil. M+H.sup.+=234.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.41 (br s, 1H), 8.03 (s, 1H), 7.41 (s, 1H), 6.37 (s, 1H), 4.63 (s, 2H), 3.91 (s, 3H), 3.41 (s, 3H), 2.68 (s, 3H).

Step 3: 2-(Methoxymethyl)-5-methyl-1H-indole-6-carboxylic acid (117A-3)

[1235] To a solution of methyl 2-(methoxymethyl)-5-methyl-1H-indole-6-carboxylate (90.0 mg, 386 mol, 1.0 eq) in a mixture of MeOH (4.0 mL) and THF (2.0 mL) was added NaOH (2 M, 1.0 mL, 5.2 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with MTBE (2.0 mL3). The aqueous layer was basified to pH 4 using HCl (1 M aqueous) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(methoxymethyl)-5-methyl-1H-indole-6-carboxylic acid (60.0 mg), which was used in the next step without any further purification. M+H.sup.+=220.0 (LCMS).

Step 4: 2-(Methoxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 240)

[1236] To a solution of 2-(methoxymethyl)-5-methyl-1H-indole-6-carboxylic acid (60.0 mg, 274 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (50.2 mg, 274 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (83.1 mg, 821 mol, 114 L, 3.0 eq), EDCI (78.7 mg, 411 mol, 1.5 eq) and HOBt (55.5 mg, 411 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Methoxymethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (5.20 mg, 12.3 mol, 5% yield, HCl salt) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.23-10.99 (m, 1H), 9.02 (s, 1H), 8.70 (d, J=8.9 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.7 Hz, 2H), 7.61-7.43 (m, 3H), 7.20 (s, 1H), 7.04 (s, 1H), 6.24 (s, 1H), 4.47 (s, 2H), 3.23 (s, 3H), 2.13 (s, 3H), 1.36 (s, 2H), 1.17 (br d, J=1.1 Hz, 2H).

Example 118: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (Compound 180)

##STR00952##

Step 1: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (Compound 180)

[1237] To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (210 mg, 690 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (139 mg, 759 mol, 1.1 eq) in DCM (5.0 mL) was added TEA (209 mg, 2.07 mmol, 288 L, 3.0 eq), followed by HOBt (140 mg, 1.04 mmol, 1.5 eq) and EDCI (198 mg, 1.04 mmol, 1.5 eq). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (8.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (270 mg, 533 mol, 77% yield) was obtained as a white solid. M+H.sup.+=470.1 (LCMS); 1H NMR (400 MHZ, CD.sub.3OD) 8.68-8.60 (m, 1H), 7.93-7.86 (m, 2H), 7.83-7.77 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.46-7.41 (m, 1H), 7.21-7.15 (m, 1H), 7.11-7.03 (m, 1H), 6.17-6.10 (m, 1H), 4.35-4.25 (m, 2H), 2.17-2.12 (m, 3H), 1.47-1.42 (m, 11H), 1.32-1.21 (m, 2H).

Example 119: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 170)

##STR00953##

Step 1: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 170)

[1238] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (200 mg, 426 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 60 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (130 mg, 352 mol, 83% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=370.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.67-8.56 (m, 1H), 7.94-7.87 (m, 2H), 7.84-7.78 (m, 1H), 7.61-7.41 (m, 3H), 7.29-7.25 (m, 1H), 7.14-7.10 (m, 1H), 6.47-6.44 (m, 1H), 4.24-4.19 (m, 2H), 2.17-2.13 (m, 3H), 1.50-1.43 (m, 2H), 1.35-1.27 (m, 2H).

Example 120: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-2-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 248)

##STR00954##

Step 1: 1-(Naphthalen-2-yl)cyclopropanamine (120A-2)

[1239] A mixture of 2-naphthonitrile (2.00 g, 13.1 mmol, 307 L, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (4.08 g, 14.4 mmol, 4.24 mL, 1.1 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 9.57 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (3.71 g, 26.1 mmol, 3.22 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(Naphthalen-2-yl)cyclopropanamine (400 mg, 2.03 mmol, 16% yield) was obtained as a yellow solid. M+H.sup.+=184.1 (LCMS).

Step 2: tert-Butyl((5-methyl-6-((1-(naphthalen-2-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (120A-3)

[1240] To a solution of 1-(naphthalen-2-yl)cyclopropanamine (150 mg, 819 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (299 mg, 982 mol, 1.2 eq) in DCM (2.0 mL) were added EDCI (235 mg, 1.23 mmol, 1.5 eq), HOBt (166 mg, 1.23 mmol, 1.5 eq) and TEA (248 mg, 2.46 mmol, 342 L, 3.0 eq). The mixture was stirred at 25 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) at 25 C. and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl((5-methyl-6-((1-(naphthalen-2-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (150 mg, 256 mol, 31% yield) was obtained as a yellow solid. M+H.sup.+=470.3 (LCMS).

Step 3: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-2-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 248)

[1241] To a mixture of tert-butyl((5-methyl-6-((1-(naphthalen-2-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (100 mg, 213 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (2 M, 10 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-2-yl)cyclopropyl)-1H-indole-6-carboxamide (65.0 mg, 176 mol, 83% yield, HCl salt) was obtained as a white solid. M+H.sup.+=370.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.37 (s, 1H), 9.03 (s, 1H), 8.53 (br s, 3H), 7.89-7.78 (m, 4H), 7.51-7.37 (m, 5H), 6.49 (s, 1H), 4.20 (s, 2H), 2.40 (s, 3H), 1.37 (br d, J=10.5 Hz, 4H).

Example 121: 2-(Aminomethyl)-5-methyl-N-(1-phenylcyclopropyl)-1H-indole-6-carboxamide (Compound 246)

##STR00955##

Step 1: tert-Butyl((5-methyl-6-((1-phenylcyclopropyl)carbamoyl)-1H-indol-2-yl)methyl) carbamate (121A-1)

[1242] To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (80.0 mg, 263 mol, 1.0 eq) and 1-phenylcyclopropanamine (35.0 mg, 263 mol, 1.0 eq) in DCM (5.0 mL) was added TEA (79.8 mg, 789 mol, 110 L, 3.0 eq), followed by EDCI (75.6 mg, 394 mol, 1.5 eq) and HOBt (53.3 mg, 394 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (8.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.5). tert-Butyl((5-methyl-6-((1-phenylcyclopropyl) carbamoyl)-1H-indol-2-yl)methyl)carbamate (80.0 mg, 191 mol, 73% yield) was obtained as a yellow oil. M+H.sup.+=420.2 (LCMS).

Step 2: 2-(Aminomethyl)-5-methyl-N-(1-phenylcyclopropyl)-1H-indole-6-carboxamide (Compound 246)

[1243] To a solution of tert-butyl((5-methyl-6-((1-phenylcyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (80.0 mg, 191 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-phenylcyclopropyl)-1H-indole-6-carboxamide (9.20 mg, 21.2 mol, 11% yield, TFA salt) was obtained as a white solid. M+H.sup.+=320.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 11.19-11.04 (m, 1H), 8.91-8.82 (m, 1H), 8.29-8.19 (m, 2H), 7.51-7.42 (m, 1H), 7.40-7.14 (m, 6H), 6.60-6.12 (m, 1H), 4.23-4.13 (m, 2H), 2.39-2.35 (m, 3H), 1.31-1.20 (m, 4H).

Example 122: N-(1-([1,1-Biphenyl]-4-yl)cyclopropyl)-2-(aminomethyl)-5-methyl-1H-indole-6-carboxamide (Compound 244)

##STR00956##

Step 1: tert-Butyl(1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamate (122A-2)

[1244] A mixture of tert-butyl(1-(4-bromophenyl)cyclopropyl)carbamate (1.00 g, 3.20 mmol, 1.0 eq), phenylboronic acid (781 mg, 6.40 mmol, 2.0 eq) and K.sub.2CO.sub.3 (2 M, 6.41 mL, 4.0 eq) in DMF (30 mL) was degassed and purged with N.sub.2 three times. To the mixture was added Pd(PPh.sub.3).sub.4 (370 mg, 0.32 mmol, 0.1 eq). The resulting mixture was stirred at 90 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. tert-Butyl(1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamate (500 mg, 1.62 mmol, 50% yield) was obtained as a white solid. M56+H.sup.+=254.1 (LCMS).

Step 2: 1-([1,1-Biphenyl]-4-yl)cyclopropanamine (122A-3)

[1245] To a stirred solution of tert-butyl(1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamate (200 mg, 646 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give 1-([1,1-biphenyl]-4-yl)cyclopropanamine (150 mg, 720 mol, 88% yield, HCl salt) as a white solid. M+H.sup.+=210.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.98 (br s, 3H), 7.77-7.61 (m, 4H), 7.56-7.43 (m, 4H), 7.41-7.33 (m, 1H), 1.51-1.35 (m, 2H), 1.23 (s, 2H)

Step 3: tert-Butyl((6-((1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (122A-4)

[1246] To a solution of 1-([1,1-biphenyl]-4-yl)cyclopropanamine (80.8 mg, 329 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (100 mg, 329 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (99.8 mg, 987 mol, 137 L, 3 eq), EDCI (157 mg, 823 mol, 2.5 eq) and HOBt (111 mg, 823 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl((6-((1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (70.0 mg, 141 mol, 43% yield) was obtained as a white solid. M+H.sup.+=496.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.94 (s, 1H), 8.91 (s, 1H), 7.63 (dd, J=7.9, 19.9 Hz, 4H), 7.50-7.42 (m, 3H), 7.41-7.30 (m, 4H), 7.29-7.24 (m, 1H), 6.41-5.88 (m, 1H), 4.55-4.08 (m, 2H), 2.38 (s, 3H), 1.41 (s, 9H), 1.30 (s, 4H).

Step 4: N-(1-([1,1-Biphenyl]-4-yl)cyclopropyl)-2-(aminomethyl)-5-methyl-1H-indole-6-carboxamide (Compound 244)

[1247] To a stirred solution of tert-butyl((6-((1-([1,1-biphenyl]-4-yl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (60.0 mg, 121 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-([1,1-Biphenyl]-4-yl)cyclopropyl)-2-(aminomethyl)-5-methyl-1H-indole-6-carboxamide (24.8 mg, 57.4 mol, 47% yield, HCl salt) was obtained as a white solid. M+H.sup.+=396.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =11.24 (s, 1H), 8.94 (s, 1H), 8.37 (br s, 3H), 7.79-7.56 (m, 4H), 7.54-7.42 (m, 3H), 7.38-7.33 (m, 3H), 6.48 (s, 1H), 4.20 (s, 2H), 2.40 (s, 3H), 1.31 (s, 4H).

Example 123: 2-(Aminomethyl)-N-(1-(3-bromophenyl)cyclopropyl)-5-methyl-1H-indole-6-carboxamide (Compound 232)

##STR00957##

Step 1: tert-Butyl((6-((1-(3-bromophenyl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (123A-2)

[1248] To a solution of 1-(3-bromophenyl)cyclopropanamine (209 mg, 990 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (300 mg, 990 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (299 mg, 2.96 mmol, 412 L, 3.0 eq), EDCI (472 mg, 2.46 mmol, 2.5 eq) and HOBt (333 mg, 2.46 mmol, 2.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl((6-((1-(3-bromophenyl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (200 mg, 401 mol, 41% yield) was obtained as a yellow solid. M+H.sup.+=498.1 (LCMS).

Step 2: 2-(Aminomethyl)-N-(1-(3-bromophenyl)cyclopropyl)-5-methyl-1H-indole-6-carboxamide (Compound 232)

[1249] To a stirred solution of tert-butyl((6-((1-(3-bromophenyl)cyclopropyl)carbamoyl)-5-methyl-1H-indol-2-yl)methyl)carbamate (70.0 mg, 140 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-N-(1-(3-bromophenyl)cyclopropyl)-5-methyl-1H-indole-6-carboxamide (20.0 mg, 46.0 mol, 33% yield, HCl salt) was obtained as a white solid. M+H.sup.+=398.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.95 (s, 1H), 8.56-8.20 (m, 3H), 7.49-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.28 (t, J=7.9 Hz, 1H), 7.23-7.17 (m, 1H), 6.48 (s, 1H), 4.38-4.03 (m, 2H), 2.38 (s, 3H), 1.30 (s, 4H).

Example 124: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 221)

##STR00958## ##STR00959##

Step 1: tert-Butyl methyl(prop-2-yn-1-yl)carbamate (124A-2)

[1250] A mixture of tert-butyl prop-2-yn-1-ylcarbamate (500 mg, 3.22 mmol, 1.0 eq) in THF (15 mL) was degassed and purged with N.sub.2 three times. To the mixture was added sodium hydride (177 mg, 4.43 mmol, 60% purity, 1.5 eq) at 0 C. and the mixture was stirred at the same temperature for 30 min, then Mel (629 mg, 4.43 mmol, 276 L, 1.5 eq) was added. The mixture was stirred at 25 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl methyl(prop-2-yn-1-yl)carbamate (430 mg, 2.54 mmol, 79% yield) as a yellow oil, which was used in the next step without any further purification. .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.13-3.97 (m, 2H), 2.94-2.90 (m, 3H), 2.24-2.19 (m, 1H), 1.49-1.46 (m, 9H).

Step 2: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (124A-3)

[1251] To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (700 mg, 2.40 mmol, 1.0 eq), tert-butyl methyl(prop-2-yn-1-yl)carbamate (427 mg, 2.53 mmol, 1.1 eq), CuI (91.6 mg, 481 mol, 0.2 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (169 mg, 240 mol, 0.1 eq) was added TEA (8.4 mL). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (20 mL) and extracted with DCM (15 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2.

[1252] Methyl 5-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (500 mg, 1.50 mmol, 63% yield) was obtained as a yellow solid. M+H.sup.+=333.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.29-7.27 (m, 1H), 7.15-7.13 (m, 1H), 4.36-4.28 (m, 2H), 3.90-3.85 (m, 3H), 2.99-2.98 (m, 3H), 2.46-2.39 (m, 3H), 1.51-1.47 (m, 9H).

Step 3: Methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (124A-4)

[1253] To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (500 mg, 1.50 mmol, 1.0 eq) in DCE (15 mL) was added Cu(OAc).sub.2 (683 mg, 3.76 mmol, 2.5 eq). The mixture was stirred at 90 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (500 mg, 1.50 mmol, 100% yield) was obtained as yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.13-8.98 (m, 1H), 8.04-7.98 (m, 1H), 7.41-7.37 (m, 1H), 6.36-6.25 (m, 1H), 4.52-4.35 (m, 2H), 3.96-3.85 (m, 3H), 2.90-2.85 (m, 3H), 2.72-2.62 (m, 3H), 1.51 (br s, 9H).

Step 4: 2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (124A-5)

[1254] To a stirred solution of methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (200 mg, 602 mol, 1.0 eq) in a mixture of MeOH (2.0 mL) and THF (6.0 mL) was added NaOH (2 M aqueous, 4.0 mL, 14 eq). The resulting mixture was stirred at 20 C. for 2 h, then at 70 C. for another 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with TBME (5.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with DCM (5.0 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (200 mg) as a red solid, which was used in the next step without any further purification. M+H.sup.+=319.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.42-7.39 (m, 1H), 6.99-6.98 (m, 1H), 6.34-6.32 (m, 1H), 2.89-2.88 (m, 2H), 2.73-2.70 (m, 3H), 2.29-2.27 (m, 3H), 1.44 (s, 9H).

Step 5: tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (124A-6)

[1255] To a solution of 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (200 mg, 314 mol, 1.0 eq) in DCM (8.0 mL) were added 1-(naphthalen-1-yl)cyclopropanamine (57.6 mg, 314 mol, 1.0 eq) and TEA (95.4 mg, 942 mol, 131 L, 3.0 eq), followed by EDCI (90.3 mg, 471 mol, 1.5 eq) and HOBt (63.7 mg, 471 mol, 1.5 eq). The resulting mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL). The product was extracted with DCM (10 mL4) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (60.0 mg, 124 mol, 40% yield) was obtained as a yellow oil. M+H.sup.+=484.3 (LCMS).

Step 6: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 221)

[1256] To a solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (60.0 mg, 124 mol, 1.0 eq) in EtOAc (4.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (10.7 mg, 26.9 mol, 22% yield) was obtained as a white solid. M+H.sup.+=384.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.67-8.60 (m, 1H), 7.95-7.88 (m, 2H), 7.84-7.78 (m, 1H), 7.62-7.55 (m, 1H), 7.54-7.41 (m, 2H), 7.32-7.29 (m, 1H), 7.16-7.12 (m, 1H), 6.55-6.50 (m, 1H), 4.32-4.26 (m, 2H), 2.72-2.67 (m, 3H), 2.20-2.13 (m, 3H), 1.50-1.43 (m, 2H), 1.35-1.27 (m, 2H).

Example 125: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 173)

##STR00960##

Step 1: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 173)

[1257] To a solution of 2-(aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (90.0 mg, 244 mol, 1.0 eq) in MeOH (6.0 mL) was added TEA (50.0 L), followed by the addition of formaldehyde (2.94 g, 36.3 mmol, 2.7 mL, 37% purity in water, 149 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, and then NaBH.sub.3CN (123 mg, 1.95 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (8.0 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (32.8 mg, 81.1 mol, 33% yield, TFA salt) was obtained as a white solid. M+H.sup.+=398.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.20-11.16 (m, 1H), 9.10-9.06 (m, 1H), 8.70-8.63 (m, 1H), 7.97-7.90 (m, 1H), 7.86-7.81 (m, 2H), 7.61-7.43 (m, 3H), 7.33-7.29 (m, 1H), 7.14-7.10 (m, 1H), 6.57-6.52 (m, 1H), 4.38-4.33 (m, 2H), 2.73-2.70 (m, 6H), 2.14-2.11 (m, 3H), 1.39-1.34 (m, 2H), 1.20-1.16 (m, 2H).

Example 126: 2-(1-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 273)

##STR00961## ##STR00962##

Step 1: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methylbenzoate (126A-1)

[1258] To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (400 mg, 1.37 mmol, 1.0 eq), tert-butyl but-3-yn-2-ylcarbamate (244 mg, 1.44 mmol, 90.0 L, 1.1 eq), CuI (5.23 mg, 27.5 mol, 0.02 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (19.3 mg, 27.5 mol, 0.02 eq) was added TEA (3.48 g, 34.4 mmol, 4.78 mL, 25 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methylbenzoate (410 mg, 1.23 mmol, 90% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.32-7.28 (m, 1H), 7.13 (s, 1H), 4.78-4.68 (m, 1H), 3.88-3.85 (m, 3H), 2.47-2.40 (m, 3H), 1.53-1.50 (m, 3H), 1.49-1.44 (m, 9H).

Step 2: Methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (126A-2)

[1259] To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methylbenzoate (410 mg, 1.23 mmol, 1.0 eq) in DCE (30 mL) was added Cu(OAc) 2 (560 mg, 3.09 mmol, 2.5 eq). The mixture was stirred at 130 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with DCM (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (320 mg, 963 mol, 64% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.13-8.96 (m, 1H), 7.94-7.87 (m, 1H), 7.18-7.10 (m, 1H), 6.19-6.12 (m, 1H), 4.90-4.80 (m, 1H), 4.78-4.68 (m, 1H), 3.81-3.78 (m, 3H), 2.61-2.52 (m, 3H), 1.52 (d, J=6.9 Hz, 3H), 1.40-1.35 (m, 9H).

Step 3: 2-(1-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (126A-3)

[1260] To a solution of methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (120 mg, 361 mol, 1.0 eq) in a mixture of THF (7.0 mL) and MeOH (1.8 mL) was added NaOH (2 M in aqueous, 1.8 mL, 10 eq). The mixture was stirred at 20 C. for 16 h. Then stirred at 70 C. for another 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (10 mL2). The aqueous was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with DCM (15 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (90.0 mg, 283 mol, 78% yield) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=319.2 (LCMS).

Step 4: tert-Butyl(1-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (126A-4)

[1261] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (44.0 mg, 240 mol, 1.0 eq) in DCM (5.0 mL) were added 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (90.0 mg, 240 mol, 1.0 eq), TEA (72.9 mg, 721 mol, 100 L, 3.0 eq), EDCI (69.1 mg, 360 mol, 1.5 eq) and HOBt (48.7 mg, 360 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.5). tert-Butyl(1-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (100 mg, 207 mol, 86% yield) was obtained as a yellow oil. M+H.sup.+=484.2 (LCMS).

Step 5: 2-(1-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 273)

[1262] To a solution of tert-butyl(1-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (80.0 mg, 165.43 mol, 1.0 eq) in EtOAc (4.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(1-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (25.0 mg, 59.5 mol, 36% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=384.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.32-11.24 (m, 1H), 9.08-9.01 (m, 1H), 8.76-8.68 (m, 1H), 8.63-8.47 (m, 3H), 7.98-7.90 (m, 1H), 7.87-7.78 (m, 2H), 7.62-7.44 (m, 3H), 7.30-7.23 (m, 1H), 7.14-7.07 (m, 1H), 6.44-6.35 (m, 1H), 4.60-4.49 (m, 1H), 2.19-2.13 (m, 3H), 1.61-1.54 (m, 3H), 1.40-1.35 (m, 2H), 1.22-1.13 (m, 2H).

Example 127: 5-Methyl-2-(morpholin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 260)

##STR00963## ##STR00964##

Step 1: tert-Butyl 3-formylmorpholine-4-carboxylate (127A-2)

[1263] To a stirred solution of (COCl).sub.2 (643 mg, 5.06 mmol, 0.40 mL, 1.1 eq) in DCM (18 mL) was added DMSO (863 mg, 11.1 mmol, 0.80 mL, 2.4 eq) at 78 C. After 15 min, a solution of tert-butyl 3-formylmorpholine-4-carboxylate (1.00 g, 4.60 mmol, 1.0 eq) in DCM (10 mL) was added to the mixture dropwise. The reaction mixture was stirred at 78 C. for another 2 h. TEA (2.33 g, 23.0 mmol, 3.20 mL, 5.0 eq) was added and the reaction mixture was stirred at 78 C. for 30 min then was warmed to 20 C. and stirred for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (15 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-formylmorpholine-4-carboxylate (1.00 g, 70% purity) as a colorless oil, which was used in the next step without any further purification.

Step 2: tert-Butyl 3-ethynylmorpholine-4-carboxylate (127A-3)

[1264] To a solution of tert-butyl 3-formylmorpholine-4-carboxylate (1.00 g, 4.65 mmol, 1.0 eq) and dimethyl(1-diazo-2-oxopropyl)phosphonate (1.34 g, 6.97 mmol, 1.5 eq) in MeOH (30 mL) was added K.sub.2CO.sub.3 (2.57 g, 18.6 mmol, 4.0 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (15 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-ethynylmorpholine-4-carboxylate (800 mg, 85% purity) as a colorless oil, which was used in the next step without any further purification.

Step 3: tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)morpholine-4-carboxylate (127A-4)

[1265] A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (317 mg, 1.09 mmol, 1.0 eq), tert-butyl 3-ethynylmorpholine-4-carboxylate (230 mg, 1.09 mmol, 1.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (76.4 mg, 109 mol, 0.1 eq) and CuI (10.4 mg, 54.4 mol, 0.05 eq) in TEA (5.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 70 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl) morpholine-4-carboxylate (400 mg, 1.07 mmol, 49% yield) was obtained as a brown oil. M56+H.sup.+=319.1 (LCMS).

Step 4: tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (127A-5)

[1266] To a solution of tert-butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)morpholine-4-carboxylate (100 mg, 267 mol, 1.0 eq) in DCE (10 mL) was added Cu(OAc) 2 (97.0 mg, 534 mol, 2.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 1 h in a microwave (400 W). TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=2/1, R.sub.f=0.7). tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (80.0 mg, 214 mol, 40% yield) was obtained as a white solid.

Step 5: 2-(4-(tert-Butoxycarbonyl) morpholin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (127A-6)

[1267] To a solution of tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (70.0 mg, 187 mol, 1.0 eq) in a mixture of THF (4.0 mL) and MeOH (1.0 mL) was added NaOH (2 M aqueous, 500 L, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and washed with MTBE (2.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(4-(tert-butoxycarbonyl) morpholin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (70.0 mg, 80% purity) as a white solid, which was used in the next step without any further purification. M+H.sup.+=361.1 (LCMS)

Step 6: tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (127A-7)

[1268] To a solution of 2-(4-(tert-butoxycarbonyl) morpholin-3-yl)-5-methyl-1H-indole-6-carboxylic acid (70.0 mg, 194 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (28.5 mg, 155 mol, 0.8 eq) in DCM (5.0 mL) were added TEA (39.3 mg, 388 mol, 54.4 L, 2.0 eq), EDCI (44.7 mg, 233 mol, 1.2 eq) and HOBt (31.5 mg, 233 mol, 1.2 eq). The mixture was stirred at 20 C. for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (70.0 mg, 133 mol, 69% yield) was obtained as a white solid. M+H.sup.+=526.2 (LCMS)

Step 7: 5-Methyl-2-(morpholin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 260)

[1269] To a stirred solution of tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl) morpholine-4-carboxylate (50.0 mg, 95.1 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-2-(morpholin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (16.9 mg, 35.7 mol, 38% yield, HCl salt) was obtained as a white solid. M+H.sup.+=426.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.29 (br s, 1H), 9.84 (br s, 2H), 9.16-8.96 (m, 1H), 8.78-8.63 (m, 1H), 7.98-7.92 (m, 1H), 7.86-7.80 (m, 2H), 7.62-7.44 (m, 3H), 7.32-7.28 (m, 1H), 7.15-7.10 (m, 1H), 6.58-6.50 (m, 1H), 4.73-4.50 (m, 1H), 4.17-3.94 (m, 2H), 3.91-3.75 (m, 2H), 3.31-3.19 (m, 2H), 2.16 (s, 3H), 1.43-1.32 (m, 2H), 1.23-1.13 (m, 2H).

Example 128: 2-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 202)

##STR00965##

Step 1: Methyl 5-amino-4-(4-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methylbenzoate (128A-1)

[1270] To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq), tert-butyl but-3-yn-1-ylcarbamate (349 mg, 2.06 mmol, 1.2 eq), CuI (65.4 mg, 344 mol, 0.2 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (121 mg, 172 mol, 0.1 eq) was added TEA (4.35 g, 42.9 mmol, 6.0 mL, 25 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methyl benzoate (420 mg, 1.26 mmol, 74% yield) was obtained as a yellow oil. M+H.sup.+=333.2 (LCMS).

Step 2: Methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (128A-2)

[1271] To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-2-methyl benzoate (300 mg, 903 mol, 1.0 eq) in DCE (15 mL) was added Cu(OAc).sub.2 (410 mg, 2.26 mmol, 2.5 eq). The mixture was stirred at 90 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (210 mg, 632 mol, 70% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.84-8.58 (m, 1H), 8.02-7.96 (m, 1H), 7.35 (s, 1H), 6.27-6.15 (m, 1H), 3.91-3.88 (m, 3H), 3.55-3.43 (m, 2H), 3.05-2.92 (m, 2H), 2.69-2.63 (m, 3H), 1.46-1.42 (m, 9H).

Step 3: 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (128A-3)

[1272] To a solution of methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (200 mg, 602 mol, 1.0 eq) in a mixture of THF (6.0 mL) and MeOH (2.0 mL) was added NaOH (2 M in aqueous, 4.2 mL, 14 eq). The mixture was stirred at 20 C. for 2 h, then at 70 C. for another 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (10 mL2). The aqueous was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (210 mg, 90% purity) as a yellow solid, which was used in the next step without any further purification. MH.sup.=317.2 (LCMS).

Step 4: tert-Butyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (128A-4)

[1273] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (104 mg, 569 mol, 1.0 eq) and 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (201 mg, 569 mol, 90% purity, 1.0 eq) in DCM (5.0 mL) were added TEA (173 mg, 1.71 mmol, 237 L, 3.0 eq), EDCI (164 mg, 853 mol, 1.5 eq) and HOBt (115 mg, 853 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (170 mg, 352 mol, 62% yield) was obtained as a yellow oil. M+H.sup.+=484.3 (LCMS).

Step 5: 2-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 202)

[1274] To a solution of tert-butyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (170 mg, 352 mol, 1.0 eq) in DCM (10 mL) was added TFA (10.0 g, 87.8 mmol, 6.50 mL, 250 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 60 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (120 mg, 313 mol, 89% yield, TFA salt) was obtained as a white solid. M+H.sup.+=384.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.66-8.61 (m, 1H), 7.94-7.88 (m, 2H), 7.83-7.78 (m, 1H), 7.61-7.55 (m, 1H), 7.53-7.41 (m, 2H), 7.22-7.19 (m, 1H), 7.07-7.05 (m, 1H), 6.22-6.19 (m, 1H), 3.28-3.23 (m, 2H), 3.11-3.05 (m, 2H), 2.18-2.14 (m, 3H), 1.48-1.43 (m, 2H), 1.34-1.28 (m, 2H).

Example 129: 5-Methyl-2-(2-(methylamino)ethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 222)

##STR00966## ##STR00967##

Step 1: tert-Butyl but-3-yn-1-yl(methyl)carbamate (129A-2)

[1275] To a mixture of tert-butyl but-3-yn-1-ylcarbamate (500 mg, 2.95 mmol, 1.0 eq) in THF (15 mL) was added sodium hydride (177 mg, 4.43 mmol, 60% purity, 1.5 eq) at 0 C. The mixture was stirred at 0 C. for 30 min under a N.sub.2 atmosphere, and Mel (629 mg, 4.43 mmol, 276 L, 1.5 eq) was added. The resulting mixture was stirred at 25 C. for 4 h. TLC indicated that the starting material was completely consumed. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl but-3-yn-1-yl(methyl)carbamate (520 mg, 2.84 mmol, 96% yield) as a yellow oil, which was used in the next step without any further purification. .sup.1H NMR (400 MHZ, CDCl.sub.3) 3.45-3.36 (m, 2H), 3.35-3.25 (m, 1H), 2.94-2.91 (m, 3H), 2.45-2.38 (m, 2H), 1.47 (s, 9H).

Step 2: Methyl 5-amino-4-(4-((tert-butoxycarbonyl)(methyl)amino)but-1-yn-1-yl)-2-methylbenzoate (129A-3)

[1276] To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (700 mg, 2.40 mmol, 1.0 eq), tert-butyl but-3-yn-1-yl(methyl)carbamate (507 mg, 2.77 mmol, 1.2 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (169 mg, 240 mol, 0.1 eq) and CuI (91.6 mg, 481 mol, 0.2 eq) was added TEA (6.08 g, 60.1 mmol, 8.40 mL, 25 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (20 mL) and extracted with DCM (15 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 1/2. to Methyl 5-amino-4-(4-((tert-butoxycarbonyl)(methyl)amino)but-1-yn-1-yl)-2-methylbenzoate (570 mg, 1.65 mmol, 68% yield) was obtained as a yellow oil. M+H.sup.+=347.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.27-7.24 (m, 1H), 7.12-7.09 (m, 1H), 3.89-3.84 (m, 3H), 3.56-3.44 (m, 2H), 3.01-2.91 (m, 3H), 2.75-2.66 (m, 2H), 2.46-2.39 (m, 3H), 1.50-1.44 (m, 9H).

Step 3: Methyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (129A-4)

[1277] To a solution of methyl 5-amino-4-(4-((tert-butoxycarbonyl)(methyl)amino)but-1-yn-1-yl)-2-methylbenzoate (570 mg, 1.65 mmol, 1.0 eq) in DCE (20 mL) was added Cu(OAc) 2 (747 mg, 4.11 mmol, 2.5 eq). The mixture was stirred at 90 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (440 mg, 1.27 mmol, 77% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.05-7.95 (m, 1H), 7.36-7.32 (m, 1H), 7.13-7.07 (m, 1H), 6.23-6.18 (m, 1H), 3.88-3.85 (m, 3H), 3.14-3.01 (m, 2H), 2.89-2.79 (m, 3H), 2.73-2.69 (m, 2H), 2.44-2.41 (m, 3H), 1.47 (s, 9H).

Step 4: 2-(2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (129A-5)

[1278] To a solution of methyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylate (440 mg, 1.27 mmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 8.9 mL, 14 eq). The resulting mixture was stirred 20 C. for 2 h, then at 70 C. for another 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (5.0 mL3). The aqueous was acidified to pH 5 with HCl (1 M aqueous) and extracted with DCM (10 mL8), the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (410 mg, 1.23 mmol, 97% yield) as a red solid, which was used in the next step without any further purification. MH.sup.=331.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.21-8.16 (m, 1H), 7.43-7.39 (m, 1H), 6.24-6.21 (m, 1H), 3.56-3.47 (m, 2H), 3.12-3.00 (m, 2H), 2.73-2.70 (m, 3H), 2.49-2.46 (m, 3H), 1.46-1.42 (m, 9H).

Step 5: tert-Butyl methyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (129A-6)

[1279] To a solution of 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl-1H-indole-6-carboxylic acid (100 mg, 301 mol, 1.0 eq) in DCM (8.0 mL) were added 1-(naphthalen-1-yl)cyclopropanamine (55.1 mg, 301 mol, 1.0 eq), TEA (91.3 mg, 903 mol, 126 L, 3.0 eq), EDCI (86.5 mg, 451 mol, 1.5 eq) and HOBt (61.0 mg, 451 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.4). tert-Butyl methyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)ethyl)carbamate (90.0 mg, 181 mol, 60% yield) was obtained as a yellow oil. M+H.sup.+=498.2 (LCMS).

Step 6: 5-Methyl-2-(2-(methylamino)ethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 222)

[1280] To a solution of tert-butyl methyl(2-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)-1H-indol-2-yl)ethyl)carbamate (90.0 mg, 181 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.08 g, 27.0 mmol, 2.00 mL, 149 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-Methyl-2-(2-(methylamino)ethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (18.6 mg, 46.8 mol, 26% yield, TFA salt) was obtained as a white solid. M+H.sup.+=398.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.22-9.10 (m, 1H), 8.60-8.54 (m, 1H), 7.92-7.86 (m, 2H), 7.84-7.77 (m, 1H), 7.60-7.53 (m, 1H), 7.52-7.40 (m, 2H), 7.01-6.97 (m, 1H), 6.52-6.47 (m, 1H), 3.27-3.19 (m, 2H), 2.96-2.86 (m, 2H), 2.77-2.72 (m, 3H), 1.92-1.87 (m, 3H), 1.46-1.38 (m, 2H), 1.33-1.25 (m, 2H).

Example 130: 5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 213)

##STR00968##

Step 1: 5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 213)

[1281] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (90.2 mg, 492 mol, 1.0 eq) and 5-methyl-2-(morpholinomethyl)-1H-indole-6-carboxylic acid (135 mg, 492 mol, 1.0 eq) in DCM (10 mL) were added TEA (149 mg, 1.48 mmol, 206 L, 3.0 eq), EDCI (142 mg, 738 mol, 1.5 eq) and HOBt (99.8 mg, 738 mol, 1.5 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 55%-75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-2-(morpholinomethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (24.6 mg, 55.7 mol, 11% yield, FA salt) was obtained as a white solid. M+H.sup.+=440.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.09-8.90 (m, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.62-7.45 (m, 3H), 7.26 (s, 1H), 7.18 (s, 1H), 6.54 (s, 1H), 6.27 (s, 1H), 3.86-3.67 (m, 6H), 2.56 (br s, 4H), 2.29 (s, 3H), 1.61-1.55 (m, 2H), 1.45-1.36 (m, 2H).

Example 131: 2-((Benzylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 229)

##STR00969## ##STR00970##

Step 1: tert-Butyl benzyl(prop-2-yn-1-yl)carbamate (131A-2)

[1282] A solution of tert-butyl prop-2-yn-1-ylcarbamate (500 mg, 3.22 mmol, 1.0 eq) in THF (10 mL) was degassed and purged with N.sub.2 three times. To the mixture was added sodium hydride (193 mg, 4.83 mmol, 60% purity, 1.5 eq) in portions at 0 C. The mixture was stirred at the same temperature for 30 min. Then (bromomethyl)benzene (827 mg, 4.83 mmol, 574 L, 1.5 eq) was added and the resulting mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (15 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl benzyl(prop-2-yn-1-yl)carbamate (260 mg, 1.06 mmol, 33% yield) was obtained as a white solid. M56+H.sup.+=190.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.37-7.31 (m, 2H), 7.28 (br dd, J=4.0, 6.3 Hz, 3H), 4.57 (s, 2H), 4.20-3.80 (m, 2H), 2.22 (br s, 1H), 1.58-1.43 (m, 9H).

Step 2: Methyl 5-amino-4-(3-(benzyl(tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (131A-3)

[1283] To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (150 mg, 515 mol, 1.0 eq) and tert-butyl benzyl(prop-2-yn-1-yl)carbamate (164 mg, 670 mol, 1.3 eq) in THF (2.0 mL) were added Pd(PPh.sub.3).sub.4 (11.9 mg, 10.3 mol, 0.02 eq), copper (I) iodide (1.96 mg, 10.3 mol, 0.02 eq) and TEA (130 mg, 1.29 mmol, 179 L, 2.5 eq) at 20 C. The resulting mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-amino-4-(3-(benzyl(tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (150 mg, 367 mol, 71% yield) was obtained as a colorless oil. M+H.sup.+=409.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.63-7.39 (m, 7H), 4.80 (s, 2H), 4.57-4.36 (m, 2H), 4.06 (s, 3H), 2.62 (s, 3H), 1.69 (br s, 9H).

Step 3: Methyl 2-((benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (131A-4)

[1284] A solution of methyl 5-amino-4-(3-(benzyl(tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-methylbenzoate (150 mg, 367 mol, 1.0 eq) in THF (30 mL) was degassed and purged with N.sub.2 three times. To the mixture was added Cu(OAc) 2 (167 mg, 918 mol, 2.5 eq) at 20 C. The resulting mixture was stirred at 130 C. for 5 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.6). Methyl 2-((benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (90.0 mg, 220 mol, 60% yield) was obtained as a colorless oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.18-9.02 (m, 1H), 8.02 (br s, 1H), 7.38 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.31 (br d, J=6.7 Hz, 1H), 7.22 (br d, J=5.5 Hz, 2H), 6.24 (s, 1H), 4.40 (s, 4H), 3.91 (s, 3H), 2.68 (s, 3H), 1.51 (br s, 9H).

Step 4: 2-((Benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (131A-5)

[1285] To a solution of methyl 2-((benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylate (80.0 mg, 196 mol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 3.0 mL, 31 eq). The mixture was stirred at 70 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with MTBE (5.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-((benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (90.0 mg), which was used in the next step without any further purification. M+H.sup.+=395.2 (LCMS).

Step 5: tert-Butyl benzyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (131A-6)

[1286] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (40.0 mg, 218 mol, 1.0 eq) and 2-((benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-indole-6-carboxylic acid (86.1 mg, 218 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (66.3 mg, 655 mol, 91.2 L, 3.0 eq), EDCI (83.7 mg, 437 mol, 2.0 eq) and HOBt (59.0 mg, 437 mol, 2.0 eq). The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/5, R.sub.f=0.4). tert-Butyl benzyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (70.0 mg, 125 mol, 57% yield) was obtained as a colorless oil. M+H.sup.+=560.4 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.90 (br s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.46 (m, 2H), 7.36-7.28 (m, 3H), 7.25 (s, 1H), 7.22-7.13 (m, 2H), 6.54 (s, 1H), 6.16 (s, 1H), 4.40-4.32 (m, 4H), 2.29 (s, 3H), 1.48 (br s, 9H), 1.43-1.38 (m, 2H), 1.27 (t, J=7.2 Hz, 2H).

Step 6: 2-((Benzylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 229)

[1287] To a stirred solution of tert-butyl benzyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)-1H-indol-2-yl)methyl)carbamate (50.0 mg, 89.3 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-((Benzylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (4.80 mg, 9.14 mol, 10% yield, HCl salt) was obtained as a white solid. M+H.sup.+=460.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.99-9.68 (m, 3H), 8.58 (br d, J=7.5 Hz, 1H), 7.91 (br dd, J=7.2, 14.7 Hz, 2H), 7.81 (br d, J=8.6 Hz, 1H), 7.55-7.38 (m, 5H), 7.34 (br s, 3H), 6.89 (br s, 1H), 6.70-6.53 (m, 1H), 6.05 (br d, J=1.8 Hz, 1H), 3.97-3.75 (m, 4H), 2.07 (s, 3H), 1.56 (br d, J=3.4 Hz, 2H), 1.39 (br s, 2H).

Example 132: 5-Methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indole-2-carboxylic acid (Compound 204)

##STR00971##

Step 1: 5-Methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indole-2-carboxylic acid (Compound 204)

[1288] To a solution of 5-amino-4-iodo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 226 mol, 1.0 eq) and 2-oxopropanoic acid (99.6 mg, 1.13 mmol, 79.6 L, 5.0 eq) in DMF (8.0 mL) was added 1,4-diazabicyclo[2.2.2]octane (76.1 mg, 678 mol, 74.6 L, 3.0 eq). The mixture was stirred at 20 C. for 30 min. Then the mixture was added Pd(OAc) 2 (2.54 mg, 11.3 mol, 0.05 eq) and stirred at 105 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL2) then dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indole-2-carboxylic acid (9.73 mg, 25.3 mol, 11% yield, FA salt) was obtained as a yellow solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.72-11.61 (m, 1H), 9.16-9.09 (m, 1H), 8.71-8.65 (m, 1H), 7.98-7.91 (m, 1H), 7.87-7.81 (m, 2H), 7.62-7.51 (m, 3H), 7.50-7.44 (m, 1H), 7.37-7.34 (m, 1H), 7.13-7.10 (m, 1H), 2.13-2.09 (m, 3H), 1.40-1.34 (m, 2H), 1.21-1.16 (m, 2H).

Example 133: 5-Methyl-N.SUP.6.-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (Compound 205)

##STR00972## ##STR00973##

Step 1: 6-(Methoxycarbonyl)-5-methyl-1H-indole-2-carboxylic acid (133A-1)

[1289] To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq) and 2-oxopropanoic acid (756 mg, 8.59 mmol, 605 L, 5.0 eq) in DMF (15 mL) was added 1,4-diazabicyclo[2.2.2]octane (578 mg, 5.15 mmol, 567 L, 3.0 eq). The reaction mixture was stirred at 20 C. for 30 min, then Pd(OAc) 2 (19.3 mg, 85.9 mol, 0.05 eq) was added. The mixture was stirred at 105 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (103 mL), were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 6-(methoxycarbonyl)-5-methyl-1H-indole-2-carboxylic acid (420 mg, 92% purity) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=233.9 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.04-11.92 (m, 1H), 8.03-7.99 (m, 1H), 7.97-7.93 (m, 1H), 7.57-7.51 (m, 1H), 7.06-6.99 (m, 1H), 3.85-3.82 (m, 3H), 2.57-2.54 (m, 3H).

Step 2: Methyl 2-carbamoyl-5-methyl-1H-indole-6-carboxylate (133A-2)

[1290] To a solution of 6-(methoxycarbonyl)-5-methyl-1H-indole-2-carboxylic acid (200 mg, 858 mol, 1.0 eq) and HOBt (151 mg, 1.11 mmol, 1.3 eq) in DMF (10 mL) was added EDCI (214 mg, 1.11 mmol, 1.3 eq). The reaction mixture was stirred at 20 C. for 0.6 h, then NH.sub.3.Math.H.sub.2O (5.46 g, 39.0 mmol, 6.0 mL, 25% purity in water, 46 eq) was added. The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL4). The combined organic layers were washed with brine (202 mL) then the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product methyl 2-carbamoyl-5-methyl-1H-indole-6-carboxylate (270 mg, 70% purity) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=233.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.80-11.75 (m, 1H), 8.08-8.04 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.94 (m, 1H), 7.52-7.49 (m, 1H), 6.89-6.84 (m, 1H), 3.84-3.80 (m, 3H), 2.57-2.55 (m, 3H).

Step 3: 2-Carbamoyl-5-methyl-1H-indole-6-carboxylic acid (133A-3)

[1291] To a solution of methyl 2-carbamoyl-5-methyl-1H-indole-6-carboxylate (200 mg, 603 mol, 70% purity, 1.0 eq) in MeOH (10 mL) was added NaOH (1 M, 3.1 mL, 5.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and washed with MTBE (10 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 2-carbamoyl-5-methyl-1H-indole-6-carboxylic acid (150 mg, 80% purity) as a yellow solid, which was used in the next step without any further purification. MH.sup.=217.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.76-11.67 (m, 1H), 8.08-7.97 (m, 2H), 7.50-7.42 (m, 2H), 7.10-7.05 (m, 1H), 6.91-6.84 (m, 1H), 2.57-2.55 (m, 3H).

Step 4: 5-Methyl-N.SUP.6.-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (Compound 205)

[1292] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (67.2 mg, 367 mol, 1.0 eq) and 2-carbamoyl-5-methyl-1H-indole-6-carboxylic acid (100 mg, 367 mol, 1.0 eq) were added TEA (111 mg, 1.10 mmol, 153 L, 3.0 eq), EDCI (105 mg, 550 mol, 1.5 eq) and HOBt (74.3 mg, 550 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7030 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-N.sup.6-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (29.0 mg, 75.6 mol, 21% yield, FA salt) was obtained as a white solid. M+H.sup.+=384.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.50-11.43 (m, 1H), 9.12-9.05 (m, 1H), 8.71-8.64 (m, 1H), 7.98-7.88 (m, 2H), 7.87-7.79 (m, 2H), 7.62-7.43 (m, 3H), 7.35-7.27 (m, 2H), 7.14-7.08 (m, 1H), 7.01-6.95 (m, 1H), 2.12-2.08 (m, 3H), 1.36 (br s, 2H), 1.20-1.12 (m, 2H).

Example 134: N.SUB.2.-Methoxy-N.SUB.2,5.-dimethyl-N.SUP.6.-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (Compound 225)

##STR00974##

Step 1: N.SUB.2.-Methoxy-N.SUB.2,5.-dimethyl-N.SUP.6.-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (Compound 225)

[1293] To a solution of 5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indole-2-carboxylic acid (70.0 mg, 182 mol, 1.0 eq) and N,O)-dimethylhydroxylamine (26.6 mg, 273 mol, 1.5 eq, HCl salt) in DCM (3.0 mL) were added TEA (55.3 mg, 546 mol, 76.0 L, 3.0 eq) and T.sub.3P (232 mg, 364 mol, 217 L, 50% purity in EtOAc, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N.sub.2-Methoxy-N.sup.2,5-dimethyl-N.sup.6-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-2,6-dicarboxamide (18.6 mg, 41.7 mol, 23% yield) was obtained as a white solid. M+H.sup.+=428.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.5 (s, 1H), 9.1 (s, 1H), 8.7 (d, J=8.19 Hz, 1H), 8.0 (d, J=7.95 Hz, 1H), 7.8-7.9 (m, 2H), 7.5-7.6 (m, 2H), 7.5 (t, J=7.64 Hz, 1H), 7.4 (s, 1H), 7.2 (s, 1H), 7.0 (d, J=1.34 Hz, 1H), 3.8 (s, 3H), 3.3 (s, 3H), 2.1 (s, 3H), 1.4 (s, 2H), 1.2-1.2 (m, 2H).

Example 135: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-phenyl-1H-indole-6-carboxamide (Compound 226)

##STR00975## ##STR00976##

Step 1: Methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (135A-1)

[1294] A solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq), ethynylbenzene (158 mg, 1.55 mmol, 170 L, 1.5 eq) and TEA (209 mg, 2.06 mmol, 287 L, 2.0 eq) in a mixture of H.sub.2O (7.5 mL) and toluene (15 mL) was degassed and purged with N.sub.2 three times. To the mixture were added Pd(PPh.sub.3).sub.2Cl.sub.2 (21.7 mg, 30.9 mol, 0.03 eq) and CuI (1.96 mg, 10.3 mol, 0.01 eq). The resulting mixture was stirred at 70 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. Methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (250 mg, 942 mol, 91% yield) was obtained as a brown solid. M+H.sup.+=266.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.57-7.51 (m, 2H), 7.41-7.35 (m, 3H), 7.33 (s, 1H), 7.25 (s, 1H), 3.89 (s, 3H), 2.47 (s, 3H).

Step 2: Methyl 5-methyl-2-phenyl-1H-indole-6-carboxylate (135A-2)

[1295] A mixture of methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (216 mg, 814 mol, 1.0 eq) in DCE (20 mL) was degassed and purged with N.sub.2 three times. To the mixture was added Cu(OAc) 2 (370 mg, 2.04 mmol, 2.5 eq) dropwise at 20 C. The resulting mixture was stirred at 90 C. for 5 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.7). Methyl 5-methyl-2-phenyl-1H-indole-6-carboxylate (150 mg, 565 mol, 69% yield) was obtained as a brown solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.50 (br s, 1H), 8.10 (s, 1H), 7.51-7.44 (m, 3H), 7.40-7.34 (m, 2H), 7.27-7.24 (m, 1H), 6.77 (d, J=1.1 Hz, 1H), 3.93 (s, 3H), 2.70 (s, 3H).

Step 3: 5-Methyl-2-phenyl-1H-indole-6-carboxylic acid (135A-3)

[1296] To a solution of methyl methyl 5-methyl-2-phenyl-1H-indole-6-carboxylate (70 mg, 264 mol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (5.0 mL) was added NaOH (2 M aqueous, 1.5 mL, 10 eq). The mixture was stirred at 70 C. for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, diluted with H.sub.2O (5.0 mL) and washed with MTBE (3.0 mL3). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-methyl-2-phenyl-1H-indole-6-carboxylic acid (70 mg) as a white solid, which was used in the next step without any further purification.

Step 4: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-phenyl-1H-indole-6-carboxamide (Compound 226)

[1297] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (58.3 mg, 318 mol, 1.0 eq) and 5-methyl-2-phenyl-1H-indole-6-carboxylic acid (80.0 mg, 318 mol, 1.0 eq) in DCM (5 mL) were added TEA (96.7 mg, 955 mol, 133 L, 3.0 eq), EDCI (122 mg, 637 mol, 2.0 eq) and HOBt (86.0 mg, 637 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-phenyl-1H-indole-6-carboxamide (21.1 mg, 50.7 mol, 16% yield) was obtained as a yellow solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.47 (s, 1H), 9.09 (s, 1H), 8.73 (d, J=8.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.89-7.79 (m, 4H), 7.65-7.53 (m, 2H), 7.52-7.41 (m, 3H), 7.35-7.24 (m, 2H), 7.11 (s, 1H), 6.80 (d, J=1.4 Hz, 1H), 2.18 (s, 3H), 1.43-1.35 (m, 2H), 1.23-1.16 (m, 2H).

Example 136: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-(pyridin-2-yl)-1H-indole-6-carboxamide (Compound 234)

##STR00977## ##STR00978##

Step 1: Methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl)benzoate (136A-1)

[1298] A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (1.00 g, 3.44 mmol, 1.0 eq), TEA (695 mg, 6.87 mmol, 956 L, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (72.3 mg, 103 mol, 0.03 eq), CuI (6.54 mg, 34.3 mol, 0.01 eq) and 2-ethynylpyridine (531 mg, 5.15 mmol, 521 L, 1.5 eq) in a mixture of toluene (50 mL) and H.sub.2O (25 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 70 C. for 3 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl)benzoate (800 mg, 3.00 mmol, 87% yield) was obtained as a yellow solid.

Step 2: Methyl 5-methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylate (136A-2)

[1299] To the solution of methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl)benzoate (150 mg, 564 mol, 1.0 eq) in DMF (7.5 mL) was added 1-BuOK (1 M in THF, 1.18 mL, 2.1 eq). The reaction mixture was stirred at 90 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL2), and then dried over Na.sub.2SO.sub.4, concentrated under vacuum to give methyl 5-methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylate (45.0 mg, 169 mol, 10% yield) as a yellow gum. M+H.sup.+=267.2 (LCMS).

Step 3: 5-Methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylic acid (136A-3)

[1300] To a solution of methyl 5-methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylate (45.0 mg, 169 mol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (3.0 mL) was added NaOH (2 M in aqueous, 845 L, 10 eq). The mixture was stirred at 25 C. for 1 h and then at 70 C. for another 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and the pH was adjusted to 6 using HCl (1 M aqueous), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H.sub.2O (5.0 mL), dried under vacuum to give the crude product 5-methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylic acid (40.0 mg) as a yellow solid.

Step 4: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-(pyridin-2-yl)-1H-indole-6-carboxamide (Compound 234)

[1301] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (29.1 mg, 159 mol, 1.0 eq) and 5-methyl-2-(pyridin-2-yl)-1H-indole-6-carboxylic acid (40.0 mg, 157 mol, 1.0 eq) in DMF (4.0 mL) were added TEA (48.1 mg, 477 mol, 66.2 L, 3.0 eq), EDCI (60.8 mg, 317 mol, 2.0 eq) and HOBt (42.9 mg, 317 mol, 2.0 eq). The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were washed with brine (5 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-(pyridin-2-yl)-1H-indole-6-carboxamide (9.20 mg, 21.5 mol, 14% yield) was obtained as a yellow solid. M+H.sup.+=418.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 11.63 (d, J=0.9 Hz, 1H), 9.08 (s, 1H), 8.71 (d, J=8.5 Hz, 1H), 8.59 (d, J=4.1 Hz, 1H), 7.95 (dd, J=3.8, 7.7 Hz, 2H), 7.88-7.81 (m, 3H), 7.63-7.51 (m, 2H), 7.51-7.45 (m, 1H), 7.29 (s, 2H), 7.17 (s, 1H), 7.03 (d, J=1.4 Hz, 1H), 2.13 (s, 3H), 1.42-1.34 (m, 2H), 1.21-1.15 (m, 2H).

Example 137:1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 201)

##STR00979##

Step 1:1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 201)

[1302] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (100 mg, 294 mol, 1.0 eq) in THF (4.0 mL) was added sodium hydride (23.5 mg, 294 mol, 60% purity, 2.0 eq) at 0 C. for 30 min, followed by Mel (41.7 mg, 294 mol, 9.14 L, 1.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 50%-80% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (60.0 mg, 166 mol, 63% yield, HCl salt) was obtained as a white solid. M+H.sup.+=355.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.65-8.57 (m, 1H), 8.16-8.08 (m, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.93 (br d, J=8.4 Hz, 1H), 7.73-7.56 (m, 3H), 7.41 (d, J=18.6 Hz, 2H), 7.14 (d, J=2.0 Hz, 1H), 6.70 (br s, 1H), 6.46 (br s, 1H), 3.79 (s, 3H), 2.40 (s, 3H), 1.72 (br s, 2H), 1.54 (s, 2H).

Example 138: 1-Cyclobutyl-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 296)

##STR00980##

Step 1: 1-Cyclobutyl-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 296)

[1303] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (80.0 mg, 235 mol, 1.0 eq) and cyclobutanol (50.8 mg, 705 mol, 3.0 eq) in toluene (4.0 mL) was added CMBP (56.7 mg, 235 mol, 1.0 eq). The mixture was stirred at 90 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 40%-70% B over 7 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 1-cyclobutyl-5-methyl-N-[1-(1-naphthyl)cyclopropyl]indole-6-carboxamide (18.4 mg, 46.3 mol, 20% yield) as a white solid. M+H.sup.+=395.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (s, 1H), 8.72 (d, J=8.3 Hz, 1H), 8.01-7.91 (m, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.66-7.51 (m, 3H), 7.47 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.18 (s, 1H), 6.34 (d, J=3.0 Hz, 1H), 4.83 (quin, J=8.5 Hz, 1H), 2.42-2.27 (m, 4H), 2.11 (s, 3H), 1.86-1.73 (m, 2H), 1.44-1.36 (m, 2H), 1.24-1.14 (m, 2H).

Example 139: 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 218)

##STR00981##

Step 1: tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (139A-1)

[1304] To a mixture of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (200 mg, 588 mol, 1.0 eq), tert-butyl 3-iodoazetidine-1-carboxylate (332 mg, 1.76 mmol, 2.0 eq) and Cs.sub.2CO.sub.3 (384 mg, 1.76 mmol, 2.0 eq) in DMF (2.5 mL) was stirred at 150 C. for 30 min in a microwave (400 W). TLC indicated that 30% of the starting material still remained and 40% of the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL4). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (60.0 mg, 100 mol, 18% yield) was obtained as a yellow gum.

Step 2: 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 218)

[1305] To a solution of tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (55.0 mg, 111 mol, 1.0 eq) in DCM (10 mL) was added TFA (2.3 mL). The resulting mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (19.7 mg, 38.8 mol, 35% yield, TFA salt) was obtained as a white solid. M+H.sup.+=396.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 2H), 8.69 (d, J=8.3 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.88-7.82 (m, 2H), 7.79 (d, J=3.3 Hz, 1H), 7.62-7.45 (m, 3H), 7.30 (s, 1H), 7.25 (s, 1H), 6.52 (d, J=3.1 Hz, 1H), 5.50 (br t, J=7.9 Hz, 1H), 4.50-4.29 (m, 4H), 2.09 (s, 3H), 1.39 (br s, 2H), 1.24-1.16 (m, 2H).

Example 140: 5-Methyl-1-(1-methylazetidin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 290)

##STR00982##

Step 1: 5-Methyl-1-(1-methylazetidin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 290)

[1306] To a solution of 1-(azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (50.0 mg, 83.4 mol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (50 L), followed by the addition of formaldehyde (27.1 mg, 334 mol, 24.8 L, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (42.0 mg, 667 mol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (8.0 mL) and extracted with EtOAc (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Methyl-1-(1-methylazetidin-3-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (11.0 mg, 26.6 mol, 16% yield) was obtained as a yellow solid. M+H.sup.+=410.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.02-8.96 (m, 1H), 8.74-8.67 (m, 1H), 7.97-7.91 (m, 1H), 7.88-7.78 (m, 2H), 7.64-7.44 (m, 3H), 7.29-7.20 (m, 2H), 6.41-6.35 (m, 1H), 5.02-4.89 (m, 1H), 3.75-3.60 (m, 2H), 3.30-3.25 (m, 2H), 2.32 (br d, J=2.4 Hz, 3H), 2.16-2.07 (m, 3H), 1.44-1.34 (m, 2H), 1.15 (br s, 2H).

Example 141: 1-(Azetidin-3-ylmethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 239)

##STR00983##

Step 1: tert-Butyl 3-((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate (141A-1)

[1307] A mixture of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (150 mg, 441 mol, 1.0 eq), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (262 mg, 881 mol, 2.0 eq) and cesium carbonate (287 mg, 881 mol, 2.0 eq) in DMF (2 mL) was stirred at 150 C. for 30 min in a microwave (400 W). LCMS indicated that 50% starting material remained and 50% desired mass was detected. The mixture reaction was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). tert-Butyl 3-((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate (120 mg, crude) was obtained as a white solid. M+H.sup.+=510.3 (LCMS).

Step 2: 1-(Azetidin-3-ylmethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 239)

[1308] To a stirred solution of tert-butyl 3-((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate (120 mg, 235 mol, 1.0 eq) in DCM (10 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 1-(Azetidin-3-ylmethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (22.9 mg, 43.7 mol, 6% yield, TFA salt) was obtained as a white solid. M+H.sup.+=410.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.61 (br dd, J=2.5, 4.1 Hz, 1H), 8.55-8.44 (m, 1H), 7.98-7.91 (m, 1H), 7.90-7.80 (m, 2H), 7.60-7.44 (m, 3H), 7.38 (d, J=3.1 Hz, 1H), 7.27 (s, 2H), 6.35 (d, J=3.0 Hz, 1H), 4.34 (d, J=7.4 Hz, 2H), 3.94-3.80 (m, 2H), 3.75-3.63 (m, 2H), 2.08 (s, 3H), 1.43-1.35 (m, 2H), 1.24-1.15 (m, 2H).

Example 142: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1-(oxetan-3-ylmethyl)-1H-indole-6-carboxamide (Compound 295)

##STR00984##

Step 1: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1-(oxetan-3-ylmethyl)-1H-indole-6-carboxamide (Compound 295)

[1309] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (80.0 mg, 235 mol, 1.0 eq) in DMF (4.0 mL) were added Cs.sub.2CO.sub.3 (230 mg, 705 mol, 3.0 eq) and 3-(iodomethyl)oxetane (93.1 g, 470 mol, 2.0 eq). The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 43%-73% B over 7 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1-(oxetan-3-ylmethyl)-1H-indole-6-carboxamide (39.3 mg, 95.4 mol, 41% yield) as a white solid. M+H.sup.+=411.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.98-7.90 (m, 1H), 7.84 (dd, J=2.3, 7.7 Hz, 2H), 7.61-7.45 (m, 3H), 7.40 (d, J=3.0 Hz, 1H), 7.23 (d, J=12.8 Hz, 2H), 6.30 (d, J=2.8 Hz, 1H), 4.56 (dd, J=6.1, 7.8 Hz, 2H), 4.44-4.30 (m, 4H), 3.42-3.34 (m, 1H), 2.09 (s, 3H), 1.46-1.37 (m, 2H), 1.24-1.15 (m, 2H).

Example 143: 1-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 203)

##STR00985##

Step 1: 1-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 203)

[1310] To a mixture of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (80.0 mg, 235 mol, 1.0 eq) in acetonitrile (4.0 mL) was added sodium hydride (18.8 mg, 470 mol, 60% purity, 2.0 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 0 C. for 10 min. To the mixture was added 2-chloroethanamine (27.3 mg, 235 mol, 1.0 eq, HCl salt), followed by TEA (23.8 mg, 235 mol, 32.7 L, 1.0 eq). The mixture was stirred at 20 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 1-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (10.6 mg, 25.2 mol, 11% yield, HCl salt) was obtained as a white solid. M+H.sup.+=384.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.02 (s, 1H), 8.70 (d, J=8.2 Hz, 1H), 7.95-7.82 (m, 5H), 7.60-7.45 (m, 3H), 7.38 (d, J=3.1 Hz, 1H), 7.29 (d, J=9.4 Hz, 2H), 6.38 (d, J=2.9 Hz, 1H), 4.30 (t, J=6.8 Hz, 2H), 3.16-3.09 (m, 1H), 3.18-3.08 (m, 1H), 2.10 (s, 3H), 1.44-1.36 (m, 2H), 1.22-1.15 (m, 2H).

Example 144: 3,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 212)

##STR00986##

Step 1: Methyl 5-(allylamino)-4-iodo-2-methylbenzoate (144A-1)

[1311] To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq) and K.sub.2CO.sub.3 (427 mg, 3.09 mmol, 3.0 eq) in DMF (5.0 mL) was added 3-bromoprop-1-ene (125 mg, 1.03 mmol, 1.0 eq) slowly. The mixture was stirred at 25 C. for 60 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-(allylamino)-4-iodo-2-methylbenzoate (103 mg, 311 mol, 30% yield) was obtained as a white oil. M+H.sup.+=331.9 (LCMS).

Step 2: Methyl 3,5-dimethyl-1H-indole-6-carboxylate (144A-2)

[1312] To a solution of methyl 5-(allylamino)-4-iodo-2-methylbenzoate (103 mg, 311 mol, 1.0 eq) in DMF (8.0 mL) were added Na.sub.2CO.sub.3 (82.4 mg, 778 mol, 2.5 eq), TBAC (95.1 mg, 342 mol, 95.7 L, 1.1 eq) and Pd(OAc) 2 (6.98 mg, 31.1 mol, 0.1 eq). The resulting mixture was stirred at 100 C. for 2 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/5, R.sub.f=0.5). Methyl 3,5-dimethyl-1H-indole-6-carboxylate (30.0 mg, 148 mol, 47% yield) was obtained as a brown solid.

Step 3: 3,5-Dimethyl-1H-indole-6-carboxylic acid (144A-3)

[1313] To a solution of methyl 3,5-dimethyl-1H-indole-6-carboxylate (70.0 mg, 344 mol, 1.0 eq) in a mixture of THF (3.5 mL) and MeOH (3.5 mL) was added NaOH (2 M aqueous, 1.72 mL, 10 eq). The mixture was stirred at 25 C. for 1 h then at 70 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with MTBE (5.0 mL2). The aqueous was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 3,5-dimethyl-1H-indole-6-carboxylic acid (60.0 mg, 317 mol, 92% yield) as a white solid.

Step 4: 3,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 212)

[1314] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (58.1 mg, 317 mol, 1.0 eq) and 3,5-dimethyl-1H-indole-6-carboxylic acid (60.0 mg, 317 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (96.3 mg, 951 mol, 132 L, 3.0 eq), EDCI (91.2 mg, 476 mol, 1.5 eq) and HOBt (64.3 mg, 476 mol, 1.5 eq). The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (10040 mm, 3 m); flow rate: 25 mL/min; gradient: 55%-75% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 3,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (32.1 mg, 81.9 mol, 26% yield, HCl salt) was obtained as a white solid. M+H.sup.+=355.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.48 (br d, J=8.7 Hz, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.81 (br d, J=8.2 Hz, 2H), 7.64-7.55 (m, 1H), 7.48 (s, 2H), 7.14 (s, 1H), 6.95 (s, 1H), 6.54 (br s, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.58-1.56 (m, 2H), 1.41 (s, 2H).

Example 145: 3-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 292)

##STR00987##

Step 1: (E)-Methyl 5-methyl-3-(2-nitrovinyl)-1H-indole-6-carboxylate (145A-1)

[1315] To a solution of methyl 5-methyl-1H-indole-6-carboxylate (460 mg, 2.43 mmol, 1.0 eq) and (E)-N,N-dimethyl-2-nitroethenamine (282 mg, 2.43 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (277 mg, 2.43 mmol, 0.18 mL, 1.0 eq). The mixture was stirred at 20 C. for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc (5 mL). (E)-Methyl 5-methyl-3-(2-nitrovinyl)-1H-indole-6-carboxylate (300 mg, 1.15 mmol, 47% yield) was obtained as a yellow solid. M+H.sup.+=261.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.40-8.33 (m, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.95-7.89 (m, 1H), 7.72 (s, 1H), 3.90 (s, 3H), 2.71 (s, 3H).

Step 2: Methyl 5-methyl-3-(2-nitroethyl)-1H-indole-6-carboxylate (145A-2)

[1316] To a solution of (E)-methyl 5-methyl-3-(2-nitrovinyl)-1H-indole-6-carboxylate (300 mg, 1.15 mmol, 1.0 eq) in a mixture of THF (15 mL) and MeOH (5.0 mL) was added NaBH.sub.4 (131 mg, 3.46 mmol, 3.0 eq) at 0 C. Then the mixture was stirred at 20 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. Methyl 5-methyl-3-(2-nitroethyl)-1H-indole-6-carboxylate (230 mg, 877 mol, 76% yield) was obtained as a white solid. M+H.sup.+=263.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.21-8.11 (m, 1H), 8.09-8.04 (m, 1H), 7.41-7.37 (m, 1H), 7.22-7.17 (m, 1H), 4.79-4.53 (m, 2H), 4.01-3.77 (m, 3H), 3.64-3.35 (m, 2H), 2.83-2.59 (m, 3H).

Step 3: 5-Methyl-3-(2-nitroethyl)-1H-indole-6-carboxylic acid (145A-3)

[1317] A solution of methyl 5-methyl-3-(2-nitroethyl)-1H-indole-6-carboxylate (70.0 mg, 267 mol, 1.0 eq) in HCl (2 M aqueous, 2.0 mL) was stirred at 110 C. for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with NaOH (2 M aqueous) to adjust the pH to 6. The mixture was concentrated under vacuum to remove the water completely. The mixture was treated with MeOH/DCM (V/V=10/1, 2.0 mL) then filtered. The filter cake was washed with MeOH/DCM (V/V=10/1, 2.0 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give crude product 5-methyl-3-(2-nitroethyl)-1H-indole-6-carboxylic acid (100 mg, 80% purity) as a grey solid. M+H.sup.+=249.1 (LCMS).

Step 4: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-(2-nitroethyl)-1H-indole-6-carboxamide (145A-4)

[1318] To a solution of 5-methyl-3-(2-nitroethyl)-1H-indole-6-carboxylic acid (100 mg, 403 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (73.8 mg, 403 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (81.5 mg, 806 mol, 0.12 mL, 2.0 eq), EDCI (92.7 mg, 483 mol, 1.2 eq) and HOBt (65.3 mg, 483 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.4). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-(2-nitroethyl)-1H-indole-6-carboxamide (15.0 mg, 36.3 mol, 9% yield) was obtained as a white solid. M+H.sup.+=414.2 (LCMS).

Step 5:3-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 292)

[1319] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-(2-nitroethyl)-1H-indole-6-carboxamide (15.0 mg, 36.3 mol, 1.0 eq) in a mixture of MeOH (2.0 mL) and H.sub.2O (0.5 mL) were added iron powder (10.1 mg, 181 mol, 5.0 eq) and NH.sub.4Cl (9.70 mg, 181 mol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) the mixture was filtered through a pad of Celite and the slurry was washed with EtOAc several times and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 3-(2-Aminoethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (1.2 mg, 3.13 mol, 9% yield, HCl salt) was obtained as a white solid. M+H.sup.+=384.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.64 (d, J=8.5 Hz, 1H), 7.94-7.88 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.61-7.55 (m, 1H), 7.53-7.42 (m, 2H), 7.31 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 3.16 (br d, J=7.3 Hz, 2H), 3.05 (d, J=7.4 Hz, 2H), 2.21 (s, 3H), 1.52-1.42 (m, 2H), 1.31 (br d, J=1.9 Hz, 2H).

Example 146: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 207)

##STR00988##

Step 1: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 207)

[1320] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (100 mg, 294 mol, 1.0 eq) in AcOH (10 mL) was added NaBH.sub.3CN (36.9 mg, 588 mol, 2.0 eq), the resulting mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (40.0 mg, 116 mol, 40% yield) was obtained as a white solid. M+H.sup.+=343.0 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.19 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.88-7.79 (m, 2H), 7.61-7.44 (m, 3H), 7.16 (s, 1H), 6.92 (s, 1H), 3.60 (br t, J=7.9 Hz, 2H), 3.06 (br t, J=7.7 Hz, 2H), 2.00 (s, 3H), 1.36 (br d, J=1.5 Hz, 2H), 1.21-1.15 (m, 2H).

Example 147: 1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 210)

##STR00989##

Step 1: 1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 210)

[1321] To a solution of 1,5-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (50.0 mg, 141 mol, 1.0 eq) in AcOH (1.0 mL) was added NaBH.sub.3CN (17.7 mg, 282 mol, 2.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 1,5-Dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (31.7 mg, 80.7 mol, 57% yield, HCl salt) was obtained as a white solid. M+H.sup.+=357.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04-8.97 (m, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.96-7.90 (m, 1H), 7.82 (t, J=6.7 Hz, 2H), 7.46 (s, 3H), 6.98-6.79 (m, 1H), 6.55-6.35 (m, 1H), 3.33-3.25 (m, 2H), 2.89-2.81 (m, 2H), 2.70-2.66 (m, 3H), 1.91 (s, 3H), 1.35 (br d, J=1.0 Hz, 2H), 1.17 (s, 2H).

Example 148: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (Compound 249)

##STR00990##

Step 1: Methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (148A-2)

[1322] To a solution of methyl 2-methyl-5-nitrobenzoate (5.00 g, 25.6 mmol, 1.0 eq) and methyl 2-chloroacetate (3.06 g, 28.2 mmol, 1.1 eq) in DMF (50 mL) was slowly added a solution of t-BuOK (7.19 g, 64.1 mmol, 2.5 eq) in DMF (100 mL) at 0 C. and the mixture was stirred at 0 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (100 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (4.00 g, 15.0 mmol, 29% yield) was obtained as a yellow solid. M+H.sup.+=268.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.73 (s, 1H), 7.25 (s, 1H), 4.05 (s, 2H), 3.95 (s, 3H), 3.73 (s, 3H), 2.70 (s, 3H).

Step 2: Methyl 5-methyl-2-oxoindoline-6-carboxylate (148A-3)

[1323] A solution of methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (400 mg, 1.69 mmol, 1.0 eq) in HCl (1 M aqueous, 16 mL, 9.5 eq) was stirred at 100 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-methyl-2-oxoindoline-6-carboxylate (200 mg, 975 mol, 58% yield) was obtained as a brown solid. M+H.sup.+=206.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.43 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 3.81 (s, 3H), 3.51 (s, 2H), 2.45 (s, 3H).

Step 3: 5-Methyl-2-oxoindoline-6-carboxylic acid (148A-4)

[1324] A solution of methyl 5-methyl-2-oxoindoline-6-carboxylate (150 mg, 731 mol, 1.0 eq) in HCl (2 M aqueous, 5.0 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-methyl-2-oxoindoline-6-carboxylic acid (100 mg), which was used in the next step without any further purification. M+H.sup.+=192.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.39 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 3.49 (s, 2H), 2.46 (s, 3H).

Step 4: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (Compound 249)

[1325] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (47.9 mg, 262 mol, 1.0 eq) and 5-methyl-2-oxoindoline-6-carboxylic acid (50.0 mg, 262 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (79.4 mg, 785 mol, 109 L, 3.0 eq), EDCI (100 mg, 523 mol, 2.0 eq) and HOBt (70.7 mg, 523 mmol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (13.5 mg, 37.9 mol, 14% yield, FA salt) was obtained as a white solid. M+H.sup.+=357.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.26 (s, 1H), 9.10 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.82 (t, J=7.4 Hz, 2H), 7.61-7.42 (m, 3H), 6.96 (s, 1H), 6.46 (s, 1H), 3.40 (s, 2H), 1.98 (s, 3H), 1.33 (s, 2H), 1.19-1.13 (m, 2H).

Example 149: 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (Compound 243)

##STR00991##

Step 1: Methyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-nitrobenzoate (149A-1)

[1326] To a solution of methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (500 mg, 1.87 mmol, 1.0 eq) in DMF (50 mL) was slowly added Mel (664 mg, 4.68 mmol, 291 L, 2.5 eq), 15-crown-5 (103 mg, 468 mol, 92.8 L, 0.25 eq) and sodium hydride (187 mg, 4.68 mmol, 60% purity, 2.5 eq) at 0 C. The mixture was stirred at 0 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-nitrobenzoate (600 mg, crude) was obtained as a white solid. M+H.sup.+=296.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.54 (s, 1H), 7.46 (s, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 2.73 (s, 3H), 1.68 (s, 6H).

Step 2: Methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (149A-2)

[1327] To a solution of methyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-nitrobenzoate (300 mg, 1.02 mmol, 1.0 eq) in MeOH (60 mL) was added 10% palladium on carbon (300 mg). The mixture was degassed and purged with H.sub.2 three times, and then the mixture was stirred at 50 C. for 16 h under a H.sub.2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum to give the crude product methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (200 mg, 857 mol, 84% yield) as a yellow oil. M+H.sup.+=234.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.06 (br s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 3.90 (s, 3H), 2.59 (s, 3H), 1.42 (s, 6H).

Step 3: 3,3,5-Trimethyl-2-oxoindoline-6-carboxylic acid (149A-3)

[1328] To a solution of methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (100 mg, 429 mol, 1.0 eq) in a mixture of MeOH (2.5 mL) and THF (7.5 mL) was added NaOH (2 M aqueous, 4.5 mL, 21 eq). The mixture was stirred at 70 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with MTBE (3.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with 2-methyltetrahydrofuran (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methyl benzoic acid (90.0 mg), which was used in the next step without any further purification. M+H.sup.+=220.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 12.88-12.61 (m, 1H), 10.38 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 2.47 (s, 3H), 1.25 (s, 6H).

Step 4: 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (Compound 243)

[1329] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (75.2 mg, 411 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (90.0 mg, 411 mol, 1.0 eq) in DCM (10 mL) were added TEA (125 mg, 1.23 mmol, 171 L, 3.0 eq), EDCI (157 mg, 821 mol, 2.0 eq) and HOBt (111 mg, 821 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (45.3 mg, 117 mol, 28% yield) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.22 (s, 1H), 9.12 (s, 1H), 8.62 (d, J=8.2 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.82 (dd, J=7.8, 10.3 Hz, 2H), 7.61-7.42 (m, 3H), 7.05 (s, 1H), 6.47 (s, 1H), 1.97 (s, 3H), 1.32 (br s, 2H), 1.21-1.14 (m, 8H).

Example 150: 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 262)

##STR00992##

Step 1: Methyl 3,3,5-trimethylindoline-6-carboxylate (150A-1)

[1330] To a solution of methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (200 mg, 857 mol, 1.0 eq) in THF (50 mL) was slowly added BH.sub.3.Math.THF (1 M, 2.14 mL, 2.5 eq) at 0 C. The mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. MeOH (5.0 mL) was added and stirred at 70 C. for 1 h. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 3,3,5-trimethylindoline-6-carboxylate (160 mg, 730 mol, 85% yield) was obtained as a white solid. M+H.sup.+=220.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.19 (s, 1H), 6.90 (s, 1H), 3.86 (s, 3H), 3.33 (s, 2H), 2.51 (s, 3H), 1.31 (s, 6H).

Step 2: 3,3,5-Trimethylindoline-6-carboxylic acid (150A-2)

[1331] A solution of methyl 3,3,5-trimethylindoline-6-carboxylate (100 mg, 456 mol, 1.0 eq) in HCl (2 M aqueous, 1 mL) was stirred at 100 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 3,3,5-trimethylindoline-6-carboxylic acid (50.0 mg), which was used in the next step without any further purification. M+H.sup.+=206.1 (LCMS).

Step 3: 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 262)

[1332] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (44.6 mg, 244 mol, 1.0 eq) and 3,3,5-trimethylindoline-6-carboxylic acid (50.0 mg, 244 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (49.3 mg, 487 mol, 67.8 L, 2.0 eq), EDCI (56.0 mg, 292 mol, 1.2 eq) and HOBt (39.5 mg, 292 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 3,3,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (7.50 mg, 17.2 mol, 7% yield) was obtained as a yellow solid. M+H.sup.+=371.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.96 (s, 1H), 8.64 (d, J=8.1 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.80 (dd, J=7.7, 9.9 Hz, 2H), 7.59-7.41 (m, 4H), 6.72 (s, 1H), 6.15 (s, 1H), 3.09 (s, 2H), 1.90 (s, 3H), 1.30 (br s, 2H), 1.15 (s, 8H).

Example 151: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 190)

##STR00993##

Step 1: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (151A-1)

[1333] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (225 mg, 479 mol, 1.0 eq) in HOAc (15 mL) was added NaBH.sub.3CN (60.2 mg, 958 mol, 2.0 eq). The resulting mixture was stirred at 25 C. for 16 h. TLC indicated that that the starting material was completely consumed. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5), and the combined organic layers were washed with saturated aqueous Na.sub.2CO.sub.3 solution (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from I/O to 1/1. tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (115 mg, 243.86 mol, 51% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.43 (d, J=8.5 Hz, 1H), 7.91 (dd, J=7.8, 15.6 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.60-7.43 (m, 4H), 6.81 (s, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.89-4.74 (m, 1H), 3.98 (br dd, J=2.4, 4.1 Hz, 1H), 3.27-3.15 (m, 1H), 3.04 (dd, J=8.9, 16.4 Hz, 1H), 2.67 (dd, J=7.6, 16.1 Hz, 1H), 2.07 (s, 3H), 1.54 (br d, J=1.8 Hz, 2H), 1.42 (s, 9H), 1.38 (br s, 2H).

Step 2: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 190)

[1334] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (110 mg, 188 mol, 1.0 eq) in DCM (7.0 mL) was added TFA (1.56 mL). The mixture was stirred at 25 C. for 10 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (12.1 mg, 29.8 mol, 16% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=372.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.92 (s, 1H), 8.63 (d, J=8.3 Hz, 1H), 7.97-7.86 (m, 4H), 7.83-7.74 (m, 2H), 7.61-7.29 (m, 3H), 6.79 (s, 1H), 6.21 (s, 1H), 3.99-3.87 (m, 1H), 3.04-2.96 (m, 1H), 2.88-2.75 (m, 2H), 2.69 (br d, J=7.1 Hz, 1H), 1.89 (s, 3H), 1.30 (m, 2H), 1.18-1.09 (m, 2H).

Example 152: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 231)

##STR00994##

Step 1: tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (152A-1)

[1335] To a solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (90.0 mg, 186 mol, 1.0 eq) in AcOH (5.0 mL) was added NaBH.sub.3CN (23.4 mg, 372.21 mol, 2.0 eq). The resulting mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by the addition of saturated aqueous Na.sub.2CO.sub.3 (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (420 mg, 92% purity) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=486.2 (LCMS).

Step 2: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (Compound 231)

[1336] To a solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (110 mg, 181 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 2.4 mL), the mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)indo line-6-carboxamide (15.4 mg, 36.0 mol, 20% yield, HCl salt) was obtained as a yellow solid solid. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.97-8.90 (m, 1H), 8.65 (br d, J=8.5 Hz, 2H), 7.98-7.89 (m, 1H), 7.85-7.75 (m, 2H), 7.60-7.41 (m, 3H), 6.83-6.78 (m, 1H), 6.25-6.20 (m, 1H), 4.05-3.97 (m, 1H), 3.64-3.62 (m, 3H), 3.15-2.65 (m, 5H), 1.95-1.87 (m, 3H), 1.36-1.28 (m, 2H), 1.19-1.10 (m, 2H).

Example 153: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (Compound 176)

##STR00995##

Step 1: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (Compound 176)

[1337] To a solution of 5-methyl-1H-indazole-6-carboxylic acid (50.0 mg, 284 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (52.0 mg, 284 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (86.2 mg, 851 mol, 119 L, 3.0 eq), EDCI (81.6 mg, 426 mol, 1.5 eq) and HOBt (57.5 mg, 426 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) at 25 C. and extracted with EtOAc (2.0 mL3). The combined organic layers were washed with brine (2.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (15.5 mg, 45.0 mol, 16% yield, HCl salt) was obtained as a white solid. M+H.sup.+=342.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.24-9.19 (m, 1H), 8.18-8.14 (m, 1H), 7.98-7.91 (m, 2H), 7.88-7.80 (m, 2H), 7.61-7.45 (m, 5H), 6.64 (s, 1H), 2.12 (s, 3H), 1.42-1.35 (m, 2H), 1.22-1.15 (m, 2H).

Example 154: 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (Compound 304) and 2-(azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2H-indazole-6-carboxamide (Compound 305)

##STR00996## ##STR00997##

Step 1: tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indazol-1-yl)azetidine-1-carboxylate (154A-1) and tert-butyl 3-(5-methyl-6-((1-(naphthalene-1-yl)cyclopropyl)carbamoyl)-2H-indazol-2-yl)azetidine-1-carboxylate (154A-2)

[1338] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (150 mg, 439 mol, 1.0 eq) and tert-butyl 3-iodoazetidine-1-carboxylate (249 mg, 879 mol, 2.0 eq) in DMF (5.0 mL) was added cesium carbonate (429 mg, 1.32 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R/1=0.4, R/2=0.6). tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indazol-1-yl) azetidine-1-carboxylate (140 mg, 282 mol, 64% yield) was obtained as a colorless oil. M+H.sup.+=497.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 7.97-7.91 (m, 1H), 7.85 (dd, J=3.0, 7.6 Hz, 2H), 7.60-7.45 (m, 4H), 7.39 (s, 1H), 5.64-5.53 (m, 1H), 4.33-4.26 (m, 2H), 4.18 (br s, 2H), 2.05 (s, 3H), 1.41 (s, 11H), 1.23-1.19 (m, 2H). tert-Butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2H-indazol-2-yl)azetidine-1-carboxylate (50.0 mg, 101 mol, 23% yield) was obtained as a colorless oil. M56+H.sup.+=441.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21 (s, 1H), 8.69 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.87-7.80 (m, 2H), 7.63-7.57 (m, 1H), 7.56-7.51 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 5.54-5.40 (m, 1H), 4.36 (br t, J=8.2 Hz, 2H), 4.20 (br d, J=4.0 Hz, 2H), 2.10 (s, 3H), 1.42 (s, 9H), 1.38 (br s, 2H), 1.19 (s, 2H).

Step 2: 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (Compound 304)

[1339] To a stirred solution of tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-indazol-1-yl)azetidine-1-carboxylate (70.0 mg, 141 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 1-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indazole-6-carboxamide (22.3 mg, 50.9 mol, 36% yield, HCl salt) was obtained as a white solid. M+H.sup.+=397.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.38-9.23 (m, 2H), 9.20 (s, 1H), 8.66 (d, J=8.1 Hz, 1H), 8.21 (s, 1H), 7.97-7.92 (m, 1H), 7.86 (dd, J=4.1, 7.6 Hz, 2H), 7.62-7.44 (m, 5H), 5.78 (t, J=7.6 Hz, 1H), 4.45-4.31 (m, 4H), 2.07 (s, 3H), 1.46-1.36 (m, 2H), 1.27-1.16 (m, 2H).

Step 3: 2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2H-indazole-6-carboxamide (Compound 305)

[1340] To a stirred solution of tert-butyl 3-(5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2H-indazol-2-yl)azetidine-1-carboxylate (70.0 mg, 141 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (800 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(Azetidin-3-yl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2H-indazole-6-carboxamide (20.9 mg, 40.9 mol, 51% yield, TFA salt) was obtained as a white solid. M+H.sup.+=397.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (s, 1H), 9.15 (br d, J=10.1 Hz, 1H), 8.97-8.86 (m, 1H), 8.69 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.84 (t, J=8.1 Hz, 2H), 7.64-7.51 (m, 2H), 7.51-7.42 (m, 2H), 7.32 (s, 1H), 5.67 (quin, J=7.5 Hz, 1H), 4.54-4.34 (m, 4H), 2.10 (s, 3H), 1.39 (s, 2H), 1.26-1.17 (m, 2H).

Example 155: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 197)

##STR00998##

Step 1: Methyl 5-hydroxy-4-iodo-2-methylbenzoate (155A-1)

[1341] To a solution of methyl 5-hydroxy-2-methylbenzoate (1.00 g, 6.02 mmol, 1.0 eq) in AcOH (10 mL) was added NIS (1.49 g, 6.62 mmol, 1.1 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5-hydroxy-4-iodo-2-methylbenzoate (1.70 g, 5.82 mmol, 97% yield) was obtained as a white solid. M+H.sup.+=293.0 (LCMS).

Step 2: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (155A-2)

[1342] To a solution of methyl 5-hydroxy-4-iodo-2-methylbenzoate (1.70 g, 5.82 mmol, 1.0 eq) and tert-butyl prop-2-yn-1-ylcarbamate (903 mg, 5.82 mmol, 1.0 eq) in a mixture of H.sub.2O (10 mL) and toluene (20 mL) were added TEA (1.18 g, 11.6 mmol, 1.62 mL, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (123 mg, 175 mol, 0.03 eq) and CuI (111 mg, 582 mol, 0.1 eq). The mixture was stirred at 70 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/7. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (1.00 g, 3.13 mmol, 54% yield) was obtained as a yellow oil. M56+H.sup.+=264.1 (LCMS).

Step 3: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylic acid (155A-3)

[1343] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (800 mg, 2.51 mmol, 1.0 eq) in a mixture of THF (5.0 mL) and EtOH (5.0 mL) was added NaOH (2 M in aqueous, 3.2 mL). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with MTBE (2.0 mL3). The aqueous layer was basified to pH 4 using HCl (1 M aqueous) and extracted with EtOAc (8.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylic acid (700 mg) as a white solid. M56+H.sup.+=250.1 (LCMS).

Step 4: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (155A-4)

[1344] To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylic acid (700 mg, 2.29 mmol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (441 mg, 2.41 mmol, 20.0 L, 1.0 eq) in DCM (10 mL) were added TEA (696 mg, 6.88 mmol, 957 L, 3.0 eq), EDCI (879 mg, 4.59 mmol, 2.0 eq) and HOBt (620 mg, 4.59 mmol, 2.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (800 mg, 1.70 mmol, 74% yield) was obtained as a white solid. M+H.sup.+=471.3 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.42-8.36 (m, 1H), 7.91-7.79 (m, 2H), 7.76-7.70 (m, 1H), 7.54-7.37 (m, 3H), 7.16-7.12 (m, 2H), 6.47-6.36 (m, 2H), 4.87-4.79 (m, 1H), 4.46-4.22 (m, 2H), 2.22-2.15 (m, 3H), 1.41-1.39 (m, 2H), 1.35 (br s, 9H), 1.35-1.31 (m, 2H).

Step 5: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 197)

[1345] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (80.0 mg, 640 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (26.6 mg, 65.5 mol, 19% yield, HCl salt) was obtained as a white solid. M+H.sup.+=371.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18 (s, 1H), 8.67 (d, J=8.3 Hz, 1H), 8.54 (br s, 2H), 7.97-7.91 (m, 1H), 7.83 (s, 2H), 7.62-7.44 (m, 3H), 7.43-7.41 (m, 1H), 7.27-7.22 (m, 1H), 6.96-6.90 (m, 1H), 4.40-4.16 (m, 2H), 2.13 (s, 3H), 1.60-1.31 (m, 2H), 1.27-1.06 (m, 2H).

Example 156: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 198)

##STR00999##

Step 1: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 198)

[1346] To a solution of 2-(aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (70.0 mg, 189 mol, 1.0 eq, HCl salt) in MeOH (2.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (15.3 mg, 189 mol, 14.1 L, 37% purity, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (11.9 mg, 189 mol, 1.0 eq) was added. The reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (30.9 mg, 77.5 mol, 41% yield, HCl salt) was obtained as a white solid. M+H.sup.+=399.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 8.70-8.61 (m, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.63-7.43 (m, 4H), 7.30-7.26 (m, 1H), 7.13-7.09 (m, 1H), 4.51 (br s, 2H), 2.74 (br s, 6H), 2.11 (s, 3H), 1.42-1.33 (m, 2H), 1.24-1.14 (m, 2H).

Example 157: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 220)

##STR01000##

Step 1: Methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (157A-1)

[1347] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (200 mg, 626 mol, 1.0 eq) in DMF (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added sodium hydride (50.1 mg, 1.25 mmol, 60% purity, 2.0 eq) dropwise at 0 C. for 30 min, then iodomethane (88.9 mg, 626 mol, 39.0 L, 1.0 eq) was added and the mixture was stirred at 0 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (220 mg, 660 mol, 53% yield) was obtained as a colorless oil. M56+H.sup.+=278.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.05 (s, 1H), 7.37 (s, 1H), 6.61-6.44 (m, 1H), 4.61-4.47 (m, 2H), 3.92 (s, 3H), 3.01-2.91 (m, 3H), 2.70-2.64 (m, 3H), 1.52-1.46 (m, 9H).

Step 2: 2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofuran-6-carboxylic acid (157A-2)

[1348] To a solution of methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofuran-6-carboxylate (200 mg, 600 mol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (15 mL) was added NaOH (2 M aqueous, 6.3 mL, 21 eq). The mixture was stirred at 25 C. for 1 h. Then the mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, H.sub.2O (20 mL) was added, and the mixture was washed with MTBE (5.0 mL3). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with 2-methyltetrahydrofuran (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methyl benzoic acid (180 mg), which was used in the next step without any further purification. M+H.sup.+=320.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.20 (s, 1H), 7.40 (s, 1H), 6.61-6.49 (m, 1H), 4.56 (br d, J=14.8 Hz, 2H), 2.98 (br s, 3H), 2.73 (s, 3H), 1.54-1.46 (m, 9H).

Step 3: tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (157A-3)

[1349] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (100 mg, 546 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofuran-6-carboxylic acid (174 mg, 546 mol, 1.0 eq) in DCM (10 mL) were added TEA (166 mg, 1.64 mmol, 228 L, 3.0 eq), EDCI (209 mg, 1.09 mmol, 2.0 eq) and HOBt (148 mg, 1.09 mmol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (150 mg, 311 mol, 57% yield) was obtained as a white solid. M+H.sup.+=485.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47 (d, J=8.4 Hz, 1H), 8.00-7.88 (m, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.64-7.45 (m, 3H), 7.23 (s, 2H), 6.55-6.38 (m, 2H), 4.53-4.40 (m, 2H), 2.97-2.84 (m, 3H), 2.27 (s, 3H), 1.46 (br s, 9H), 0.91-0.83 (m, 4H).

Step 4: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (Compound 220)

[1350] To a stirred solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)benzofuran-2-yl)methyl)carbamate (50.0 mg, 103 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzofuran-6-carboxamide (9.04 mg, 21.5 mol, 21% yield, HCl salt) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20 (s, 1H), 8.67 (d, J=8.2 Hz, 1H), 7.97-7.92 (m, 1H), 7.84 (t, J=7.6 Hz, 2H), 7.62-7.44 (m, 4H), 7.26 (s, 1H), 7.01 (s, 1H), 4.36 (s, 2H), 2.57 (s, 3H), 2.13 (s, 3H), 1.39 (s, 2H), 1.25-1.17 (m, 2H).

Example 158: (S)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 235) and (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 236)

##STR01001##

Step 1: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (158A-1)

[1351] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)nbenzo furan-2-yl)methyl)carbamate (200 mg, 425 mol, 1.0 eq) in i-PrOH (20 mL) was added 10% palladium on carbon (100 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for three times. The mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with i-PrOH (4.0 mL5). The combined filtrates were concentrated under vacuum to give the crude product tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (400 mg) as a colorless oil. M56+H.sup.+=417.2 (LCMS).

Step 2: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydro benzofuran-6-carboxamide (158A-2)

[1352] To a solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (400 mg, 846 mol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 498 L). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (120 mg, 293 mol, 17% yield, HCl salt) was obtained as a white solid. M+H.sup.+=373.3 (LCMS).

Step 3: (S)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 235) and (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 236)

[1353] 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (120 mg, 293 mol, HCl salt) was further separated by SFC (DAICEL CHIRALPAK AD column (25030 mm, 10 m); flow rate: 3.4 mL/min; gradient: 42%-42% B over 8 min; mobile phase A: CO.sub.2, mobile phase B: 0.1% isopropyl amine in EtOH). (R)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carb oxamide (17.8 mg) was obtained as a white solid. M+H.sup.+=373.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47-8.42 (m, 1H), 7.95-7.85 (m, 2H), 7.82-7.76 (m, 1H), 7.64-7.40 (m, 3H), 6.87 (s, 1H), 6.53 (s, 1H), 4.88-4.65 (m, 1H), 3.17 (br dd, J=9.2, 16.1 Hz, 1H), 3.00-2.71 (m, 3H), 2.09 (s, 3H), 1.57-1.51 (m, 2H), 1.42-1.34 (m, 2H). (S)-2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (15.4 mg) was obtained as a white solid. M+H.sup.+=373.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.47-8.42 (m, 1H), 7.95-7.85 (m, 2H), 7.82-7.76 (m, 1H), 7.64-7.40 (m, 3H), 6.87 (s, 1H), 6.53 (s, 2H), 4.88-4.65 (m, 1H), 3.17 (br dd, J=9.2, 16.1 Hz, 1H), 3.00-2.71 (m, 3H), 2.09 (s, 3H), 1.57-1.51 (m, 2H), 1.42-1.34 (m, 2H).

Example 159: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 230)

##STR01002##

Step 1: tert-Butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (159A-1)

[1354] To a solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzofuran-2-yl)methyl)carbamate (60.0 mg, 61.9 mol, 1.0 eq) in i-PrOH (20 mL) was added 10% palladium on carbon (60.0 mg). The mixture was degassed and purged with H.sub.2 three times and then the mixture was stirred at 25 C. for 4 h under a H.sub.2 atmosphere. LCMS indicated that 40% starting material still remained and 50% desired mass was detected. The combined organic layers were filtered through a pad of Celite and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.3). tert-Butylmethyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2,3-dihydro benzofuran-2-yl)methyl)carbamate (40.0 mg, 41.1 mol, 33% yield) was obtained as a yellow oil. M56+H.sup.+=431.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.44 (d, J=8.4 Hz, 1H), 7.92 (dd, J=7.6, 15.7 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H), 7.61-7.44 (m, 3H), 6.90 (s, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 4.99-4.84 (m, 1H), 3.67-3.48 (m, 1H), 3.22-3.11 (m, 1H), 2.93-2.88 (m, 3H), 2.85 (d, J=7.2 Hz, 1H), 2.81 (d, J=7.2 Hz, 1H), 2.10 (s, 3H), 1.44 (br s, 9H), 1.41-1.37 (m, 2H), 1.30-1.25 (m, 2H).

Step 2: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 230)

[1355] To a stirred solution of tert-butyl methyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (30.0 mg, 61.7 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (8.20 mg, 19.0 mol, 31% yield, HCl salt) was obtained as a white solid. M+H.sup.+=387.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 2H), 8.89-8.75 (m, 1H), 8.64 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.81 (dd, J=7.6, 13.6 Hz, 2H), 7.62-7.49 (m, 2H), 7.48-7.43 (m, 1H), 7.01 (s, 1H), 6.44 (s, 1H), 5.14-4.96 (m, 1H), 3.30 (dd, J=9.4, 16.6 Hz, 1H), 3.23-3.14 (m, 1H), 3.08 (ddd, J=4.6, 8.5, 12.7 Hz, 1H), 2.90 (dd, J=6.5, 16.2 Hz, 1H), 2.56 (br t, J=5.3 Hz, 3H), 1.98 (s, 3H), 1.33 (s, 2H), 1.24-1.10 (m, 2H).

Example 160: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 224)

##STR01003##

Step 1: 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (Compound 224)

[1356] To a solution of 2-(aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (101 mg, 270 mol, 1.0 eq, HCl salt) in MeOH (3.0 mL) was added TEA (50 L), followed by the addition of formaldehyde (46.7 mg, 540 mmol, 59.1 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (33.9 mg, 540 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2,3-dihydrobenzo furan-6-carboxamide (17.5 mg, 42.8 mol, 16% yield HCl salt) was obtained as a white solid. M+H.sup.+=401.1 (LCMS); 1H NMR (400 MHZ, CDCl.sub.3) 12.80-12.43 (m, 1H), 8.55-8.42 (m, 1H), 7.90 (br dd, J=7.7, 11.2 Hz, 2H), 7.79 (br d, J=8.1 Hz, 1H), 7.62-7.41 (m, 3H), 6.90-6.80 (m, 1H), 6.57-6.47 (m, 1H), 5.40 (br s, 1H), 3.47-3.24 (m, 2H), 3.19-3.05 (m, 1H), 2.98-2.83 (m, 6H), 2.79-2.68 (m, 1H), 2.11-1.97 (m, 3H), 1.63-1.47 (m, 2H), 1.44-1.30 (m, 2H).

Example 161: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-propyl-2,3-dihydrobenzofuran-6-carboxamide (Compound 397)

##STR01004##

Step 1: (Z)-Methyl 4-iodo-2-methyl-5-(pent-2-en-1-yloxy)benzoate (161A-1)

[1357] A mixture of methyl 5-hydroxy-4-iodo-2-methylbenzoate (500 mg, 1.71 mmol, 1.0 eq) and (Z)-pent-2-en-1-ol (221 mg, 2.57 mmol, 1.5 eq) in toluene (25 mL) was degassed and purged with N.sub.2 three times. To the mixture was added CMBP (620 mg, 2.57 mmol, 1.5 eq) dropwise at 20 C. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (Z)-Methyl 4-iodo-2-methyl-5-(pent-2-en-1-yloxy)benzoate (400 mg, 1.11 mmol, 65% yield) was obtained as a colorless oil. M+H.sup.+=361.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.77 (s, 1H), 7.35-7.27 (m, 1H), 5.70-5.50 (m, 2H), 4.73-4.58 (m, 2H), 3.84-3.78 (m, 3H), 2.44-2.35 (m, 3H), 2.17-2.08 (m, 2H), 1.00-0.94 (m, 3H).

Step 2: Methyl 5-methyl-3-propylbenzofuran-6-carboxylate (161A-2)

[1358] A mixture of methyl(Z)-methyl 4-iodo-2-methyl-5-(pent-2-en-1-yloxy)benzoate (500 mg, 1.71 mmol, 1.0 eq) in DMF (25 mL) was degassed and purged with N.sub.2 three times. To the mixture were added Pd(OAc) 2 (24.9 mg, 111 mol, 0.1 eq), TBAC (340 mg, 1.22 mmol, 342 L, 1.1 eq) and sodium carbonate (294 mg, 2.78 mmol, 2.5 eq). The mixture was stirred at 100 C. for 18 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-methyl-3-propylbenzofuran-6-carboxylate (200 mg, 861 mol, 78% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.97 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 3.87-3.81 (m, 3H), 2.64-2.57 (m, 5H), 1.74-1.59 (m, 2H), 0.96-0.91 (m, 3H).

Step 3: Methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (161A-3)

[1359] To a solution of methyl 5-methyl-3-propylbenzofuran-6-carboxylate (160 mg, 689 mol, 1.0 eq) in i-PrOH (10 mL) was added 10% palladium on carbon (100 mg). The mixture was degassed and purged with H.sub.2 three times. The resulting mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The combined organic layers were filtered through Celite pad and the filtrate was concentrated under vacuum to give the crude product methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (80.0 mg, 341 mol, 50% yield) as a yellow oil. M+H.sup.+=235.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.31 (s, 1H), 7.03 (s, 1H), 4.65 (t, J=8.8 Hz, 1H), 4.22 (dd, J=6.6, 8.7 Hz, 1H), 3.87 (s, 3H), 3.52-3.35 (m, 1H), 2.53 (s, 3H), 1.82-1.71 (m, 1H), 1.61-1.32 (m, 3H), 0.97 (t, J=7.3 Hz, 3H).

Step 4: 5-Methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylic acid (161A-4)

[1360] To a solution of methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (80.0 mg, 196 mol, 1.0 eq) in a mixture of MeOH (1.6 mL) and THF (3.2 mL) was added NaOH (2 M aqueous, 3.6 mL, 21 eq). The mixture was stirred at 70 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with MTBE (3.0 mL3). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-methyl-3-propyl-2,3-dihydro benzofuran-6-carboxylic acid (80.0 mg) as a yellow oil, which was used in the next step without any further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.57 (br s, 1H), 7.13 (d, J=3.4 Hz, 2H), 4.62 (t, J=8.9 Hz, 1H), 4.18 (dd, J=6.7, 8.8 Hz, 1H), 3.49-3.39 (m, 1H), 2.43 (s, 3H), 1.35 (s, 4H), 0.91 (t, J=7.2 Hz, 3H).

Step 5: 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-propyl-2,3-dihydrobenzofuran-6-carboxamide (Compound 397)

[1361] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (58.2 mg, 318 mol, 1.0 eq) and 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylic acid (70.0 mg, 318 mol, 1.0 eq) in DMF (8 mL) were added TEA (64.3 mg, 636 mol, 88.5 L, 2 eq), EDCI (73.1 mg, 381 mol, 1.2 eq) and HOBt (51.5 mg, 381 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-propyl-2,3-dihydrobenzofuran-6-carboxamide (45.5 mg, 117 mol, 37% yield) was obtained as a white solid. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.7, 10.8 Hz, 2H), 7.60-7.42 (m, 3H), 6.96 (s, 1H), 6.41 (s, 1H), 4.54 (t, J=8.9 Hz, 1H), 4.11 (dd, J=6.4, 8.7 Hz, 1H), 3.39-3.33 (m, 1H), 1.95 (s, 3H), 1.67-1.56 (m, 1H), 1.46-1.24 (m, 5H), 1.16 (br d, J=3.5 Hz, 2H), 0.92-0.84 (m, 3H).

Example 162: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-5-carboxamide (Compound 223)

##STR01005##

Step 1: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-5-carboxamide (Compound 223)

[1362] To a mixture of 6-methyl-1H-indole-5-carboxylic acid (60.0 mg, 343 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (62.8 mg, 343 mol, 8.75 L, 1.0 eq) in DCM (5.0 mL) was added TEA (104 mg, 1.03 mmol, 143 L, 3.0 eq), followed by EDCI (98.5 mg, 514 mol, 1.5 eq) and HOBt (69.4 mg, 514 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-5-carboxamide (64.2 mg, 186 mol, 54% yield) was obtained as a white solid. M+H.sup.+=341.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.08-10.87 (m, 1H), 9.01-8.90 (m, 1H), 8.78-8.64 (m, 1H), 7.97-7.91 (m, 1H), 7.87-7.79 (m, 2H), 7.63-7.43 (m, 3H), 7.32-7.28 (m, 1H), 7.27-7.18 (m, 1H), 7.13-7.05 (m, 1H), 6.37-6.31 (m, 1H), 2.22-2.15 (m, 3H), 1.43-1.30 (m, 2H), 1.22-1.11 (m, 2H).

Example 163: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 280)

##STR01006##

Step 1: Methyl 5-amino-4-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (163A-1)

[1363] To a solution of methyl 4,5-diamino-2-methylbenzoate (300 mg, 1.66 mmol, 1.0 eq) and 2-((tert-butoxycarbonyl)amino) acetic acid (292 mg, 1.66 mmol, 1.0 eq) in THF (9.0 mL) was added N,N-methanediylidenedicyclohexanamine (687 mg, 3.33 mmol, 674 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/4. Methyl 5-amino-4-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (200 mg, 593 mmol, 53% yield) was obtained as a white solid. M+H.sup.+=338.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.95 (s, 1H), 7.80 (s, 1H), 6.56 (s, 1H), 5.40 (br t, J=5.7 Hz, 1H), 3.94 (d, J=5.7 Hz, 2H), 3.81 (s, 3H), 2.51 (s, 3H), 1.48 (s, 9H).

Step 2: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (163A-2)

[1364] A solution of methyl 5-amino-4-(2-((tert-butoxycarbonyl)amino) acetamido)-2-methylbenzoate (200 mg, 593 mol, 1.0 eq) in acetic acid (7.0 mL) was stirred at 80 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (200 mg) was obtained as a white solid. M+H.sup.+=320.3 (LCMS).

Step 3: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (163A-3)

[1365] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylate (180 mg, 564 mol, 1.0 eq) in a mixture of H.sub.2O (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 845 L, 3.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with MTBE (15 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (150 mg), which was used in the next step without any further purification. M+H.sup.+=306.3 (LCMS).

Step 4: tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (163A-4)

[1366] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (32.7 mg, 179 mol, 0.8 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 328 mol, 1.0 eq) in DCM (10 mL) were added TEA (45.2 mg, 446 mol, 62.1 L, 2.0 eq), EDCI (51.3 mg, 268 mol, 1.2 eq) and HOBt (36.2 mg, 268 mol, 1.2 eq). The mixture was stirred at 20 C. for 18 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.7). tert-Butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (100 mg, crude) was obtained as a colorless oil. M+H.sup.+=471.3 (LCMS).

Step 5: 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 280)

[1367] To a stirred solution of tert-butyl((5-methyl-6-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (30.0 mg, 63.8 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-benzo[d]imidazole-6-carboxamide (11.7 mg, 31.6 mol, 50% yield, HCl salt) was obtained as a white solid. M+H.sup.+=371.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.15 (s, 1H), 8.73-8.54 (m, 4H), 7.95 (d, J=7.8 Hz, 1H), 7.83 (dd, J=2.7, 7.7 Hz, 2H), 7.62-7.51 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 4.30 (br s, 2H), 2.19 (s, 3H), 1.39 (s, 2H), 1.23-1.14 (m, 2H).

Example 164: 2-(Aminomethyl)-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]thiazole-5-carboxamide (Compound 245)

##STR01007##

Step 1: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylate (164A-1)

[1368] A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq), tert-butyl(2-amino-2-thioxoethyl)carbamate (196 mg, 1.03 mmol, 1.0 eq) and CuO (82.0 mg, 1.03 mmol, 1.0 eq) in DMF (6.0 mL) was degassed and purged with N.sub.2 three times. Pd.sub.2 (dba) 3 (18.9 mg, 21.6 mol, 1.1 eq) and DPPF (28.6 mg, 51.5 mol, 0.05 eq) were added and the mixture was stirred at 60 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylate (340 mg, 1.11 mmol, 99% yield) was obtained as a white solid. M+H.sup.+=337.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =8.32 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 4.51 (br d, J=6.1 Hz, 2H), 3.87 (s, 3H), 2.61 (s, 3H), 1.42 (s, 9H).

Step 2: 2-(((tert-Butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylic acid (164A-2)

[1369] To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylate (340 mg, 1.11 mmol, 1.0 eq) in a mixture of THF (10 mL) and H.sub.2O (5.0 mL) was added LiOH.Math.H.sub.2O (102 mg, 2.71 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and washed with MTBE (15 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylic acid (340 mg), which was used in the next step without any further purification. M+H.sup.+=323.0 (LCMS).

Step 3: tert-Butyl((6-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzo[d]thiazol-2-yl)methyl)carbamate (164A-3)

[1370] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (56.8 mg, 310 mol, 1.0 eq) and 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[d]thiazole-5-carboxylic acid (100 mg, 310 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (94.2 mg, 931 mol, 130 L, 3.0 eq), EDCI (119 mg, 620 mol, 2.0 eq) and HOBt (83.8 mg, 620 mol, 2.0 eq). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl((6-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzo[d]thiazol-2-yl)methyl)carbamate (110 mg), which was used in the next step without any further purification. M+H.sup.+=488.3 (LCMS).

Step 4: 2-(Aminomethyl)-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]thiazole-5-carboxamide (Compound 245)

[1371] To a stirred solution of tert-butyl((6-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzo[d]thiazol-2-yl)methyl)carbamate (100 mg, 205 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 5%-35% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-(Aminomethyl)-6-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]thiazole-5-carboxamide (74.7 mg, 173 mol, 84% yield, HCl salt) was obtained as a white solid. M+H.sup.+=388.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.32 (s, 1H), 8.78-8.53 (m, 4H), 7.99-7.93 (m, 2H), 7.85 (t, J=7.9 Hz, 2H), 7.65-7.45 (m, 4H), 4.58 (br s, 2H), 2.21 (s, 3H), 1.46-1.20 (m, 4H).

Example 165: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (Compound 238)

##STR01008##

Step 1: Methyl 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (165A-1)

[1372] To a solution of methyl 4,5-diamino-2-methylbenzoate (400 mg, 2.22 mmol, 1.0 eq) in MeCN (40 mL) was added CDI (396 mg, 2.44 mmol, 1.1 eq). The resulting mixture was stirred at 70 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (340 mg, 1.65 mmol, 74% yield) was obtained as a white solid. M+H.sup.+=207.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.89 (br s, 1H), 10.71 (s, 1H), 7.41 (s, 1H), 6.84 (s, 1H), 3.78 (s, 3H), 2.55-2.52 (m, 3H).

Step 2: 6-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (165A-2)

[1373] To a solution of methyl 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (120 mg, 582 mol, 1.0 eq) in MeOH (5.0 mL) was added NaOH (2 M aqueous, 1.08 mL, 3.5 eq). The mixture was stirred at 50 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (3.0 mL) and extracted with MTBE (5.0 mL2). The aqueous was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (110 mg) as a white solid. M+H.sup.+=193.2 (LCMS).

Step 3: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (Compound 238)

[1374] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (105 mg, 572 mol, 1.0 eq) and 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (110 mg, 572 mol, 1.0 eq) in DCM (18 mL) were added TEA (174 mg, 1.72 mmol, 239 L, 3.0 eq), EDCI (219 mg, 1.14 mmol, 2.0 eq) and HOBt (155 mg, 1.14 mmol, 2.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (20.0 mg, 56.0 mol, 10% yield) was obtained as a white solid. M+H.sup.+=358.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.59 (s, 1H), 10.49 (s, 1H), 8.99 (s, 1H), 8.67 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.85-7.78 (m, 2H), 7.62-7.42 (m, 3H), 6.64 (d, J=13.0 Hz, 2H), 2.07 (s, 3H), 1.40-1.29 (m, 2H), 1.20-1.08 (m, 2H).

Example 166: 1,3,6-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (Compound 237)

##STR01009##

Step 1: Methyl 1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (166A-1)

[1375] To a solution of methyl 6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (100 mg, 485 mol, 1.0 eq) in DMF (5.0 mL) were added CH.sub.3I (413 mg, 2.91 mmol, 181 L, 6.0 eq) and K.sub.2CO.sub.3 (402 mg, 2.91 mmol, 6.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.2). Methyl 1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (88.0 mg, 376 mol, 77% yield) was obtained as a white solid. M+H.sup.+=235.2 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 7.59 (s, 1H), 7.11 (s, 1H), 3.82 (s, 3H), 3.34 (s, 6H), 2.58 (s, 3H).

Step 2: 1,3,6-Trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (166A-2)

[1376] To a solution of methyl 1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (70.0 mg, 299 mol, 1.0 eq) in MeOH (3.5 mL) was added NaOH (2 M aqueous, 523 L, 3.5 eq). The mixture was stirred at 50 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (3.0 mL) and extracted with MTBE (5.0 mL2). The aqueous was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL5), the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (60.0 mg) as a white solid. M+H.sup.+=221.0 (LCMS).

Step 3: 1,3,6-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (Compound 237)

[1377] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (83.2 mg, 454 mol, 1.0 eq) and 1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 454 mol, 1.0 eq) in DCM (15 mL) were added TEA (138 mg, 1.36 mmol, 190 L, 3.0 eq), EDCI (174 mg, 908 mol, 2.0 eq) and HOBt (123 mg, 908 mol, 2.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 1,3,6-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (36.8 mg, 95.5 mol, 21% yield) was obtained as a white solid. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 1H), 8.69 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.84 (dd, J=3.7, 7.6 Hz, 2H), 7.61-7.44 (m, 3H), 6.91 (d, J=5.0 Hz, 2H), 3.26 (d, J=8.4 Hz, 6H), 2.10 (s, 3H), 1.42-1.34 (m, 2H), 1.23-1.15 (m, 2H).

Example 167: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 297)

##STR01010##

Step 1: Methyl 7-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (167A-1)

[1378] To a solution of methyl 4,5-diamino-2-methylbenzoate (400 mg, 2.22 mmol, 1.0 eq) in DMA (8.0 mL) were added NaHCO.sub.3 (1.86 g, 22.2 mmol, 10 eq) and 1,2-dibromoethane (500 mg, 2.66 mmol, 200 mL, 1.2 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL5). The combined organic layers were washed with brine (20 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 7-methyl-1,2,3,4-tetrahydro quinoxaline-6-carboxylate (200 mg, 969 mol, 44% yield) was obtained as a yellow solid. M+H.sup.+=207.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.01 (s, 1H), 6.18 (s, 1H), 6.12 (br s, 1H), 5.36 (br s, 1H), 3.67 (s, 3H), 3.26 (br d, J=2.8 Hz, 2H), 3.16-3.10 (m, 2H), 1.96 (s, 3H).

Step 2: 1-tert-Butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-1,7(2H)-dicarboxylate (167A-2)

[1379] To a solution of methyl 7-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (200 mg, 969 mol, 1.0 eq) in DMF (20 mL) was added sodium hydride (96.9 mg, 2.42 mmol, 60% purity, 2.5 eq) at 0 C., followed by di-tert-butyl dicarbonate (529 mg, 2.42 mmol, 557 L, 2.5 eq). The resulting mixture was stirred at 25 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-tert-Butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-1,7(2H)-dicarboxylate (150 mg, 489 mol, 50% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.99 (s, 1H), 6.82 (br s, 1H), 6.39 (s, 1H), 3.71 (s, 3H), 3.58 (br t, J=4.9 Hz, 2H), 3.28 (br d, J=3.0 Hz, 2H), 2.38 (s, 3H), 1.46 (s, 9H).

Step 3: 4-(tert-Butoxycarbonyl)-7-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (167A-3)

[1380] To a solution of 1-tert-butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-1,7(2H)-dicarboxylate (150 mg, 489 mol, 1.0 eq) in a mixture of THF (7.5 mL) and MeOH (7.5 mL) was added NaOH (2 M aqueous, 1.22 mL, 5.0 eq). The resulting mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and adjust the pH to 6 using HCl (1 M aqueous), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H.sub.2O (5.0 mL) and dried under vacuum to give 4-(tert-butoxycarbonyl)-7-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (100 mg, 342 mol, 70% yield) as an orange solid, which was used in the next step without any further purification. MH.sup.=291.0 (LCMS).

Step 4: tert-Butyl 6-methyl-7-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-3,4-dihydro quinoxaline-1 (2H)-carboxylate (167A-4)

[1381] To a solution of 4-(tert-butoxycarbonyl)-7-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (100 mg, 342 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (62.7 mg, 342 mol, 1.0 eq) in DMF (10 mL) were added TEA (104 mg, 1.03 mmol, 143 L, 3.0 eq), EDCI (78.7 mg, 411 mol, 1.2 eq) and HOBt (55.5 mg, 411 mol, 1.2 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL), and a precipitate was formed. The mixture was filtered and the filter cake was washed with H.sub.2O (5.0 mL) and dried under vacuum to give tert-butyl 6-methyl-7-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-3,4-dihydroquinoxaline-1 (2H)-carboxylate (130 mg, 284 mol, 83% yield) as an orange solid. M+H.sup.+=458.2 (LCMS).

Step 5: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 297)

[1382] To a solution of tert-butyl 6-methyl-7-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-3,4-dihydroquinoxaline-1 (2H)-carboxylate (130 mg, 284 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 10 mL). The resulting mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated at 30 C. under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (35.9 mg, 90.5 mol, 32% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=358.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.93 (br s, 1H), 8.65 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.87-7.74 (m, 2H), 7.63-7.37 (m, 3H), 6.83-6.66 (m, 1H), 6.46 (br s, 1H), 3.40-3.25 (m, 4H), 1.99 (s, 3H), 1.32 (br s, 2H), 1.15 (br s, 2H).

Example 168: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide (Compound 227)

##STR01011##

Step 1: Methyl 6-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (168A-1)

[1383] To a solution of methyl 6-methylquinoline-7-carboxylate (51.0 mg, 254 mol, 1.0 eq) in i-PrOH (12 mL) was added 10% palladium on carbon (10 mg, 254 mol, 1.0 eq) at 20 C. under a N.sub.2 atmosphere. The mixture was degassed and purged with H.sub.2 three times, then stirred at 50 C. for 4 h under a H.sub.2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was allowed to cool to room temperature, filtered through a pad of Celite and the filter cake was washed with i-PrOH (4.0 mL3). The combined filtrates were concentrated to give the crude product methyl 6-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (70.0 mg), which was used in the next step without any further purification. M+H.sup.+=206.2 (LCMS).

Step 2: 6-Methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (168A-2)

[1384] To a solution of methyl 6-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (70.0 mg, 341 mol, 1.0 eq) in THF (2.0 mL) was added a mixture of LiOH (24.5 mg, 1.02 mmol, 3.0 eq) in H.sub.2O (1.0 mL). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with MTBE (1.0 mL3). The aqueous layer was basified to pH 5 using HCl (1 M aqueous) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 6-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (50.0 mg), which was used in the next step without any further purification. M+H.sup.+=192.1 (LCMS).

Step 3: 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydroquinoline-7-carb oxamide (Compound 227)

[1385] To a solution of 6-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (26.1 mg, 136 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (25.0 mg, 136 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (41.1 mg, 409 mol, 57.0 L, 3.0 eq), EDCI (65.4 mg, 341 mol, 1.5 eq) and HOBt (46.1 mg, 341 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 6-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1,2,3,4-tetrahydro quinoline-7-carboxamide (11.5 mg, 28.2 mol, 10% yield, HCl salt) was obtained as a white solid. M+H.sup.+=357.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04 (br s, 1H), 8.63 (d, J=8.3 Hz, 1H), 7.96-7.90 (m, 1H), 7.86-7.77 (m, 2H), 7.61-7.42 (m, 3H), 6.88-6.78 (m, 1H), 6.61-6.49 (m, 1H), 3.25-3.12 (m, 3H), 1.93-1.71 (s, 6H), 1.33 (br s, 2H), 1.22-1.11 (m, 2H).

Example 169: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxamide (Compound 334)

##STR01012##

Step 1: 3-(6-(Methoxycarbonyl)-5-methyl-1H-indol-3-yl)propanoic acid (169A-1)

[1386] To a solution of methyl 5-methyl-1H-indole-6-carboxylate (400 mg, 2.11 mmol, 1.0 eq) in AcOH (2 mL) were added acetyl acetate (432 mg, 4.23 mmol, 396 L, 2.0 eq) and acrylic acid (381 mg, 5.29 mmol, 2.5 eq). The mixture was stirred at 50 C. for 72 h. LCMS indicated that 40% of the starting material remained and 50% of the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 3-(6-(Methoxycarbonyl)-5-methyl-1H-indol-3-yl)propanoic acid (200 mg, 765 mol, 36% yield) was obtained as a pale yellow solid. M+H.sup.+=262.2 (LCMS).

Step 2: Methyl 3-(3-chloro-3-oxopropyl)-5-methyl-1H-indole-6-carboxylate (169A-2)

[1387] To a solution of 3-(6-methoxycarbonyl-5-methyl-1H-indol-3-yl)propanoic acid (170 mg, 651 mol, 1.0 eq) in DCM (4.0 mL) was added SOCl.sub.2 (310 mg, 2.60 mmol, 189 L, 4.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 20 C. for 1 h. LCMS (the sample was quenched with MeOH) indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give methyl 3-(3-chloro-3-oxopropyl)-5-methyl-1H-indole-6-carboxylate (180 mg) as a brown solid, which was used in the next step without any further purification. M+H.sup.+=276.2 (LCMS).

Step 3: Methyl 7-methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylate (169A-3)

[1388] To a solution of AlCl.sub.3 (343 mg, 2.57 mmol, 141 L, 4.0 eq) in DCE (10 mL) was added methyl 3-(3-chloro-3-oxopropyl)-5-methyl-1H-indole-6-carboxylate (180 mg, 644 mol, 1.0 eq). The mixture was stirred at 20 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NaHCO.sub.3 (20 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.6). Methyl 7-methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylate (50.0 mg) was obtained as a crude brown solid. M+H.sup.+=244.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.86 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 3.85 (s, 3H), 3.06-3.01 (m, 2H), 2.96-2.90 (m, 2H), 2.58 (s, 3H).

Step 4: 7-Methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylic acid (169A-4)

[1389] To a solution of 7-methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylate (40.0 mg, 164 mol, 1.0 eq) in a mixture of THF (3.0 mL) and H.sub.2O (1.0 mL) was added NaOH (32.9 mg, 822 mol, 5.0 eq). The mixture was stirred at 80 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H.sub.2O (5.0 mL) and washed with MTBE (5.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 7-methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylic acid (37.0 mg), which was used in the next step without any further purification. MH.sup.=227.8 (LCMS).

Step 5: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxamide (Compound 334)

[1390] To a solution of 7-methyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxylic acid (30.0 mg, 130 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (24.0 mg, 131 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (40.0 mg, 393 mol, 54.7 L, 3.0 eq), EDCI (62.7 mg, 327 mol, 2.5 eq) and HOBt (44.2 mg, 327 mol, 2.5 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-6-carboxamide (20.0 mg, 49.5 mol, 38% yield) was obtained as a white solid. M+H.sup.+=395.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 1.57 (s, 1H), 9.22 (s, 1H), 8.69 (br d, J=7.8 Hz, 1H), 7.95 (br d, J=7.6 Hz, 1H), 7.84 (br d, J=7.6 Hz, 2H), 7.68-7.45 (m, 4H), 7.11 (s, 1H), 2.97 (br s, 2H), 2.86 (br s, 2H), 2.14 (s, 3H), 1.38 (br s, 2H), 1.19 (br s, 2H).

Example 170: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-2,3,9,9a-tetrahydro-1H-imidazo[1,5-a]indole-6-carboxamide (Compound 194)

##STR01013##

Step 1: 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-2,3,9,9a-tetrahydro-1H-imidazo[1,5-a]indole-6-carboxamide (Compound 194)

[1391] To a solution of 2-(aminomethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)indoline-6-carboxamide (90.0 mg, 185 mol, 1.0 eq, TFA salt) and TEA (467 mg, 4.62 mmol, 643 L, 25 eq) in acetonitrile (12 mL) at 0 C. was added a solution of triphosgene (55.0 mg, 185 mol, 1.0 eq) in acetonitrile (3.0 mL) over 5 min under a N.sub.2 atmosphere. The mixture was stirred at the same temperature for another 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into aqueous NaOH (0.05 M, 60 mL) and extracted with DCM (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-60% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 7-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-3-oxo-2,3,9,9a-tetrahydro-1H-imidazo[1,5-a]indole-6-carboxamide (14.6 mg, 33.3 mol, 18% yield) was obtained as a white solid. M+H.sup.+=398.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.82 (dd, J=2.4, 7.8 Hz, 2H), 7.60-7.42 (m, 3H), 7.02 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.57 (dd, J=6.8, 8.9 Hz, 1H), 3.67 (t, J=9.2 Hz, 1H), 3.27 (br dd, J=6.9, 9.1 Hz, 1H), 3.16 (dd, J=9.2, 16.4 Hz, 1H), 2.92 (dd, J=8.9, 16.5 Hz, 1H), 1.95 (s, 3H), 1.41-1.30 (m, 2H), 1.26-1.07 (m, 2H).

Example 171: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-fluorophenyl)cyclopropyl)-2-methylbenzamide (Compound 272)

##STR01014##

Step 1: 1-(2-Fluorophenyl)cyclopropanamine (171A-2)

[1392] A solution of 2-fluorobenzonitrile (1.00 g, 8.26 mmol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (2.35 g, 8.26 mmol, 2.44 mL, 1.0 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 6.06 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (2.34 g, 16.5 mmol, 2.04 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (10 mL), and extracted with MTBE (30 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(2-Fluorophenyl)cyclopropanamine (400 mg, 2.65 mmol, 32% yield) was obtained as a colorless oil. M+H.sup.+=152.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-fluorophenyl)cyclopropyl)-2-methyl benzamide (Compound 272)

[1393] To a solution of 1-(2-fluorophenyl)cyclopropanamine (100 mg, 483 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (108 mg, 483 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (147 mg, 1.45 mmol, 202 L, 3.0 eq), EDCI (139 mg, 724 mol, 1.5 eq) and HOBt (78.0 mg, 724 mol, 1.5 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-fluorophenyl)cyclopropyl)-2-methyl benzamide (109 mg, 288 mol, 60% yield) was obtained as a white solid. M+H.sup.+=357.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.23-10.10 (m, 1H), 8.98 (s, 1H), 7.62-7.55 (m, 1H), 7.32-7.24 (m, 1H), 7.17-7.09 (m, 3H), 6.94 (dd, J=2.7, 8.3 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.30 (t, J=4.9 Hz, 2H), 3.47 (q, J=5.2 Hz, 2H), 2.82 (d, J=4.9 Hz, 6H), 2.12 (s, 3H), 1.23-1.17 (m, 2H), 1.17-1.13 (m, 2H).

Example 172: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-fluorophenyl)cyclopropyl)-2-methylbenzamide (Compound 252)

##STR01015##

Step 1: Methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (172A-1)

[1394] A mixture of methyl 5-hydroxy-2-methylbenzoate (5.00 g, 30.1 mmol, 1.0 eq), 2-(dimethylamino) ethanol (2.68 g, 30.1 mmol, 3.02 mL, 1.0 eq), TMAD (10.4 g, 60.2 mmol, 2.0 eq) and PPh.sub.3 (15.8 g, 60.2 mmol, 2.0 eq) in toluene (150 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL3). The combined EtOAc layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (6.00 g, 25.3 mmol, 84% yield) was obtained as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.43 (d, J=2.6 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.03 (dd, J=2.8, 8.4 Hz, 1H), 4.18-4.03 (m, 2H), 3.87 (s, 3H), 2.76 (t, J=5.4 Hz, 2H), 2.47 (s, 3H), 2.34 (s, 6H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylbenzoic acid (172A-2)

[1395] A solution of methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (4.00 g, 16.8 mmol, 1.0 eq) in HCl (2 M aqueous, 20 mL) was stirred at 110 C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, basified to pH 6 using NaOH (2 M aqueous) the mixture was concentrated under vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (2.00 g, HCl salt) as a white solid.

Step 3: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-fluorophenyl)cyclopropyl)-2-methylbenzamide (Compound 252)

[1396] To a stirred solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 224 mol, 1.0 eq) and 1-(3-fluorophenyl)cyclopropanamine (33.9 mg, 224 mol, 1.0 eq) in DMF (1.0 mL) were added EDCI (64.4 mg, 336 mol, 1.5 eq), HOBt (45.4 mg, 336 mol, 1.5 eq) and TEA (68.0 mg, 672 mol, 3.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-(2-(dimethylamino)ethoxy)-N-(1-(3-fluorophenyl)cyclopropyl)-2-methylbenzamide (8.60 mg, 24.1 mol, 11% yield, HCl salt) as a white solid. M+H.sup.+=357.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 12.90-12.56 (m, 1H), 7.17-7.04 (m, 5H), 6.94-6.86 (m, 2H), 4.55 (br d, J=1.1 Hz, 2H), 3.55-3.36 (m, 2H), 2.92 (br s, 6H), 2.36 (s, 3H), 1.48-1.35 (m, 4H).

Example 173: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-fluorophenyl)cyclopropyl)-2-methylbenzamide (Compound 259)

##STR01016##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-fluorophenyl)cyclopropyl)-2-methyl benzamide (Compound 259)

[1397] To a solution of 1-(4-fluorophenyl)cyclopropanamine (100 mg, 661 mol, 1.2 eq) and 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (123 mg, 551 mol, 1.0 eq) in DCM (1.0 mL) were added TEA (167 mg, 1.65 mmol, 230 L, 3.0 eq), EDCI (159 mg, 827 mol, 1.5 eq) and HOBt (112 mg, 827 mol, 1.5 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-fluorophenyl)cyclopropyl)-2-methyl benzamide (118 mg, 326 mol, 59% yield) was obtained as a white solid. M+H.sup.+=357.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 12.97-12.63 (m, 1H), 7.46-7.38 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 7.04-6.96 (m, 3H), 6.90 (s, 1H), 6.85 (dd, J=2.6, 8.4 Hz, 1H), 4.57-4.49 (m, 2H), 3.47-3.38 (m, 2H), 2.93 (d, J=4.8 Hz, 6H), 2.33 (s, 3H), 1.42-1.35 (m, 2H), 1.34-1.28 (m, 2H).

Example 174: N-(1-(2-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 251)

##STR01017##

Step 1: N-(1-(2-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 251)

[1398] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 224 mol, 1.0 eq) and 1-(2-bromophenyl)cyclopropanamine (47.5 mg, 224 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (45.3 mg, 448 mol, 62.3 L, 2.0 eq), EDCI (51.5 mg, 267 mol, 1.2 eq) and HOBt (36.3 mg, 269 mol, 1.2 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(2-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (20.2 mg, 48.1 mol, 21% yield) was obtained as a yellow gum. M+H.sup.+=417.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.80 (dd, J=1.6, 7.6 Hz, 1H), 7.55 (dd, J=0.9, 7.9 Hz, 1H), 7.31 (dt, J=1.1, 7.5 Hz, 1H), 7.15 (dt, J=1.6, 7.7 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.89-6.82 (m, 2H), 6.78 (s, 1H), 4.04 (t, J=5.6 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.35 (s, 6H), 2.24 (s, 3H), 1.32 (dd, J=4.3, 14.1 Hz, 4H).

Example 175: N-(1-(3-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 261)

##STR01018##

Step 1: N-(1-(3-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 261)

[1399] A mixture of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (351 mg, 472 mol, 2.0 eq), 1-(3-bromophenyl)cyclopropanamine (50.0 mg, 236 mol, 1.0 eq), TEA (71.6 mg, 707 mol, 98.4 L, 3.0 eq), HOBt (47.8 mg, 354 mol, 1.5 eq) and EDCI (67.8 mg, 354 mol, 1.5 eq) in DCM (3.0 mL) was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (41.6 mg, 100 mol, 42% yield, HCl salt) was obtained as a pink solid. M+H.sup.+=417.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.56-10.42 (m, 1H), 9.09-9.04 (m, 1H), 7.43-7.35 (m, 2H), 7.29-7.24 (m, 1H), 7.22-7.17 (m, 2H), 7.01-6.96 (m, 2H), 4.39-4.33 (m, 2H), 3.54-3.44 (m, 2H), 2.85-2.81 (m, 6H), 2.28-2.22 (m, 3H), 1.28 (br d, J=5.0 Hz, 4H).

Example 176: N-(1-(4-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 258)

##STR01019##

Step 1: 1-(4-Bromophenyl)cyclopropanamine (176A-1)

[1400] To a stirred solution of tert-butyl(1-(4-bromophenyl)cyclopropyl)carbamate (300 mg, 961 mol, 1.0 eq) in EtOAc (6.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 2 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 C. to give 1-(4-bromophenyl)cyclopropanamine (230 mg, 932 mol, 97% yield, HCl salt) as a white solid.

Step 2: N-(1-(4-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 258)

[1401] To a solution of 1-(4-bromophenyl)cyclopropanamine (80.0 mg, 322 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (71.9 mg, 322 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (97.7 mg, 966 mol, 134 L, 3.0 eq), EDCI (154 mg, 805 mol, 2.5 eq) and HOBt (109 mg, 805 mol, 2.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(4-Bromophenyl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (12.8 mg, 27.9 mol, 9% yield) was obtained as a yellow gum. M+H.sup.+=417.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.97 (s, 1H), 7.48 (s, 2H), 7.18 (d, J=8.5 Hz, 3H), 6.93 (s, 2H), 4.05 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.8 Hz, 2H), 2.36-2.17 (m, 9H), 1.25 (br d, J=5.5 Hz, 4H)

Example 177: N-(1-(2-chlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 326)

##STR01020##

Step 1: 1-(2-Chlorophenyl)cyclopropanamine (177A-2)

[1402] A mixture of 2-chlorobenzonitrile (500 mg, 2.39 mmol, 1.0 eq) in anhydrous Et.sub.2O (35 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (1.14 g, 4.00 mmol, 1.18 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 2.67 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (1.03 g, 7.27 mmol, 897 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 1-(2-chlorophenyl)cyclopropanamine (600 mg) as a brown oil. M+H.sup.+=168.1 (LCMS).

Step 2: tert-Butyl(1-(2-Chlorophenyl)cyclopropyl)carbamate (177A-3)

[1403] To a solution of 1-(2-chlorophenyl)cyclopropanamine (600 mg, 3.58 mmol, 1.0 eq) in DCM (30 mL) were added TEA (724 mg, 7.16 mmol, 996 L, 2.0 eq) and Boc.sub.2O (937 mg, 4.30 mmol, 987 L, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (30 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl(1-(2-chlorophenyl)cyclopropyl)carbamate (360 mg) as a white solid. M56+H.sup.+=212.0 (LCMS).

Step 3: 1-(2-Chlorophenyl)cyclopropanamine (177A-4)

[1404] To a stirred solution of tert-butyl(1-(2-chlorophenyl)cyclopropyl)carbamate (360 mg, 1.34 mmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 15 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give product 1-(2-chlorophenyl)cyclopropanamine (260 mg, HCl salt) as a brown solid. M+H.sup.+=168.0 (LCMS).

Step 4: N-(1-(2-Chlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 326)

[1405] To a solution of 1-(2-chlorophenyl)cyclopropanamine (50.0 mg, 298 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (133 mg, 596 mol, 2.0 eq) in DMF (2.0 mL) were added TEA (90.5 mg, 895 mol, 174 L, 3.0 eq), EDCI (68.6 mg, 501 mol, 1.2 eq) and HOBt (48.4 mg, 358 mol, 1.2 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(2-Chlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (37.7 mg, 90.6 mol, 30% yield, FA salt) was obtained as a white solid. M+H.sup.+=373.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.56 (br s, 1H), 8.39 (s, 1H), 7.79 (dd, J=1.9, 7.4 Hz, 1H), 7.36 (dd, J=1.4, 7.5 Hz, 1H), 7.25-7.18 (m, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.93-6.68 (m, 3H), 4.21 (t, J=5.1 Hz, 2H), 3.13 (t, J=5.0 Hz, 2H), 2.62 (s, 6H), 2.22 (s, 3H), 1.32 (d, J=4.4 Hz, 2H), 1.28 (d, J=4.4 Hz, 2H).

Example 178: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(0-tolyl)cyclopropyl)benzamide (Compound 282)

##STR01021##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(o-tolyl)cyclopropyl)benzamide (Compound 282)

[1406] To a mixture of 1-(o-tolyl)cyclopropanamine (100 mg, 679 mol, 1.1 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (138 mg, 618 mol, 1.0 eq) in DCM (2.0 mL) were added EDCI (178 mg, 926 mol, 1.5 eq), HOBt (125 mg, 926 mol, 1.5 eq) and TEA (187 mg, 1.85 mmol, 3.0 eq) at 25 C. The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(o-tolyl)cyclopropyl)benzamide (32.4 mg, 91.9 mol, 15% yield, HCl salt) was obtained as a yellow gum. M+H.sup.+=353.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.51 (br s, 1H), 8.90 (s, 1H), 7.59 (br d, J=5.9 Hz, 1H), 7.15-7.08 (m, 4H), 6.94-6.89 (m, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.30 (br t, J=5.0 Hz, 2H), 3.49-3.42 (m, 2H), 2.80 (d, J=4.9 Hz, 6H), 2.48 (s, 3H), 2.07 (s, 3H), 1.18-1.11 (m, 2H), 1.07-0.99 (m, 2H).

Example 179: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(m-tolyl)cyclopropyl)benzamide (Compound 255)

##STR01022##

Step 1: 1-(m-Tolyl)cyclopropanamine (179A-2)

[1407] A mixture of 3-methylbenzonitrile (1.00 g, 8.54 mmol, 1.02 mL, 1.0 eq) in anhydrous Et.sub.2O (40 mL) was degassed and purged with N.sub.2 three times. The mixture was cooled to 78 C. under a N.sub.2 atmosphere. To this mixture was added Ti(i-PrO).sub.4 (2.67 g, 9.39 mmol, 2.77 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 6.26 mL, 2.2 eq) was added dropwise over 1 h to maintain the temperature between 78 C. and 73 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (2.42 g, 17.1 mmol, 2.11 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (40 mL) and MTBE (10 mL), and extracted with MTBE (40 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(m-Tolyl)cyclopropanamine (200 mg, 1.36 mmol, 16% yield) was obtained as a yellow oil. M+H.sup.+=148.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(m-tolyl)cyclopropyl)benzamide (Compound 255)

[1408] To a solution of 1-(m-tolyl)cyclopropanamine (70.0 mg, 475 mol, 1.0 eq) and 5-(2-(dimethyl amino)ethoxy)-2-methylbenzoic acid (106 mg, 475 mol, 1.0 eq) in DMF (1.0 mL) were added TEA (96.2 mg, 951 mol, 132 L, 2.0 eq), EDCI (109 mg, 571 mol, 1.2 eq) and HOBt (77.1 mg, 571 mol, 1.2 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/ethanol=10/1, R.sub.f=0.2). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(m-tolyl)cyclopropyl)benzamide (70.8 mg, 201 mol, 42% yield) was obtained as a white solid. M+H.sup.+=353.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.24-7.18 (m, 1H), 7.17-7.07 (m, 3H), 7.03 (d, J=7.4 Hz, 1H), 6.97 (d, J=2.6 Hz, 1H), 6.88 (dd, J=2.8, 8.4 Hz, 1H), 6.41 (s, 1H), 4.10 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.4 Hz, 2H), 2.40 (s, 6H), 2.36 (s, 3H), 2.35 (s, 3H), 1.36 (s, 4H).

Example 180: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(p-tolyl)cyclopropyl)benzamide (Compound 253)

##STR01023##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(p-tolyl)cyclopropyl)benzamide (Compound 253)

[1409] To a solution of 1-(p-tolyl)cyclopropanamine (69.2 mg, 470 mol, 1.0 eq) in DCM (8.0 mL) were added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (100 mg, 448 mol, 1.0 eq), TEA (136 mg, 1.34 mmol, 187 L, 3.0 eq), EDCI (129 mg, 672 mol, 1.5 eq) and HOBt (90.8 mg, 672 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8040 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(p-tolyl)cyclopropyl)benzam ide (68.8 mg, 194 mol, 43% yield) was obtained as a white solid. M+H.sup.+=353.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.91-8.86 (m, 1H), 7.23-7.02 (m, 5H), 6.94-6.87 (m, 2H), 4.09-4.01 (m, 2H), 2.64-2.57 (m, 3H), 2.28-2.24 (m, 3H), 2.24-2.18 (m, 8H), 1.26-1.12 (m, 4H).

Example 181: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)benzamide (Compound 321)

##STR01024##

Step 1: 1-(2-(Trifluoromethyl)phenyl)cyclopropanamine (181A-2)

[1410] A mixture of 2-(trifluoromethyl)benzonitrile (200 mg, 1.17 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (365 mg, 1.29 mmol, 379 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 858 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (331 mg, 2.34 mmol, 288 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (2.0 mL) and MTBE (15 mL), and extracted with MTBE (15 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/MeOH=10/1, R.sub.f=0.2). 1-(2-(Trifluoromethyl)phenyl)cyclopropanamine (80.0 mg, 397 mol, 34% yield) was obtained as a yellow oil. M+H.sup.+=202.0 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)benzamide (Compound 321)

[1411] To a solution of 1-(2-(trifluoromethyl)phenyl)cyclopropanamine (50.0 mg, 248 mol, 1.0 eq) and 5-[2-(dimethylamino)ethoxy]-2-methyl-benzoic acid (55.5 mg, 248 mol, 1.0 eq) in DMF (1.0 mL) were added HATU (142 mg, 372 mol, 1.5 eq) and DIEA (95.4 mg, 745 mol, 130 L, 3.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-[2-(dimethylamino)ethoxy]-2-methyl-N-[1-[2-(trifluoromethyl)phenyl]cyclopropyl]benzamide (55.8 mg, 100 mmol, 51% yield, HCl salt) as a white solid. M+H.sup.+=407.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.32 (br d, J=1.1 Hz, 1H), 8.68 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.93 (dd, J=2.6, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.29 (t, J=5.0 Hz, 2H), 3.47 (q, J=5.1 Hz, 2H), 2.81 (d, J=4.9 Hz, 6H), 2.08 (s, 3H), 1.30-1.14 (m, 4H).

Example 182: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-ethylphenyl)cyclopropyl)-2-methylbenzamide (Compound 364)

##STR01025##

Step 1: 2-Ethylbenzonitrile (182A-2)

[1412] To a solution of 1-bromo-2-ethylbenzene (2.00 g, 10.8 mmol, 1.49 mL, 1.0 eq) in DMF (17 mL) was added CuCN (1.45 g, 16.2 mmol, 3.54 mL, 1.5 eq). The mixture was stirred at 140 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (15 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 2-Ethylbenzonitrile (800 mg, 6.10 mmol, 56% yield) was obtained as a white solid. M+H.sup.+=132.1 (LCMS).

Step 2: 1-(2-Ethylphenyl)cyclopropanamine (182A-3)

[1413] A mixture of 2-ethylbenzonitrile (400 mg, 3.05 mmol, 411 L, 1.0 eq) in anhydrous Et.sub.2O (28 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (953 mg, 3.35 mmol, 990 L, 1.1 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 2.24 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (866 mg, 6.10 mmol, 753 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(2-ethylphenyl)cyclopropanamine (490 mg) as a white solid. M+H.sup.+=162.1 (LCMS).

Step 3: tert-Butyl(1-(2-ethylphenyl)cyclopropyl)carbamate (182A-4)

[1414] To a solution of 1-(2-ethylphenyl)cyclopropanamine (490 mg, 3.04 mmol, 1.0 eq) in DCM (50 mL) were added TEA (615 mg, 6.08 mmol, 846 L, 2.0 eq) and Boc.sub.2O (663 mg, 3.04 mmol, 698 L, 1.0 eq). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl(1-(2-ethylphenyl)cyclopropyl)carbamate (70.0 mg, 268 mol, 9% yield) was obtained as a white solid. M+H=262.2 (LCMS).

Step 4: 1-(2-Ethylphenyl)cyclopropanamine (182A-5)

[1415] To a stirred solution of tert-butyl(1-(2-ethylphenyl)cyclopropyl)carbamate (70.0 mg, 268 mol, 1.0 eq) in EtOAc (1.5 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product 1-(2-ethylphenyl)cyclopropanamine (70 mg, HCl salt) as a white solid. M+H.sup.+=162.1 (LCMS).

Step 5: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-ethylphenyl)cyclopropyl)-2-methylbenzamide (Compound 364)

[1416] To a solution of 1-(2-ethylphenyl)cyclopropanamine (60.0 mg, 372 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (83.1 mg, 372 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (113 mg, 1.12 mmol, 155 L, 3.0 eq), EDCI (107 mg, 558 mol, 1.5 eq) and HOBt (75.4 mg, 558 mol, 1.5 eq). The mixture was stirred at 25 C. for 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous TFA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-ethylphenyl)cyclopropyl)-2-methylbenzamide (4.5 mg, 10.7 mol, 3% yield, FA salt) was obtained as a white solid. M+H.sup.+=367.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.43-8.23 (m, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.21 (br d, J=8.2 Hz, 1H), 7.09-7.02 (m, 1H), 6.84-6.77 (m, 2H), 6.56-6.54 (m, 1H), 6.50 (s, 1H), 4.25 (br t, J=4.8 Hz, 2H), 3.15 (br t, J=4.7 Hz, 2H), 3.03-2.90 (m, 2H), 2.66 (s, 6H), 2.21 (s, 3H), 1.41-1.34 (m, 2H), 1.31 (t, J=7.6 Hz, 3H), 1.28-1.23 (m, 2H).

Example 183: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-isopropylphenyl)cyclopropyl)-2-methylbenzamide (Compound 344)

##STR01026##

Step 1: 2-Isopropylbenzonitrile (183A-2)

[1417] A mixture of K.sub.4[Fe(CN).sub.6] (370 mg, 1.00 mmol, 0.2 eq), CuI (95.6 mg, 502 mol, 0.1 eq) and 1-bromo-2-isopropyl-benzene (1.00 g, 5.02 mmol, 1.0 eq) in toluene (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture were added tetradecane (381 mg, 1.92 mmol, 500 L, 0.38 eq) and 1-butyl-1H-imidazole (624 mg, 5.02 mmol, 5.00 mL, 1.0 eq). The mixture was stirred at 160 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that some of the starting material still remained and a new main spot was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (2.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 2-Isopropylbenzonitrile (330 mg, 2.27 mmol, 45% yield) was obtained as a white solid. M+H.sup.+=146.1 (LCMS).

Step 2: 1-(2-Isopropylphenyl)cyclopropanamine (183A-3)

[1418] A mixture of 2-isopropylbenzonitrile (330 mg, 2.27 mmol, 1.0 eq) in anhydrous Et.sub.2O (23 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (710 mg, 2.50 mmol, 738 L, 1.1 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 1.67 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (645 mg, 4.55 mmol, 561 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(2-isopropylphenyl)cyclopropanamine (390 mg) as a white solid. M+H.sup.+=176.2 (LCMS).

Step 3: tert-Butyl(1-(2-isopropylphenyl)cyclopropyl)carbamate (183A-4)

[1419] To a solution of 1-(2-isopropylphenyl)cyclopropanamine (390 mg, 2.23 mmol, 1.0 eq) in DCM (50 mL) were added TEA (450 mg, 4.45 mmol, 619 L, 2.0 eq) and Boc.sub.2O (583 mg, 2.67 mmol, 613 L, 1.2 eq). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl(1-(2-isopropylphenyl)cyclopropyl)carbamate (100 mg, 363 mol, 16% yield) was obtained as a white solid. M56+H.sup.+=220.1 (LCMS).

Step 4: 1-(2-Isopropylphenyl)cyclopropanamine (183A-5)

[1420] To a stirred solution of tert-butyl(1-(2-isopropylphenyl)cyclopropyl)carbamate (100 mg, 363 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 4.1 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product 1-(2-isopropylphenyl)cyclopropanamine (100 mg, HCl salt) as a white solid. M+H.sup.+=176.2 (LCMS).

Step 5: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-isopropylphenyl)cyclopropyl)-2-methyl benzamide (Compound 344)

[1421] To a solution of 1-(2-isopropylphenyl)cyclopropanamine (90.0 mg, 513 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (91.7 mg, 411 mol, 0.8 eq) in DCM (3.0 mL) were added TEA (156 mg, 1.54 mmol, 214 L, 3.0 eq), EDCI (148 mg, 770 mol, 1.5 eq) and HOBt (104 mg, 770 mol, 1.5 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-isopropylphenyl)cyclopropyl)-2-methylbenzamide (15.6 mg, 36.6 mol, 7% yield, FA salt) was obtained as a white solid. M+H.sup.+=381.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.46 (br s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.29 (d, J=4.0 Hz, 2H), 7.18 (dd, J=4.0, 7.6 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.89-6.69 (m, 2H), 6.32 (s, 1H), 4.04 (t, J=5.5 Hz, 2H), 3.82-3.49 (m, 1H), 2.78 (t, J=5.4 Hz, 2H), 2.38 (s, 6H), 2.22 (s, 3H), 1.44-1.33 (m, 2H), 1.28 (d, J=7.0 Hz, 6H), 1.25 (br s, 2H).

Example 184: N-(1-([1,1-Biphenyl]-2-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 267)

##STR01027##

Step 1: tert-Butyl(1-(2-bromophenyl)cyclopropyl)carbamate (184A-2)

[1422] To a solution of 1-(2-bromophenyl)cyclopropanamine (500 mg, 2.36 mmol, 1.0 eq) in DCM (13 mL) were added di-tert-butyl dicarbonate (515 mg, 2.36 mmol, 542 L, 1.0 eq) and TEA (262 mg, 2.59 mmol, 361 L, 1.1 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to tert-Butyl(1-(2-bromophenyl)cyclopropyl)carbamate (660 mg, 2.11 mmol, 90% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.56-7.51 (m, 1H), 7.30-7.27 (m, 1H), 7.24 (s, 1H), 7.16-7.10 (m, 1H), 1.44-1.33 (m, 9H), 1.27-1.21 (m, 2H), 1.17-1.12 (m, 2H).

Step 2: tert-Butyl(1-([1,1-biphenyl]-2-yl)cyclopropyl)carbamate (184A-3)

[1423] A mixture of phenylboronic acid (195 mg, 1.60 mmol, 2.5 eq), tert-butyl(1-(2-bromophenyl)cyclopropyl)carbamate (200 mg, 641 mol, 1.0 eq), K.sub.2CO.sub.3 (221 mg, 1.60 mmol, 2.5 eq), Pd(dppf)Cl.sub.2 (46.9 mg, 64.1 mol, 0.1 eq) in a mixture of dioxane (8.0 mL) and H.sub.2O (2.0 mL) was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. tert-Butyl(1-([1,1-biphenyl]-2-yl)cyclopropyl)carbamate (150 mg, 485 mol, 76% yield) was obtained as a white solid.

Step 3: 1-([1,1-Biphenyl]-2-yl)cyclopropanamine (184A-4)

[1424] To a solution of tert-butyl(1-([1, l-biphenyl]-2-yl)cyclopropyl)carbamate (100 mg, 323 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude product 1-([1, l-biphenyl]-2-yl)cyclopropanamine (75.0 mg, HCl salt) as a white solid. M+H.sup.+=210.1 (LCMS).

Step 4: N-(1-([1,1-Biphenyl]-2-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 267)

[1425] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (68.1 mg, 305 mol, 1.0 eq) and 1-([1,1-biphenyl]-2-yl)cyclopropanamine (75.0 mg, 305 mol, 1.0 eq, HCl salt) in DMF (5.0 mL) were added TEA (92.7 mg, 916 mol, 127 L, 3.0 eq), EDCI (70.2 mg, 366 mol, 1.2 eq) and HOBt (49.5 mg, 366 mol, 1.2 eq). The mixture was stirred at 25 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-([1,1-Biphenyl]-2-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (31.6 mg, 68.4 mol, 22% yield, FA salt) was obtained as a yellow solid. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.20 (br s, 1H), 8.05 (s, 1H), 7.94-7.87 (m, 1H), 7.51-7.47 (m, 2H), 7.43 (t, J=7.5 Hz, 2H), 7.38-7.27 (m, 3H), 7.14 (dd, J=1.9, 7.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.82 (dd, J=2.6, 8.4 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 3.98 (t, J=5.7 Hz, 2H), 2.64 (br t, J=5.6 Hz, 2H), 2.24 (s, 6H), 2.09 (s, 3H), 1.03-0.91 (m, 4H).

Example 185: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-hydroxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 294)

##STR01028##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-hydroxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 294)

[1426] A mixture of 5-(2-(dimethylamino)ethoxy)-N-(1-(4-methoxyphenyl)cyclopropyl)-2-methylbenzamide (100 mg, 265 mol, 1.0 eq) in DCM (1.0 mL) was degassed and purged with N.sub.2 three times. The mixture was added a solution of BBr.sub.3 (1.22 g, 4.89 mmol, 471 L, 20 eq) in DCM (1.0 mL) at 78 C. and stirred at the same temperature for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-hydroxyphenyl)cyclopropyl)-2-methylbenzamide (5.50 mg, 15.4 mol, 6% yield, HCl salt) was obtained as a yellow oil. M+H.sup.+=355.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.15 (d, J=8.6 Hz, 1H), 7.10-7.05 (m, 2H), 6.94 (dd, J=2.8, 8.4 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H), 6.70-6.62 (m, 2H), 4.28-4.19 (m, 2H), 3.48-3.43 (m, 2H), 2.81 (s, 6H), 2.17 (s, 3H), 1.15-1.07 (m, 4H).

Example 186: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-methoxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 271)

##STR01029##

Step 1: 1-(4-Methoxyphenyl)cyclopropanamine (186A-2)

[1427] A mixture of 4-methoxybenzonitrile (2.00 g, 15.0 mmol, 1.0 eq) in anhydrous Et.sub.2O (100 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (4.27 g, 15.0 mmol, 4.43 mL, 1.0 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 11.0 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 30 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (4.26 g, 30.0 mmol, 3.71 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL3). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/1. 1-(4-Methoxyphenyl)cyclopropanamine (1.30 g, 7.96 mmol, 53% yield) was obtained as a yellow oil. M+H.sup.+=164.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-methoxyphenyl)cyclopropyl)-2-methyl benzamide (Compound 271)

[1428] To a solution of 1-(4-methoxyphenyl)cyclopropanamine (100 mg, 447 mol, 1.2 eq), 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (83.2 mg, 373 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (113 mg, 1.12 mmol, 156 L, 3.0 eq), EDCI (107 mg, 559 mmol, 1.5 eq) and HOBt (75.5 mg, 559 mmol, 1.5 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(4-methoxyphenyl)cyclopropyl)-2-methylbenzamide (100 mg, 265 mol, 71% yield, HCl salt) was obtained as a white solid. M+H.sup.+=369.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 12.80 (br s, 1H), 7.43-7.36 (m, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.90-6.77 (m, 4H), 4.54-4.47 (m, 2H), 3.80 (s, 3H), 3.46-3.39 (m, 2H), 2.93 (d, J=4.9 Hz, 6H), 2.31 (s, 3H), 1.38-1.32 (m, 2H), 1.31-1.26 (m, 2H).

Example 187: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-phenoxyphenyl)cyclopropyl)benzamide (Compound 298)

##STR01030##

Step 1: 1-(2-Phenoxyphenyl)cyclopropanamine (187A-2)

[1429] A mixture of 2-phenoxybenzonitrile (300 mg, 1.54 mmol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (480 mg, 1.69 mmol, 499 L, 1.1 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 1.13 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (436 mg, 3.07 mmol, 379 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (15 mL) and MTBE (15 mL), and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(2-Phenoxyphenyl)cyclopropanamine (90.0 mg, 399 mol, 26% yield) was obtained as a yellow oil. M+H.sup.+=226.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.41-7.33 (m, 3H), 7.21 (dt, J=1.6, 7.8 Hz, 1H), 7.15-6.98 (m, 4H), 6.87 (dd, J=0.9, 8.1 Hz, 1H), 1.00 (s, 2H), 0.91-0.86 (m, 2H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-phenoxyphenyl)cyclopropyl)benzamide (Compound 298)

[1430] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (178 mg, 799 mol, 2.0 eq) and 1-(2-phenoxyphenyl)cyclopropanamine (90.0 mg, 399 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (121 mg, 1.20 mmol, 167 L, 3.0 eq), EDCI (91.9 mg, 479 mol, 1.2 eq) and HOBt (64.8 mg, 479 mol, 1.2 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-phenoxyphenyl)cyclopropyl)benzamide (51.3 mg, 108 mol, 27% yield, FA) was obtained as a yellow gum. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.74 (s, 1H), 8.17 (s, 1H), 7.64 (br d, J=7.6 Hz, 1H), 7.37 (br t, J=7.9 Hz, 2H), 7.25-7.20 (m, 1H), 7.13-6.99 (m, 5H), 6.82 (br dd, J=2.1, 8.3 Hz, 1H), 6.75 (br d, J=8.0 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 3.93 (br t, J=5.5 Hz, 2H), 2.60 (br s, 2H), 2.22 (s, 6H), 2.14 (s, 3H), 1.11 (br d, J=9.9 Hz, 4H).

Example 188: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-phenoxyphenyl)cyclopropyl)benzamide (Compound 270)

##STR01031##

Step 1: tert-Butyl(1-(3-bromophenyl)cyclopropyl)carbamate (188A-1)

[1431] To a stirred solution of 1-(3-bromophenyl)cyclopropanamine (250 mg, 1.18 mmol, 1.0 eq) in DCM (5.0 mL) were added TEA (131 mg, 1.30 mmol, 180 L, 1.1 eq) and Boc.sub.2O (257 mg, 1.18 mmol, 271 L, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). tert-Butyl(1-(3-bromophenyl)cyclopropyl) carbamate (300 mg, 961 mol, 82% yield) was obtained as a white solid. M56+H.sup.+=255.9 (LCMS).

Step 2: tert-Butyl(1-(3-phenoxyphenyl)cyclopropyl)carbamate (188A-2)

[1432] A mixture of tert-butyl(2-hydroxyethyl)carbamate (50.0 mg, 160 mol, 1.0 eq), phenol (21.1 mg, 224 mol, 1.4 eq), Cs.sub.2CO.sub.3 (104 mg, 320 mol, 2.0 eq) and CuI (3.05 mg, 16.0 mol, 0.1 eq) in 1,4-dioxane (3.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added 2-(dimethylamino) acetic acid (4.95 mg, 48.1 mol, 0.3 eq). The resulting mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.6). tert-Butyl(1-(3-phenoxyphenyl)cyclopropyl)carbamate (45.0 mg, 138 mol, 86% yield) was obtained as a white solid. M+H.sup.+=326.1 (LCMS).

Step 3: 1-(3-Phenoxyphenyl)cyclopropanamine (188A-3)

[1433] To a stirred solution of tert-butyl(1-(3-phenoxyphenyl)cyclopropyl)carbamate (90.0 mg, 277 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product 1-(3-phenoxyphenyl)cyclopropanamine (50.0 mg, 168 mol, 60% yield, HCl salt) as a white solid. M+H.sup.+=226.0 (LCMS).

Step 4: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-phenoxyphenyl)cyclopropyl)benzamide (Compound 270)

[1434] To a solution of 1-(3-phenoxyphenyl)cyclopropanamine (100 mg, 382 mol, 1.0 eq, HCl salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.3 mg, 382 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (77.3 mg, 764 mol, 106 L, 2.0 eq), EDCI (110 mg, 573 mol, 1.5 eq) and HOBt (77.4 mg, 573 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-80% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-phenoxyphenyl)cyclopropyl)benzamide (24.4 mg, 52.1 mol, 14% yield) was obtained as a yellow gum. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.90 (s, 1H), 7.43-7.26 (m, 3H), 7.17-7.07 (m, 2H), 7.04-6.96 (m, 2H), 6.95-6.86 (m, 3H), 6.84-6.77 (m, 2H), 4.01 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.8 Hz, 2H), 2.21 (s, 6H), 2.15 (s, 3H), 1.25 (br d, J=1.4 Hz, 4H).

Example 189: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-phenoxyphenyl)cyclopropyl)benzamide (Compound 279)

##STR01032##

Step 1: tert-butyl(1-(4-phenoxyphenyl)cyclopropyl)carbamate (189A-1)

[1435] A mixture of tert-butyl(1-(4-bromophenyl)cyclopropyl)carbamate (100 mg, 320 mol, 1.0 eq), phenol (42.2 mg, 448 mol, 1.4 eq), Cs.sub.2CO.sub.3 (209 mg, 640 mol, 2.0 eq) and CuI (6.10 mg, 32.0 mol, 0.1 eq) in 1,4-dioxane (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added 2-(dimethylamino) acetic acid (9.91 mg, 96.1 mol, 0.3 eq) and the resulting mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.7). tert-Butyl(1-(4-phenoxy phenyl)cyclopropyl) carbamate (100 mg, 307 mol, 96% yield) was obtained as a yellow oil. M+H.sup.+=326.1 (LCMS).

Step 2: 1-(4-Phenoxyphenyl)cyclopropanamine (189A-2)

[1436] To a stirred solution of tert-butyl(1-(4-phenoxyphenyl)cyclopropyl)carbamate (100 mg, 307 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product 1-(4-phenoxyphenyl)cyclopropanamine (100 mg, HCl salt) as a white solid. M+H.sup.+=226.0 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(4-phenoxyphenyl)cyclopropyl)benzamide (Compound 279)

[1437] To a solution of 1-(4-phenoxyphenyl)cyclopropanamine (100 mg, 382 mol, 1.0 eq, HCl salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.3 mg, 382 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (77.3 mg, 764 mol, 106 L, 2.0 eq), EDCI (110 mg, 573 mol, 1.5 eq) and HOBt (77.4 mg, 573 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 50%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(4-phenoxyphenyl)cyclopropyl)benzamide (15.0 mg, 34.8 mol, 9% yield) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.93 (s, 1H), 7.42-7.33 (m, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.02-6.87 (m, 6H), 4.04 (t, J=5.8 Hz, 2H), 2.60 (br t, J=5.8 Hz, 2H), 2.27-2.15 (m, 9H), 1.23 (br d, J=7.3 Hz, 4H).

Example 190: N-(1-(2-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 327)

##STR01033##

Step 1: 2-(Benzyloxy)benzonitrile (190A-2)

[1438] To a solution of 2-hydroxybenzonitrile (2.00 g, 16.8 mmol, 1.0 eq) and K.sub.2CO.sub.3 (4.64 g, 33.6 mmol, 2.0 eq) in DMF (20 mL) was added (bromomethyl)benzene (3.45 g, 20.2 mmol, 2.39 mL, 1.2 eq). The mixture was stirred at 50 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/10. 2-(Benzyloxy)benzonitrile (3.20 g, 15.3 mmol, 91% yield) was obtained as a white solid. M+H.sup.+=210.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.59 (dd, J=1.6, 7.9 Hz, 1H), 7.55-7.44 (m, 3H), 7.44-7.38 (m, 2H), 7.38-7.33 (m, 1H), 7.08-6.96 (m, 2H), 5.23 (s, 2H).

Step 2: 1-(2-(Benzyloxy)phenyl)cyclopropanamine (190A-3)

[1439] A mixture of 2-(benzyloxy)benzonitrile (500 mg, 2.39 mmol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (747 mg, 2.63 mmol, 776 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.75 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (679 mg, 4.78 mmol, 590 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product 1-(2-(benzyloxy)phenyl)cyclopropanamine (580 mg) as a brown oil. M+H.sup.+=240.1 (LCMS).

Step 3: tert-Butyl(1-(2-(benzyloxy)phenyl)cyclopropyl)carbamate (190A-4)

[1440] To a solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (570 mg, 2.38 mmol, 1.0 eq) in DCM (30 mL) were added TEA (482 mg, 4.76 mmol, 663 L, 2.0 eq) and Boc.sub.2O (624 mg, 2.86 mmol, 657 L, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/7. tert-Butyl(1-(2-(benzyloxy)phenyl)cyclopropyl)carbamate (110 mg, 324 mol, 14% yield) was obtained as a white solid.

Step 4: 1-(2-(Benzyloxy)phenyl)cyclopropanamine (190A-5)

[1441] To a stirred solution of tert-butyl(1-(2-(benzyloxy)phenyl)cyclopropyl)carbamate (100 mg, 295 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.2 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product 1-(2-(benzyloxy)phenyl)cyclopropanamine (100 mg, HCl salt) as a white solid. M+H.sup.+=240.1 (LCMS).

Step 5: N-(1-(2-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 327)

[1442] To a solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (100 mg, 418 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (187 mg, 836 mol, 2.0 eq) in DMF (4.0 mL) were added TEA (127 mg, 1.25 mmol, 174 L, 3.0 eq), EDCI (96.1 mg, 501 mol, 1.2 eq) and HOBt (67.8 mg, 501 mol, 1.2 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10040 mm, 3 m); flow rate: 50 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(2-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (60.3 mg, 123 mol, 30% yield, FA salt) was obtained as a white solid. M+H.sup.+=445.1 (LCMS); 1H NMR (400 MHZ, CDCl.sub.3) 8.42 (s, 1H), 7.62 (dd, J=1.4, 7.4 Hz, 1H), 7.38 (br d, J=1.0 Hz, 2H), 7.33 (br d, J=7.0 Hz, 3H), 7.25 (br d, J=1.1 Hz, 1H), 7.08-6.89 (m, 3H), 6.85-6.76 (m, 2H), 6.68 (s, 1H), 5.15 (s, 2H), 4.07 (t, J=5.3 Hz, 2H), 2.93 (t, J=5.3 Hz, 2H), 2.48 (s, 6H), 2.15 (s, 3H), 1.25 (br d, J=4.9 Hz, 4H).

Example 191: N-(1-(3-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 308)

##STR01034##

Step 1: 1-(3-(Benzyloxy)phenyl)cyclopropanamine (191A-2)

[1443] To a mixture of 3-(benzyloxy)benzonitrile (300 mg, 1.43 mmol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (448 mg, 1.58 mmol, 470 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.05 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (407 mg, 2.87 mmol, 350 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(3-(benzyloxy)phenyl)cyclopropanamine (150 mg) as a brown solid, which was used in the next step without any further purification. M+H.sup.+=240.1 (LCMS).

Step 2: N-(1-(3-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 308)

[1444] To a solution of 1-(3-(benzyloxy)phenyl)cyclopropanamine (57.0 mg, 239 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (53.3 mg, 239 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (48.4 mg, 0.48 mmol, 66.5 L, 2 eq), EDCI (68.7 mg, 0.36 mmol, 1.5 eq) and HOBt (48.4 mg, 0.36 mmol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (2.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 10%-40% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (4.00 mg, 8.32 mol, 4% yield) was obtained as a white gum. M+H.sup.+=445.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.93 (s, 1H), 7.46-7.42 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.24-7.16 (m, 2H), 7.03-6.92 (m, 2H), 6.90-6.75 (m, 3H), 5.08 (s, 2H), 4.47-4.23 (m, 2H), 3.49 (br d, J=1.8 Hz, 2H), 2.85 (d, J=4.9 Hz, 6H), 2.29-2.20 (m, 3H), 1.24 (br d, J=1.8 Hz, 4H).

Example 192: N-(1-(4-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 307)

##STR01035##

Step 1: 1-(4-(Benzyloxy)phenyl)cyclopropanamine (192A-2)

[1445] A mixture of 4-(benzyloxy)benzonitrile (1.00 g, 4.78 mmol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (1.36 g, 4.78 mmol, 1.41 mL, 1.0 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 3.50 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (1.36 g, 9.59 mmol, 1.18 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(4-(Benzyloxy)phenyl)cyclopropanamine (400 mg, 1.67 mmol, 35% yield) was obtained as a yellow oil. M+H.sup.+=240.2 (LCMS).

Step 2: N-(1-(4-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 307)

[1446] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (112 mg, 501 mol, 1.2 eq) in DMF (2.0 mL) were added 1-(4-(benzyloxy)phenyl)cyclopropanamine (100 mg, 418 mol, 1.0 eq), TEA (127 mg, 1.25 mmol, 174 L, 3.0 eq), EDCI (120 mg, 627 mol, 1.5 eq) and HOBt (84.7 mg, 627 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(4-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (22.2 mg, 50.0 mol, 12% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=445.2 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 10.73-10.55 (m, 1H), 8.96 (s, 1H), 7.45-7.30 (m, 5H), 7.21-7.14 (m, 3H), 6.99-6.90 (m, 4H), 5.08 (s, 2H), 4.36 (br t, J=4.8 Hz, 2H), 3.53-3.44 (m, 2H), 2.82 (d, J=4.9 Hz, 6H), 2.25-2.19 (m, 3H), 1.24-1.10 (m, 4H).

Example 193: N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 291)

##STR01036##

Step 1: tert-Butyl(1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamate (193A-1)

[1447] A mixture of tert-butyl N-[1-(3-bromophenyl)cyclopropyl]carbamate (150 mg, 480 mol, 1.0 eq), phenylboronic acid (146 mg, 1.20 mmol, 2.5 eq), Pd(dppf)Cl.sub.2 (35.2 mg, 48.1 mol, 0.1 eq) and K.sub.2CO.sub.3 (166 mg, 1.20 mmol, 2.5 eq) in a mixture of dioxane (6.0 mL) and H.sub.2O (1.5 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/4. The crude product tert-butyl(1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamate (180 mg) was obtained as a white solid.

Step 2: 1-([1,1-Biphenyl]-3-yl)cyclopropanamine (193A-2)

[1448] To a solution of tert-butyl(1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamate (100 mg, 323 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product 1-([1,1-biphenyl]-3-yl)cyclopropanamine (120 mg, HCl salt) as a white solid, which was used in the next step without any further purification. M+H.sup.+=210.1 (LCMS).

Step 3: N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 291)

[1449] To a solution of 1-([1,1-biphenyl]-3-yl)cyclopropanamine (120 mg, 573 mol, 1.0 eq, HCl salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (154 mg, 688 mol, 1.2 eq) in DMF (4.0 mL) were added EDCI (165 mg, 860 mol, 1.5 eq), HOBt (116 mg, 860 mol, 1.5 eq) and TEA (116 mg, 1.15 mmol, 160 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (8040 mm, 3 m); flow rate: 60 mL/min; gradient: 40%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (24.5 mg, 55.5 mol, 10% yield) was obtained as an light yellow gum. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.99 (s, 1H), 7.67-7.59 (m, 1H), 7.67-7.56 (m, 1H), 7.51-7.31 (m, 6H), 7.21 (br d, J=7.6 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.97-6.88 (m, 2H), 4.07-4.02 (m, 2H), 2.64-2.58 (m, 1H), 2.61 (t, J=5.8 Hz, 1H), 2.27-2.18 (m, 9H), 1.37-1.25 (m, 4H).

Example 194: N-(1-(3-(Cyclopent-1-en-1-yl)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 264)

##STR01037##

Step 1: N-(1-(3-(Cyclopent-1-en-1-yl)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 264)

[1450] To a stirred solution of N-(1-(3-(cyclopent-1-en-1-yl)phenyl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (170 mg, 407 mol, 1.0 eq) and cyclopent-1-en-1-ylboronic acid (103 mg, 530 mol, 1.3 eq) in DMSO (5.0 mL) were added Pd(OAc) 2 (9.15 mg, 40.7 mol, 0.1 eq) and KOAc (120 mg, 1.22 mmol, 3.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(3-(Cyclopent-1-en-1-yl)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (120 mg, 297 mol, 73% yield) was obtained as a yellow solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.94 (s, 1H), 7.33 (s, 1H), 7.29-7.22 (m, 2H), 7.14 (d, J=9.3 Hz, 1H), 7.05 (br d, J=7.0 Hz, 1H), 6.95-6.89 (m, 2H), 6.24 (br s, 1H), 4.05 (t, J=5.8 Hz, 2H), 2.69-2.60 (m, 4H), 2.47 (br d, J=2.1 Hz, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 2.01-1.91 (m, 2H), 1.25 (s, 4H).

Example 195: N-(1-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 276)

##STR01038##

Step 1: N-(1-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 276)

[1451] To a solution of N-(1-(3-(cyclopent-1-en-1-yl)phenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methylbenzamide (70.0 mg, 173 mol, 1.0 eq) in EtOAc (7.0 mL) was added 10% palladium on carbon (10.0 mg) at 20 C. for 2 h under a H.sub.2 atmosphere (15 psi). LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum. N-(1-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (38.0 mg, 89.1 mol, 51% yield) was obtained as a yellow solid. M+H.sup.+=407.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.93 (br s, 1H), 7.23-7.11 (m, 3H), 7.07-7.01 (m, 1H), 6.99-6.88 (m, 3H), 4.11-3.99 (m, 2H), 3.06-2.79 (m, 1H), 2.62 (br d, J=5.5 Hz, 2H), 2.34-2.17 (m, 9H), 1.99 (br d, J=5.9 Hz, 2H), 1.81-1.46 (m, 6H), 1.23 (br s, 4H).

Example 196: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2,3,4,5-tetrahydro-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (Compound 338)

##STR01039##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2,3,4,5-tetrahydro-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (Compound 338)

[1452] To a stirred solution of N-(1-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (80.0 mg, 192 mol, 1.0 eq) and cyclohex-1-en-1-ylboronic acid (29.0 mg, 230 mol, 1.2 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (1.0 mL) were added K.sub.2CO.sub.3 (79.5 mg, 575 mol, 3.0 eq) and Pd(dppf)Cl.sub.2 (14.0 mg, 19.2 mol, 0.1 eq). The mixture was stirred at 90 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2,3,4,5-tetrahydro-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (44.3 mg, 105 mol, 55% yield, HCl salt) was obtained as a white solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.65 (br s, 1H), 8.99 (br s, 1H), 7.33-7.16 (m, 4H), 7.08 (br d, J=6.4 Hz, 1H), 7.02-6.93 (m, 2H), 6.11 (br s, 1H), 4.37 (br s, 2H), 3.54-3.48 (m, 2H), 2.83 (br s, 6H), 2.35 (br s, 2H), 2.25 (br s, 3H), 2.17 (br s, 2H), 1.72 (br s, 2H), 1.61 (br d, J=4.6 Hz, 2H), 1.25 (br s, 4H).

Example 197: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)benzamide (Compound 266)

##STR01040##

Step 1: tert-Butyl(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)carbamate (197A-1)

[1453] A mixture of pyridin-4-ylboronic acid (295 mg, 2.40 mmol, 2.5 eq), tert-butyl(1-(2-bromophenyl)cyclopropyl)carbamate (300 mg, 961 mol, 1.0 eq), K.sub.2CO.sub.3 (332 mg, 2.40 mmol, 2.5 eq), Pd(dppf)Cl.sub.2 (70.3 mg, 96.1 mol, 0.1 eq) in a mixture of dioxane (12 mL) and H.sub.2O (3.0 mL) was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)carbamate (80.0 mg, 258 mol, 27% yield) was obtained as a yellow solid. M+H.sup.+=311.1 (LCMS).

Step 2: 1-(2-(Pyridin-4-yl)phenyl)cyclopropanamine (197A-2)

[1454] To a solution of tert-butyl(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)carbamate (80.0 mg, 258 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 1-(2-(pyridin-4-yl)phenyl)cyclopropanamine (50.0 mg, 203 mol, 79% yield, HCl salt) as a yellow solid. M+H.sup.+=211.1 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)benzamide (Compound 266)

[1455] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (54.5 mg, 244 mol, 1.2 eq), 1-(2-(pyridin-4-yl)phenyl)cyclopropanamine (50.0 mg, 203 mol, 1.0 eq, HCl salt) in DMF (3.0 mL) were added TEA (61.8 mg, 610 mol, 84.9 L, 3.0 eq), EDCI (46.8 mg, 244 mol, 1.2 eq) and HOBt (33.0 mg, 244 mol, 1.2 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-(pyridin-4-yl)phenyl)cyclopropyl)benzamide (49.8 mg, 108 mol, 53% yield, FA salt) was obtained as a yellow gum. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.60 (d, J=5.9 Hz, 2H), 8.25 (s, 1H), 8.17 (s, 1H), 7.90 (dd, J=1.0, 7.5 Hz, 1H), 7.52 (d, J=5.9 Hz, 2H), 7.38 (dtd, J=1.4, 7.4, 18.6 Hz, 2H), 7.18 (dd, J=1.3, 7.3 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.6, 8.4 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 2.27 (s, 6H), 2.08 (s, 3H), 1.02 (s, 4H).

Example 198: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 355)

##STR01041##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 355)

[1456] To a solution of N-(1-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (40.0 mg, 95.9 mol, 1.0 eq) in toluene (3.0 mL) were added tributyl(thiophen-2-yl) stannane (53.7 mg, 144 mol, 45.5 L, 1.5 eq) and Pd(t-Bu.sub.3P).sub.2 (4.90 mg, 9.58 mol, 0.1 eq). The mixture was stirred at 90 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (8.40 mg, 18.0 mol, 19% yield, FA salt) was obtained as a yellow oil. M+H.sup.+=421.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (s, 1H), 8.19 (s, 1H), 7.56-7.51 (m, 2H), 7.51-7.46 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.18-7.07 (m, 3H), 6.97-6.90 (m, 2H), 4.07 (t, J=5.8 Hz, 2H), 2.64 (t, J=5.8 Hz, 2H), 2.30-2.20 (m, 9H), 1.30 (br d, J=3.8 Hz, 4H).

Example 199: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-3-yl)phenyl)cyclopropyl)benzamide (Compound 325)

##STR01042##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-3-yl)phenyl)cyclopropyl)benzamide (Compound 325)

[1457] A mixture of N-(1-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (50.0 mg, 120 mol, 1.0 eq), thiophen-3-ylboronic acid (15.3 mg, 120 mol, 1.0 eq) and Na.sub.2CO.sub.3 (38.1 mg, 359 mol, 3.0 eq) in dioxane (2.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added Pd(PPh.sub.3).sub.2Cl.sub.2 (8.41 mg, 12.0 mol, 0.1 eq). The mixture was stirred at 100 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with EtOAc (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-3-yl)phenyl)cyclopropyl)benzamide (7.50 mg, 16.4 mol, 14% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=421.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.09-10.38 (m, 1H), 9.02 (s, 1H), 7.83 (d, J=1.47 Hz, 1H), 7.62-7.70 (m, 1H), 7.44-7.57 (m, 3H), 7.30-7.40 (m, 1H), 7.16-7.25 (m, 2H), 6.94-7.05 (m, 2H), 4.35 (br t, J=4.71 Hz, 2H), 3.50 (br d, J=4.52 Hz, 2H), 2.76-2.93 (m, 6H), 2.26 (s, 3H), 1.23-1.45 (m, 4H).

Example 200: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 169)

##STR01043##

Step 1: 1-(3-(Thiophen-2-yl)phenyl)cyclopropanamine (200A-1)

[1458] To a solution of 1-(3-bromophenyl)cyclopropanamine (300 mg, 1.41 mmol, 1.0 eq) in a mixture of THF (10 mL) and H.sub.2O (2.5 mL) were added thiophen-2-ylboronic acid (253 mg, 1.98 mmol, 1.4 eq), K.sub.3PO.sub.4 (901 mg, 4.24 mmol, 3.0 eq) and Pd(dppf)Cl.sub.2 (46.1 mg, 70.7 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times, then stirred at 80 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.2). 1-(3-(Thiophen-2-yl)phenyl)cyclopropanamine (100 mg, 464 mol, 33% yield) was obtained as a yellow oil. M+H.sup.+=216.2 (LCMS).

Step 2: tert-Butyl 3-((4-methyl-3-((1-(3-(thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (200A-2)

[1459] To a solution of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (71.1 mg, 232 mol, 1.0 eq) in DCM (5.0 mL) were added 1-(3-(thiophen-2-yl)phenyl)cyclopropanamine (50.0 mg, 232 mol, 1.0 eq), TEA (70.5 mg, 697 mol, 97.0 L, 3.0 eq), EDCI (89.0 mg, 464 mol, 2.0 eq) and HOBt (62.8 mg, 464 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.3). tert-Butyl 3-((4-methyl-3-((1-(3-(thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (85.0 mg, 169 mol, 73% yield) was obtained as a colorless oil. M+H.sup.+=504.3 (LCMS).

Step 3: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 169)

[1460] To a stirred solution of tert-butyl 3-((4-methyl-3-((1-(3-(thiophen-2-yl)phenyl)cyclopropyl) carbamoyl)phenyl)amino)azetidine-1-carboxylate (85.0 mg, 169 mol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (40.2 mg, 99.5 mol, 59% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=404.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.10 (s, 1H), 7.67 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.41-7.31 (m, 3H), 7.21 (d, J=7.7 Hz, 1H), 7.11-7.08 (m, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.62-6.55 (m, 2H), 4.60-4.44 (m, 1H), 4.41-4.29 (m, 2H), 3.94 (br dd, J=6.9, 10.8 Hz, 2H), 2.26 (s, 3H), 1.37 (br d, J=3.5 Hz, 4H).

Example 201: N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylamino)-2-methylbenzamide (Compound 187)

##STR01044##

Step 1: 1-([1,1-Biphenyl]-3-yl)cyclopropanamine (201A-1)

[1461] A mixture of 1-(3-bromophenyl)cyclopropanamine (200 mg, 943 mol, 1.0 eq), phenylboronic acid (161 mg, 1.32 mmol, 1.4 eq) and potassium phosphate (601 mg, 2.83 mmol, 3.0 eq) in a mixture of H.sub.2O (2.0 mL) and THF (8.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added dichloro[1,1-bis(di-t-butylphosphino) ferrocene]palladium (II)(30.7 mg, 47.2 mol, 0.05 eq) at 25 C. The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 100/1. 1-([1,1-Biphenyl]-3-yl)cyclopropanamine (30.0 mg, 143 mol, 15% yield) was obtained as a brown solid. M+H.sup.+=210.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.60 (d, J=7.5 Hz, 2H), 7.54 (s, 1H), 7.49-7.45 (m, 2H), 7.44-7.41 (m, 2H), 7.41-7.35 (m, 2H), 1.15-1.10 (m, 2H), 1.08-1.03 (m, 2H).

Step 2: tert-Butyl 3-((3-((1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (201A-2)

[1462] To a solution of 1-([1,1-biphenyl]-3-yl)cyclopropanamine (30.0 mg, 143 mol, 1.0 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (43.9 mg, 143 mol, 1.0 eq) in DCM (10 mL) were added TEA (43.5 mg, 430 mol, 59.9 L, 3.0 eq), EDCI (55.0 mg, 287 mol, 2.0 eq) and HOBt (38.7 mg, 287 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.4). tert-Butyl 3-((3-((1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (10.0 mg, 20.1 mol, 14% yield) was obtained as a colorless oil. M+H.sup.+=498.4 (LCMS).

Step 3: N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylamino)-2-methylbenzamide (Compound 187)

[1463] To a stirred solution of tert-butyl 3-((3-((1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (100 mg, 216 mol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.10% aqueous TFA, mobile phase B: acetonitrile). N-(1-([1,1-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylamino)-2-methyl benzamide (43.1 mg, 90.3 mol, 42% yield, TFA salt) was obtained as a white solid. M+H.sup.+=398.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 8.91 (s, 1H), 8.77-8.70 (m, 1H), 7.63 (d, J=7.2 Hz, 2H), 7.51-7.44 (m, 4H), 7.42-7.34 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.53-6.49 (m, 2H), 6.35 (br d, J=6.4 Hz, 1H), 4.41-4.31 (m, 1H), 4.24 (br s, 2H), 3.78 (br s, 2H), 2.17 (s, 3H), 1.37-1.31 (m, 2H), 1.30-1.24 (m, 2H).

Example 202: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 186)

##STR01045##

Step 1: tert-Butyl(1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamate (202A-1)

[1464] To a solution of tert-butyl(1-(3-bromophenyl)cyclopropyl)carbamate (200 mg, 640 mol, 1.0 eq) in DMSO (12 mL) were added (5-formylthiophen-2-yl) boronic acid (100 mg, 640 mol, 1.0 eq), KOAc (189 mg, 1.92 mmol, 3.0 eq), Pd(OAc) 2 (14.4 mg, 64.1 mol, 0.1 eq), di-(1-adamantyl)-n-butylphosphine (45.9 mg, 128 mol, 0.2 eq) and di-tert-butyl dicarbonate (140 mg, 640 mol, 147 L, 1.0 eq). The mixture was degassed and purged with N.sub.2 three times, then stirred at 90 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). tert-Butyl(1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamate (150 mg, 437 mol, 68% yield) was obtained as a yellow oil. M+H.sup.+=344.1 (LCMS).

Step 2: 5-(3-(1-Aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (202A-2)

[1465] To a solution of tert-butyl(1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamate (120 mg, 349 mol, 1.0 eq) in EtOAc (6.0 mL) was added HCl/EtOAc (4 M, 18 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude product 5-(3-(1-aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (120 mg, HCl salt), which was used in the next step without any further purification. M+H.sup.+=244.1 (LCMS).

Step 3: tert-Butyl 3-((3-((1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (202A-3)

[1466] To a solution of 5-(3-(1-aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (120 mg, 429 mol, 1.0 eq, HCl salt) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (131 mg, 429 mol, 1.0 eq) in DCM (15 mL) were added TEA (130 mg, 1.29 mmol, 179 L, 3.0 eq), EDCI (123 mg, 643 mol, 1.5 eq) and HOBt (87.0 mg, 643 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.2). tert-Butyl 3-((3-((1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (250 mg, 409 mol, 95% yield) was obtained as a yellow oil. M+H.sup.+=532.3 (LCMS).

Step 4: tert-Butyl 3-((4-methyl-3-((1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (202A-4)

[1467] To a solution of pyrrolidine (8.03 mg, 113 mol, 9.42 L, 2.0 eq) and tert-butyl 3-((3-((1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (30.0 mg, 56.3 mol, 1.0 eq) in MeOH (3.0 mL) was added NaBH.sub.3CN (7.09 mg, 113 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-((4-methyl-3-((1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (40.0 mg), which was used in the next step without any further purification. M+H.sup.+=587.4 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 186)

[1468] To a solution of tert-butyl 3-((4-methyl-3-((1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (80.0 mg, 136 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (30.0 mg, 57.3 mol, 42% yield, HCl salt) was obtained as a white solid. M+H.sup.+=487.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.21-10.87 (m, 1H), 9.31-9.08 (m, 2H), 9.04-8.87 (m, 1H), 7.53-7.45 (m, 3H), 7.42-7.34 (m, 2H), 7.17-7.11 (m, 1H), 7.03-6.95 (m, 1H), 6.60-6.55 (m, 1H), 6.53-6.48 (m, 1H), 4.76-4.49 (m, 2H), 4.46-4.32 (m, 1H), 4.28-4.16 (m, 2H), 3.87-3.83 (m, 2H), 3.46-3.37 (m, 2H), 3.18-3.01 (m, 2H), 2.21-2.15 (m, 3H), 2.05-1.82 (m, 4H), 1.35-1.22 (m, 4H).

Example 203: 5-(Azetidin-3-ylamino)-N-(1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)-2-methylbenzamide (Compound 196)

##STR01046##

Step 1: tert-Butyl 3-((3-((1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (203A-1)

[1469] To a solution of tert-butyl 3-((3-((1-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl) carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (130 mg, 245 mol, 1.0 eq) and (1R,3S)-3-aminocyclopentanol (49.6 mg, 489 mol, 2.0 eq) in MeOH (6.0 mL) was added NaBH.sub.3CN (30.7 mg, 489 mol, 2.0 eq). The mixture was stirred at 20 C. for 20 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). tert-Butyl 3-((3-((1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (40.0 mg, 59.0 mol, 24% yield) was obtained as a colorless oil. M+H.sup.+=617.4 (LCMS).

Step 2: 5-(Azetidin-3-ylamino)-N-(1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)-2-methylbenzamide (Compound 196)

[1470] To a solution of tert-butyl 3-((3-((1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (30.0 mg, 48.6 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 2.5 mL). The mixture was stirred at 20 C. for 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-N-(1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopropyl)-2-methyl benzamide (24.4 mg, 44.1 mol, 91% yield, HCl salt) was obtained as a white solid. M+H.sup.+=517.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.31 (br d, J=4.1 Hz, 2H), 9.25-9.06 (m, 2H), 8.98-8.92 (m, 1H), 7.54-7.42 (m, 3H), 7.41-7.32 (m, 2H), 7.17-7.10 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.60-6.48 (m, 2H), 4.42-4.32 (m, 3H), 4.23 (br d, J=7.3 Hz, 2H), 4.14-4.02 (m, 2H), 3.89-3.71 (m, 2H), 2.25-2.13 (m, 4H), 1.99-1.84 (m, 2H), 1.76-1.60 (m, 3H), 1.35-1.22 (m, 4H).

Example 204: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2,3-dimethylphenyl)cyclopropyl)-2-methylbenzamide (Compound 318)

##STR01047##

Step 1: 1-(2,3-Dimethylphenyl)cyclopropanamine (204A-2)

[1471] A mixture of 2,3-dimethylbenzonitrile (1.00 g, 7.62 mmol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO)+ (2.17 g, 7.62 mmol, 2.25 mL, 1.0 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 5.59 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (2.16 g, 15.3 mmol, 1.88 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(2,3-Dimethylphenyl)cyclopropanamine (100 mg, 620 mol, 8% yield) was obtained as a yellow oil. M+H.sup.+=162.2 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2,3-dimethylphenyl)cyclopropyl)-2-methylbenzamide (Compound 318)

[1472] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (166 mg, 744 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 259 L, 3.0 eq), EDCI (178 mg, 930 mol, 1.5 eq), HOBt (126 mg, 930 mol, 1.5 eq) and 1-(2,3-dimethylphenyl)cyclopropanamine (100 mg, 620 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(2,3-dimethylphenyl)cyclopropyl)-2-methylbenzamide (51.0 mg, 139 mol, 22% yield, HCl salt) was obtained as a white solid. M+H.sup.+=367.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.56 (br s, 1H), 8.85 (s, 1H), 7.49-7.44 (m, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.05-6.97 (m, 2H), 6.94-6.90 (m, 1H), 6.76 (d, J=2.6 Hz, 1H), 4.31 (t, J=5.1 Hz, 2H), 3.49-3.40 (m, 2H), 2.80 (d, J=4.9 Hz, 6H), 2.39 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.22-1.16 (m, 2H), 1.05-0.98 (m, 2H).

Example 205: N-(1-(2,3-Dichlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 335)

##STR01048##

Step 1: 1-(2,3-Dichlorophenyl)cyclopropanamine (205A-2)

[1473] A mixture of 2,3-dichlorobenzonitrile (200 mg, 1.16 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sup.4 (363 mg, 1.28 mmol, 377 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 853 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (330 mg, 2.33 mmol, 287 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (2.0 mL) and MTBE (15 mL), and extracted with MTBE (15 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.2). 1-(2,3-Dichlorophenyl)cyclopropanamine (70.0 mg, 346 mol, 30% yield) was obtained as a yellow oil. M+H.sup.+=202.0 (LCMS).

Step 2: N-(1-(2,3-Dichlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 335)

[1474] To a solution of 1-(2,3-dichlorophenyl)cyclopropanamine (50.0 mg, 247 mol, 1.0 eq) and 5-[2-(dimethylamino)ethoxy]-2-methyl-benzoic acid (55.2 mg, 247 mol, 1.0 eq) in DMF (1.0 mL) were added HATU (141 mg, 371 mol, 1.5 eq) and DIEA (95.9 mg, 742 mol, 100 L, 3.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give N-(1-(2,3-dichlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (34.4 mg, 71.5 mol, 29% yield, HCl salt) as a white solid. M+H.sup.+=407.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.09 (br s, 1H), 9.02-8.92 (m, 1H), 7.70 (dd, J=1.2, 7.8 Hz, 1H), 7.54 (dd, J=1.2, 8.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97-6.91 (m, 1H), 6.80 (d, J=2.8 Hz, 1H), 4.29 (t, J=4.8 Hz, 2H), 3.47 (q, J=4.8 Hz, 2H), 2.82 (d, J=4.8 Hz, 6H), 2.10 (s, 3H), 1.26-1.19 (m, 2H), 1.19-1.13 (m, 2H).

Example 206: N-(1-(2-Bromo-3-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 317)

##STR01049##

Step 1: 1-(2-Bromo-3-methylphenyl)cyclopropanamine (206A-2)

[1475] A mixture of 2-bromo-3-methylbenzonitrile (200 mg, 1.02 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (290 mg, 1.02 mmol, 301 L, 1.0 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 748 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (290 mg, 2.04 mmol, 252 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(2-Bromo-3-methylphenyl)cyclopropanamine (150 mg, 633 mol, 65% yield) was obtained as a yellow oil. M+H.sup.+=226.2 (LCMS).

Step 2: N-(1-(2-Bromo-3-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 317)

[1476] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (82.9 mg, 372 mol, 1.2 eq) in DCM (2.0 mL) were added TEA (94.0 mg, 929 mol, 129 L, 3.0 eq), EDCI (89.0 mg, 464 mol, 1.5 eq), HOBt (62.8 mg, 464 mol, 1.5 eq) and 1-(2-bromo-3-methylphenyl)cyclopropanamine (70.0 mg, 310 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(2-Bromo-3-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (35.7 mg, 82.8 mol, 27% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.75 (br s, 1H), 8.79 (s, 1H), 7.59-7.52 (m, 1H), 7.27-7.18 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.96-6.90 (m, 1H), 6.81 (d, J=2.6 Hz, 1H), 4.32 (br d, J=5.1 Hz, 2H), 3.53-3.40 (m, 2H), 2.80 (d, J=4.9 Hz, 6H), 2.37 (s, 3H), 2.11 (s, 3H), 1.29-1.20 (m, 2H), 1.14-1.05 (m, 2H).

Example 207: N-(1-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 336)

##STR01050##

Step 1: 1-(3-Bromo-2-methylphenyl)cyclopropanamine (207A-2)

[1477] A mixture of 3-bromo-2-methylbenzonitrile (500 mg, 2.55 mmol, 1.0 eq) in anhydrous Et.sub.2O (25 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (725 mg, 2.55 mmol, 753 L, 1.0 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 1.87 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (724 mg, 5.10 mmol, 630 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (15 mL) and MTBE (15 mL) and extracted with MTBE (15 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (25 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(3-Bromo-2-methylphenyl)cyclopropanamine (140 mg, 619 mol, 24% yield) was obtained as a yellow gum. M+H.sup.+=226.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.43 (d, J=7.9 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 2.48 (br d, J=1.6 Hz, 3H), 0.88-0.83 (m, 2H), 0.77-0.70 (m, 2H).

Step 2: N-(1-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 336)

[1478] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (166 mg, 743 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 259 L, 3.0 eq), EDCI (178 mg, 939 mol, 1.5 eq), HOBt (125 mg, 939 mol, 1.5 eq) and 1-(3-bromo-2-methylphenyl)cyclopropanamine (140 mg, 619 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) at 25 C. and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (130 mg, 301 mol, 49% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=433.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.97-9.83 (m, 1H), 8.95 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.15-7.06 (m, 2H), 6.96-6.91 (m, 1H), 6.78 (d, J=2.6 Hz, 1H), 4.29 (t, J=5.0 Hz, 2H), 3.49-3.45 (m, 2H), 2.83 (d, J=4.9 Hz, 6H), 2.56 (s, 3H), 2.10 (s, 3H), 1.23-1.18 (m, 2H), 1.14-1.07 (m, 2H).

Example 208: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methyl-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (Compound 340)

##STR01051##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methyl-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (Compound 340)

[1479] To a solution of N-(1-(3-bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (80.0 mg, 185 mol, 1.0 eq) in a mixture of dioxane (3.0 mL) and H.sub.2O (0.8 mL) were added phenylboronic acid (33.9 mg, 278 mol, 1.5 eq), K.sub.2CO.sub.3 (76.9 mg, 556 mol, 3.0 eq) and Pd(dppf)Cl.sub.2 (13.6 mg, 18.6 mol, 0.1 eq) at 25 C. The mixture was heated to 90 C. and stirred for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) at 25 C. and extracted with EtOAc (3.0 mL3). The combined organic layers were washed with brine (3.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methyl-[1,1-biphenyl]-3-yl)cyclopropyl)benzamide (57.8 mg, 135 mol, 73% yield, HCl salt) was obtained as a white solid. M+H.sup.+=429.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.07 (br s, 1H), 8.89 (s, 1H), 7.69-7.64 (m, 1H), 7.47-7.42 (m, 2H), 7.38-7.34 (m, 1H), 7.32-7.28 (m, 2H), 7.21-7.17 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.09-7.06 (m, 1H), 6.95-6.91 (m, 1H), 6.80 (d, J=2.6 Hz, 1H), 4.29 (t, J=5.0 Hz, 2H), 3.48-3.44 (m, 2H), 2.82 (d, J=4.5 Hz, 6H), 2.37 (s, 3H), 2.12 (s, 3H), 1.24-1.19 (m, 2H), 1.15-1.10 (m, 2H).

Example 209: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)cyclopropyl)benzamide (Compound 329)

##STR01052##

Step 1: 1-(5,6,7,8-Tetrahydronaphthalen-1-yl)cyclopropanamine (209A-2)

[1480] A mixture of 5,6,7,8-tetrahydronaphthalene-1-carbonitrile (200 mg, 1.27 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (361 mg, 1.27 mmol, 375 L, 1.0 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 933 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (361 mg, 2.54 mmol, 314 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(5,6,7,8-Tetrahydronaphthalen-1-yl)cyclopropanamine (60.0 mg, 320 mol, 25% yield) was obtained as a yellow gum. M+H.sup.+=188.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.08-7.04 (m, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.92-6.87 (m, 1H), 2.94 (t, J=6.0 Hz, 2H), 2.73-2.69 (m, 2H), 1.77-1.67 (m, 4H), 0.84-0.76 (m, 2H), 0.72-0.65 (m, 2H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)cyclopropyl)benzamide (Compound 329)

[1481] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.8 mg, 384 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (97.3 mg, 961 mol, 134 L, 3.0 eq), EDCI (92.1 mg, 481 mol, 1.5 eq), HOBt (64.9 mg, 481 mol, 1.5 eq) and 1-(5,6,7,8-tetrahydronaphthalen-1-yl)cyclopropanamine (60.0 mg, 320 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) at 25 C. and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)cyclopropyl)benzamide (15.0 mg, 38.2 mol, 12% yield, HCl salt) was obtained as a white solid. M+H.sup.+=393.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.48-10.27 (m, 1H), 8.78 (s, 1H), 7.41 (br d, J=7.4 Hz, 1H), 7.11 (br d, J=8.4 Hz, 1H), 7.05-6.96 (m, 1H), 6.96-6.89 (m, 2H), 6.76 (s, 1H), 4.30 (br s, 2H), 3.46 (br d, J=4.3 Hz, 2H), 2.96 (br s, 2H), 2.81 (br d, J=3.9 Hz, 6H), 2.73 (br s, 2H), 2.09 (s, 3H), 1.74 (br d, J=4.4 Hz, 4H), 1.14 (br s, 2H), 1.02 (br s, 2H).

Example 210: N-(1-(Benzofuran-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 370)

##STR01053##

Step 1: 1-(Benzofuran-7-yl)cyclopropanamine (210A-2)

[1482] To a mixture of benzofuran-7-carbonitrile (200 mg, 1.40 mmol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sup.4 (437 mg, 1.54 mmol, 450 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.02 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (397 mg, 2.79 mmol, 350 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.2). 1-(Benzofuran-7-yl)cyclopropanamine (60.0 mg, 0.35 mmol, 25% yield) was obtained as a yellow oil. M+H.sup.+=174.1 (LCMS).

Step 2: N-(1-(Benzofuran-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 370)

[1483] To a solution of 1-(benzofuran-7-yl)cyclopropanamine (50.0 mg, 289 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (64.5 mg, 289 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (58.4 mg, 0.58 mmol, 80.3 L, 2.0 eq), EDCI (83.0 mg, 0.43 mmol, 1.5 eq) and HOBt (58.5 mg, 0.43 mmol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10040 mm, 3 m); flow rate: 50 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(Benzofuran-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (50.0 mg, 118 mol, 41% yield, FA salt) was obtained as a white gum. M+H.sup.+=379.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.18 (s, 1H), 7.88-8.04 (m, 1H), 7.45-7.55 (m, 1H), 7.29-7.37 (m, 1H), 7.17-7.24 (m, 1H), 7.08-7.14 (m, 1H), 6.87-6.97 (m, 3H), 4.07 (t, J=5.68 Hz, 2H), 2.62-2.79 (m, 2H), 2.27 (s, 6H), 2.16 (s, 3H), 1.50-1.67 (m, 2H), 1.27 (br d, J=1.71 Hz, 2H).

Example 211: N-(1-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 357)

##STR01054##

Step 1: 1-(Benzofuran-4-yl)cyclopropanamine (211A-2)

[1484] A suspension of benzofuran-4-carbonitrile (200 mg, 1.40 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (397 mg, 1.40 mmol, 412 L, 1.0 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 1.02 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (397 mg, 2.79 mmol, 345 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (15 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(benzofuran-4-yl)cyclopropanamine (120 mg), which was used in the next step without any further purification. M+H.sup.+=174.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.97 (d, J=2.2 Hz, 1H), 7.46-7.40 (m, 1H), 7.22-7.16 (m, 3H), 0.93 (t, J=2.3 Hz, 2H), 0.90 (t, J=2.3 Hz, 2H).

Step 2: N-(1-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 357)

[1485] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (170 mg, 762 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (193 mg, 1.91 mmol, 265 L, 3.0 eq), EDCI (183 mg, 953 mol, 1.5 eq), HOBt (129 mg, 953 mol, 1.5 eq) and 1-(benzofuran-4-yl)cyclopropanamine (110 mg, 635 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (69.0 mg, 182 mol, 29% yield, HCl salt) was obtained as a white solid. M+H.sup.+=379.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.63 (br s, 1H), 9.18 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.26-7.21 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.96-6.92 (m, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.33 (t, J=4.9 Hz, 2H), 3.50-3.42 (m, 2H), 2.81 (d, J=4.9 Hz, 6H), 2.07 (s, 3H), 1.25 (s, 4H).

Example 212: N-(1-(Benzo[b]thiophen-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 368)

##STR01055##

Step 1: Benzo[b]thiophene-7-carbonitrile (212A-2)

[1486] To a solution of 7-bromobenzo[b]thiophene (200 mg, 939 mol, 1.0 eq) in DMF (4.0 mL) were added Zn(CN).sub.2 (77.2 mg, 657 mol, 41.7 L, 0.7 eq) and Pd(PPh.sub.3).sub.4 (108 mg, 93.9 mol, 0.1 eq) at 25 C. under a N.sub.2 atmosphere. The mixture was stirred at 120 C. for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/5, R.sub.f=0.4). Benzo[b]thiophene-7-carbonitrile (140 mg, 879 mol, 94% yield) was obtained as a white solid. M+H.sup.+=160.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.25 (d, J=8.1 Hz, 1H), 8.06-7.91 (m, 2H), 7.69-7.53 (m, 2H).

Step 2: 1-(Benzo[b]thiophen-7-yl)cyclopropanamine (212A-3)

[1487] A mixture of benzo[b]thiophene-7-carbonitrile (140 mg, 879 mol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (250 mg, 879 mol, 260 L, 1.0 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 645 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (250 mg, 1.76 mmol, 217 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (8.0 mL) and MTBE (8.0 mL) and extracted with MTBE (8.0 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. 1-(Benzo[b]thiophen-7-yl)cyclopropane amine (80 mg, 423 mol, 48% yield) was obtained as a yellow gum, which was used in the next step without any further purification. M+H.sup.+=190.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.79-7.67 (m, 2H), 7.47 (d, J=5.5 Hz, 1H), 7.34-7.25 (m, 2H), 0.96 (t, J=2.3 Hz, 2H), 0.92 (t, J=2.3 Hz, 2H).

Step 3: N-(1-(Benzo[b]thiophen-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 368)

[1488] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (113 mg, 507 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (128 mg, 1.27 mmol, 176 L, 3.0 eq), EDCI (122 mg, 634 mol, 1.5 eq), HOBt (85.7 mg, 634 mol, 1.5 eq) and 1-(benzo[b]thiophen-7-yl)cyclopropanamine (80.0 mg, 423 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(Benzo[b]thiophen-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (93.0 mg, 236 mol, 56% yield, HCl salt) was obtained as a white solid. M+H.sup.+=395.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.65 (br s, 1H), 9.13 (s, 1H), 7.82-7.73 (m, 2H), 7.53-7.44 (m, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.99-6.91 (m, 1H), 6.89 (d, J=2.6 Hz, 1H), 4.48-4.27 (m, 2H), 3.62-3.34 (m, 2H), 2.81 (d, J=4.9 Hz, 6H), 2.08 (s, 3H), 1.34-1.23 (m, 4H).

Example 213: N-(1-(Benzo[b]thiophen-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 356)

##STR01056##

Step 1: 1-(Benzo[b]thiophen-4-yl)cyclopropanamine (213A-2)

[1489] A mixture of benzo[b]thiophene-4-carbonitrile (200 mg, 1.26 mmol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (357 mg, 1.26 mmol, 371 L, 1.0 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 921 L, 2.2 eq) was added dropwise over 1 h to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (357 mg, 2.51 mmol, 310 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (8.0 mL) and MTBE (8.0 mL) and extracted with MTBE (8.0 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product, 1-(benzo[b]thiophen-4-yl)cyclopropanamine (100 mg), which was used in the next step without any further purification. M+H.sup.+=173.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.89-7.83 (m, 1H), 7.79 (s, 2H), 7.32-7.25 (m, 2H), 0.99-0.93 (m, 2H), 0.86-0.79 (m, 2H).

Step 2: N-(1-(Benzo[b]thiophen-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 356)

[1490] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (142 mg, 634 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (160 mg, 1.58 mmol, 221 L, 3.0 eq), EDCI (152 mg, 792 mol, 1.5 eq), HOBt (107 mg, 792 mol, 1.5 eq) and 1-(benzo[b]thiophen-4-yl)cyclopropanamine (100 mg, 528 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (5.0 mL) at 25 C. and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(Benzo[b]thiophen-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (8.90 mg, 22.6 mol, 4% yield, HCl salt) was obtained as a white solid. M+H.sup.+=395.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.15-9.99 (m, 1H), 9.15 (s, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.82 (d, J=5.5 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.72 (d, J=2.3 Hz, 1H), 4.26 (br t, J=4.9 Hz, 2H), 3.48-3.42 (m, 2H), 2.80 (d, J=4.8 Hz, 6H), 2.01 (s, 3H), 1.30-1.25 (m, 2H), 1.19-1.14 (m, 2H).

Example 214: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methylbenzo[d]thiazol-7-yl)cyclopropyl)benzamide (Compound 403)

##STR01057##

Step 1: 2-Methylbenzo[d]thiazole-7-carbonitrile (214A-2)

[1491] To a mixture of 7-bromo-2-methylbenzo[d]thiazole (500 mg, 2.20 mmol, 1.0 eq) in DMF (6.0 mL) was degassed and purged with N.sub.2 three times. To the mixture were added Zn(CN).sub.2 (386 mg, 3.28 mmol, 1.5 eq), Zn (14.3 mg, 0.22 mmol, 0.1 eq), Pd.sub.2 (dba) 3 (100 mg, 0.11 mmol, 0.05 eq) and DPPF (122 mg, 0.22 mmol, 0.1 eq). The resulting mixture was stirred at 140 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (6.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. 2-Methylbenzo[d]thiazole-7-carbonitrile (300 mg, 1.72 mmol, 79% yield) was obtained as a white solid. M+H.sup.+=175.0 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.17 (dd, J=0.9, 8.2 Hz, 1H), 7.71 (dd, J=0.9, 7.6 Hz, 1H), 7.49-7.59 (m, 1H), 2.91 (s, 3H)

Step 2: 1-(2-Methylbenzo[d]thiazol-7-yl)cyclopropanamine (214A-3)

[1492] To a mixture of 2-methylbenzo[d]thiazole-7-carbonitrile (200 mg, 1.15 mmol, 1.0 eq) in anhydrous Et.sub.2O (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (489 mg, 1.72 mmol, 510 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O 840 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (326 mg, 2.30 mmol, 280 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(2-methylbenzo[d]thiazol-7-yl)cyclopropanamine (80.0 mg) as a yellow oil. M+H.sup.+=205.0 (LCMS);

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methylbenzo[d]thiazol-7-yl)cyclopropyl)benzamide (Compound 403)

[1493] To a solution of 1-(2-methylbenzo[d]thiazol-7-yl)cyclopropanamine (50.0 mg, 245 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (54.6 mg, 245 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (49.5 mg, 0.49 mmol, 68.1 L, 2.0 eq), EDCI (70.4 mg, 370 mol, 1.5 eq) and HOBt (49.6 mg, 370 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(2-methylbenzo[d]thiazol-7-yl)cyclopropyl)benzamide (10.0 mg, 22.2 mol, 9% yield, HCl salt) was obtained as a white solid. M+H.sup.+=410.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.71-7.86 (m, 1H), 7.37-7.48 (m, 2H), 7.08-7.23 (m, 1H), 6.80-7.02 (m, 2H), 4.33 (br d, J=4.25 Hz, 2H), 3.49 (br t, J=4.9 Hz, 2H), 2.71-2.92 (m, 9H), 2.01-2.18 (m, 3H), 1.29 (br d, J=5.9 Hz, 4H).

Example 215: N-(1-(Benzo[b]thiophen-3-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 346)

##STR01058##

Step 1: 1-(Benzo[b]thiophen-3-yl)cyclopropanamine (215A-2)

[1494] To a mixture of benzo[b]thiophene-3-carbonitrile (300 mg, 1.88 mmol, 1.0 eq) in anhydrous Et.sub.2O (30 mL) was degassed and purged with N.sub.2 three times. The mixture was stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (589 mg, 2.07 mmol, 610 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.38 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (535 mg, 3.77 mmol, 470 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (30 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.3). 1-(Benzo[b]thiophen-3-yl)cyclopropanamine (120 mg, 0.63 mmol, 34% yield) was obtained as a white solid. M+H.sup.+=190.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.07-8.16 (m, 1H), 7.96 (d, J=7.50 Hz, 1H), 7.52 (s, 1H), 7.33-7.46 (m, 2H), 3.06 (br s, 2H), 0.91-0.99 (m, 2H), 0.84-0.91 (m, 2H).

Step 2: N-(1-(Benzo[b]thiophen-3-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 346)

[1495] To a solution of 1-(benzo[b]thiophen-3-yl)cyclopropanamine (90.0 mg, 476 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (106 mg, 476 mol, 1.0 eq) in DCM (3 mL) were added TEA (96.2 mg, 950 mol, 132 L, 2.0 eq), EDCI (137 mg, 710 mol, 1.5 eq) and HOBt (96.4 mg, 710 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8040 mm, 3 m); flow rate: 40 mL/min; gradient: 10%-50% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(Benzo[b]thiophen-3-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (40.0 mg, 92.6 mol, 20% yield, HCl salt) was obtained as a yellow oil. M+H.sup.+=395.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.73 (br s, 1H), 9.16 (s, 1H), 8.32 (d, J=7.88 Hz, 1H), 7.95 (d, J=7.88 Hz, 1H), 7.67 (s, 1H), 7.31-7.50 (m, 2H), 7.04-7.16 (m, 1H), 6.87-6.97 (m, 1H), 6.72-6.81 (m, 1H), 4.31 (t, J=5.07 Hz, 2H), 3.45 (q, J=5.04 Hz, 2H), 2.79 (d, J=4.88 Hz, 6H), 2.03 (s, 3H), 1.13-1.28 (m, 4H).

Example 216: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-methyl-1H-indol-3-yl)cyclopropyl)benzamide (Compound 354)

##STR01059##

Step 1: 1-Methyl-1H-indole-3-carbonitrile (216A-2)

[1496] To a solution of 1H-indole-3-carbonitrile (2.00 g, 14.7 mmol, 1.0 eq) in DMF (20 mL) were added DABCO (316 mg, 2.81 mmol, 309 L, 0.2 eq) and dimethyl carbonate (21.4 g, 238 mmol, 20.0 mL, 16.9 eq). The mixture was stirred at 95 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/1. 1-Methyl-1H-indole-3-carbonitrile (2.00 g) was obtained as a brown oil. M+H.sup.+=157.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.24 (s, 1H), 7.74-7.58 (m, 2H), 7.47-7.20 (m, 2H), 3.87 (s, 3H).

Step 2: 1-(1-Methyl-1H-indol-3-yl)cyclopropanamine (216A-3)

[1497] A mixture of 1-methyl-1H-indole-3-carbonitrile (500 mg, 3.20 mmol, 1.0 eq) in anhydrous Et.sub.2O (35 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (1.00 g, 3.52 mmol, 1.04 mL, 1.1 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 2.35 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (909 mg, 6.40 mmol, 790 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (30 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(1-Methyl-1H-indol-3-yl)cyclopropanamine (80.0 mg) was obtained as a brown oil. M17+H.sup.+=170.1 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-methyl-1H-indol-3-yl)cyclopropyl)benzamide (Compound 354)

[1498] To a solution of 1-(1-methyl-1H-indol-3-yl)cyclopropanamine (50.0 mg, 268 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (59.9 mg, 268 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (81.5 mg, 805 mol, 112 L, 3.0 eq), EDCI (129 mg, 671 mol, 2.5 eq) and HOBt (90.7 mg, 671 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-methyl-1H-indol-3-yl)cyclopropyl)benzamide (13.8 mg, 30.7 mol, 11% yield, FA salt) was obtained as a white solid. M+H.sup.+=392.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.93 (s, 1H), 8.17 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.04-6.98 (m, 1H), 6.85 (dd, J=2.8, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.00 (t, J=5.8 Hz, 2H), 3.73 (s, 3H), 2.63 (t, J=5.8 Hz, 2H), 2.26-2.20 (m, 6H), 2.11 (s, 3H), 1.19-1.08 (m, 4H).

Example 217: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-phenyl-1H-indol-3-yl)cyclopropyl)benzamide (Compound 395)

##STR01060##

Step 1: 1-Phenyl-1H-indole-3-carbonitrile (217A-2)

[1499] To a solution of 1H-indole-3-carbonitrile (150 mg, 1.06 mmol, 1.0 eq) in toluene (3.0 mL) were added CuI (20.1 mg, 105 mol, 0.1 eq), K.sub.3PO.sub.4 (470 mg, 2.22 mmol, 2.1 eq), bromobenzene (198 mg, 1.27 mmol, 133 L, 1.2 eq) and N,N-dimethylethane-1,2-diamine (18.6 mg, 211 mol, 22.7 L, 0.2 eq) at 25 C. under a N.sub.2 atmosphere. The mixture was stirred at 110 C. for 24 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3) and dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 1-Phenyl-1H-indole-3-carbonitrile (200 mg, 916 mol, 87% yield) was obtained as a white solid. M+H.sup.+=219.1 (LCMS).

Step 2: 1-(1-Phenyl-1H-indol-3-yl)cyclopropanamine (217A-3)

[1500] A mixture of 1-phenyl-1H-indole-3-carbonitrile (500 mg, 2.29 mmol, 1.0 eq) in anhydrous Et.sub.2O (25 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (977 mg, 3.44 mmol, 1.01 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.68 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (650 mg, 4.58 mmol, 565 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (8.0 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 1-(1-Phenyl-1H-indol-3-yl)cyclopropanamine (130 mg, 523 mol, 23% yield) was obtained as a white solid. M+H.sup.+=249.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.78 (br d, J=7.3 Hz, 1H), 7.64-7.42 (m, 7H), 7.21-7.07 (m, 2H), 0.98 (br s, 2H), 0.87 (br s, 2H).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-phenyl-1H-indol-3-yl)cyclopropyl)benzamide (Compound 395)

[1501] To a solution of 1-(1-phenyl-1H-indol-3-yl)cyclopropanamine (70.0 mg, 282 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (75.5 mg, 338 mol, 1.2 eq) in DCM (3.0 mL) were added TEA (85.6 mg, 846 mmol, 118 L, 3.0 eq), EDCI (81.1 mg, 423 mol, 1.5 eq) and HOBt (57.1 mg, 423 mmol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(1-phenyl-1H-indol-3-yl)cyclopropyl)benzamide (41.2 mg, 82.5 mol, 29% yield, FA salt) was obtained as a white solid. M+H.sup.+=454.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.05 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.62-7.52 (m, 6H), 7.44-7.32 (m, 1H), 7.24-7.17 (m, 1H), 7.16-7.11 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.7, 8.4 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 4.00 (t, J=5.8 Hz, 2H), 2.59 (t, J=5.8 Hz, 2H), 2.20 (s, 6H), 2.13 (s, 3H), 1.24 (br d, J=3.5 Hz, 2H), 1.20 (br d, J=3.8 Hz, 2H).

Example 218: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 301)

##STR01061##

Step 1: 1-(Quinolin-5-yl)cyclopropanamine (218A-2)

[1502] A mixture of quinoline-5-carbonitrile (500 mg, 3.24 mmol, 1.0 eq) in anhydrous Et.sub.2O (40 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (1.38 g, 4.86 mmol, 1.44 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 2.38 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (921 mg, 6.49 mmol, 801 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (40 mL) and MTBE (40 mL), and extracted with MTBE (40 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (40 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(Quinolin-5-yl)cyclopropanamine (225 mg) was obtained as a brown solid. M+H.sup.+=185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 301)

[1503] To a solution of 1-(quinolin-5-yl)cyclopropanamine (80.0 mg, 434 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (97.0 mg, 434 mol, 1.0 eq) in DCM (3 mL) was added TEA (87.9 mg, 868 mol, 121 L, 2.0 eq), EDCI (125 mg, 651 mol, 1.5 eq) and HOBt (88.0 mg, 651 mol, 1.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2 (Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (13.3 mg, 29.0 mol, 7% yield) as a yellow gum. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 9.10-9.05 (m, 1H), 8.95-8.86 (m, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.90-7.83 (m, 1H), 7.75-7.67 (m, 1H), 7.63-7.52 (m, 1H), 7.07-7.00 (m, 1H), 6.88-6.80 (m, 1H), 6.65-6.58 (m, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.56-2.53 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.43-1.30 (m, 2H), 1.20 (s, 2H).

Example 219: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 374)

##STR01062##

Step 1: tert-Butyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (219A-1)

[1504] To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (192 mg, 651 mol, 1.2 eq) and 1-(quinolin-5-yl)cyclopropanamine (100 mg, 543 mol, 1.0 eq) in DCM (1.0 mL) were added TEA (165 mg, 1.63 mmol, 227 L, 3.0 eq), EDCI (156 mg, 814 mol, 1.5 eq) and HOBt (110 mg, 814 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (150 mg, 325 mol, 60% yield) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=462.2 (LCMS).

Step 2: 5-(2-Aminoethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 374)

[1505] To a stirred solution of tert-butyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (150 mg, 325 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (120 mg, 318 mol, 96% yield, HCl salt) was obtained as a white solid. M+H.sup.+=362.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.88 (d, J=8.6 Hz, 1H), 9.43 (s, 1H), 9.35-9.29 (m, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.34 (br s, 3H), 8.21-8.15 (m, 2H), 8.15-8.08 (m, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.89 (dd, J=2.6, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.13 (t, J=5.1 Hz, 2H), 3.17-3.06 (m, 2H), 1.96 (s, 3H), 1.51-1.41 (m, 2H), 1.34-1.27 (m, 2H).

Example 220: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 385)

##STR01063##

Step 1: tert-Butyl methyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (220A-1)

[1506] To a solution of 1-(quinolin-5-yl)cyclopropanamine (100 mg, 543 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (168 mg, 543 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (165 mg, 1.63 mmol, 227 L, 3.0 eq), EDCI (260 mg, 1.36 mmol, 2.5 eq) and HOBt (183 mg, 1.36 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product tert-butyl methyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy)ethyl)carbamate (250 mg) as a brown oil which was used into the next step without further purification. M+H.sup.+=476.2 (LCMS).

Step 2: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 385)

[1507] To a solution of tert-butyl methyl(2-(4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (250 mg, 526 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (44.4 mg, 107 mol, 20% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=376.1 (LCMS); 1H NMR (400 MHZ, CD.sub.3OD) 10.06 (d, J=8.5 Hz, 1H), 9.27 (dd, J=1.3, 5.4 Hz, 1H), 8.36 (dd, J=1.3, 6.9 Hz, 1H), 8.27-8.15 (m, 3H), 7.11 (d, J=8.5 Hz, 1H), 6.95 (dd, J=2.7, 8.4 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.26-4.15 (m, 2H), 3.44-3.37 (m, 2H), 2.76 (s, 3H), 2.02 (s, 3H), 1.65-1.59 (m, 2H), 1.48-1.42 (m, 2H).

Example 221: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 381)

##STR01064##

Step 1: (S)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (221A-1)

[1508] To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and(S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (508 mg, 2.72 mmol, 1.5 eq) in toluene (15 mL) were added TMAD (935 mg, 5.43 mmol, 3.0 eq) and PPh.sub.3 (1.42 g, 5.43 mmol, 3.0 eq). The resulting mixture was degassed and purged with N.sub.2 three times and then stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (500 mg, 1.49 mmol, 82% yield) was obtained as a white solid. M100+H.sup.+=236.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.49 (br d, J=1.5 Hz, 1H), 7.15 (br d, J=8.3 Hz, 1H), 7.00 (br dd, J=1.6, 8.3 Hz, 1H), 4.51 (br d, J=4.3 Hz, 1H), 4.28 (br s, 1H), 4.22-4.03 (m, 2H), 3.89 (s, 3H), 3.87 (br s, 1H), 2.52 (s, 3H), 2.42-2.13 (m, 2H), 1.42 (s, 9H).

Step 2: (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (221A-2)

[1509] To a solution of(S)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (500 mg, 1.49 mmol, 1.0 eq) in a mixture of MeOH (20 mL) and THF (10 mL) was added NaOH (2 M aqueous, 3.0 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and washed with petroleum ether (10 mL3). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product (S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (100 mg) as a white solid. M+H.sup.+=318.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.62 (d, J=2.7 Hz, 1H), 7.17 (s, 1H), 7.08 (br d, J=2.7 Hz, 1H), 4.53 (br d, J=2.0 Hz, 1H), 4.31 (br s, 1H), 4.12 (dd, J=2.9, 10.1 Hz, 1H), 4.01-3.83 (m, 2H), 2.58 (s, 3H), 2.44-2.19 (m, 2H), 1.43 (s, 9H).

Step 3: (S)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (221A-3)

[1510] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (100 mg, 311 mol, 1.0 eq) and 1-(quinolin-5-yl)cyclopropanamine (68.8 mg, 373 mol, 1.2 eq) in DMF (3.0 mL) were added TEA (94.5 mg, 933 mol, 130 L, 3.0 eq), EDCI (89.5 mg, 467 mol, 1.5 eq) and HOBt (63.1 mg, 466 mol, 1.5 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R.sub.f=0.6). (S)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine-1-carboxylate (120 mg, 246 mol, 79% yield) was obtained as a white solid. M+H.sup.+=488.3 (LCMS).

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 381)

[1511] To a stirred solution of(S)-tert-butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (110 mg, 226 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.9 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (C18 column (15030 mm, 3 m); flow rate: 60 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (43.4 mg, 86.5 mol, 39% yield, TFA salt) was obtained as a white solid. M+H.sup.+=388.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.27 (br d, J=8.3 Hz, 1H), 9.17 (s, 1H), 9.03 (dd, J=1.3, 4.3 Hz, 1H), 8.99-8.72 (m, 2H), 8.13-7.89 (m, 2H), 7.87-7.67 (m, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.80-4.51 (m, 1H), 4.34-4.07 (m, 2H), 4.03-3.69 (m, 2H), 2.47-2.18 (m, 2H), 1.95 (s, 3H), 1.39 (s, 2H), 1.29-1.20 (m, 2H).

Example 222: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 383)

##STR01065##

Step 1: (R)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (222A-1)

[1512] A mixture of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq), methyl 5-hydroxy-2-methylbenzoate (845 mg, 4.51 mmol, 1.5 eq) and PPh.sub.3 (2.37 g, 9.03 mmol, 3.0 eq) in toluene (15 mL) was degassed and purged with N.sub.2 three times. To the mixture was added TMAD (1.55 g, 9.03 mmol, 3.0 eq) in portions at 20 C. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. (R)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M+Na.sup.+=358.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.37 (d, J=2.8 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.11 (dd, J=2.8, 8.4 Hz, 1H), 4.48-4.38 (m, 1H), 4.26 (dd, J=4.6, 10.4 Hz, 1H), 4.07 (dd, J=2.9, 10.4 Hz, 1H), 3.82 (s, 3H), 3.76 (br t, J=7.4 Hz, 2H), 2.42 (s, 3H), 2.34-2.25 (m, 1H), 2.19-2.09 (m, 1H), 1.33 (s, 9H).

Step 2: (R)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (222A-2)

[1513] To a solution of (R)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (900 mg, 2.68 mmol, 1.0 eq) in a mixture of MeOH (2.0 mL) and THF (8.0 mL) was added NaOH (2 M aqueous, 3.00 mL, 5.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. H.sub.2O (10 mL) was added, and the mixture was washed with MTBE (10 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with 2,5-dimethyltetrahydrofuran (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product (R)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 622 mol, 52% yield) as a yellow gum, which was used in the next step without any further purification. M+Na.sup.+=344.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 12.50-12.40 (m, 1H), 7.36 (d, J=2.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.07 (dd, J=2.8, 8.4 Hz, 1H), 4.47-4.38 (m, 1H), 4.24 (dd, J=4.6, 10.3 Hz, 1H), 4.06 (dd, J=2.8, 10.3 Hz, 1H), 3.75 (br t, J=7.1 Hz, 2H), 2.43 (s, 3H), 2.34-2.24 (m, 1H), 2.19-2.08 (m, 1H), 1.32 (s, 9H).

Step 3: (R)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (222A-3)

[1514] To a solution of 1-(quinolin-5-yl)cyclopropanamine (86.0 mg, 467 mol, 1.0 eq) and (R)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (150 mg, 467 mol, 1.0 eq) in DMF (2.0 mL) were added TEA (142 mg, 1.40 mmol, 195 L, 3.0 eq), EDCI (134 mg, 700 mol, 1.5 eq) and HOBt (94.6 mg, 700 mmol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product (R)-tert-butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 410 mol, 88% yield), which was used in the next step without any further purification. M+H.sup.+=488.2 (LCMS).

Step 4: (R)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 383)

[1515] To a stirred solution of (R)-tert-butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 410 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.0 mL). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (120 mg, 310 mol, 76% yield, TFA salt) was obtained as a white solid. M+H.sup.+=388.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (d, J=8.5 Hz, 1H), 9.16 (s, 1H), 9.04-8.98 (m, 1H), 8.94-8.74 (m, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.1 Hz, 1H), 7.84-7.77 (m, 1H), 7.72 (dd, J=4.4, 8.5 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.65 (br d, J=4.9 Hz, 1H), 4.23 (dd, J=7.2, 11.2 Hz, 1H), 4.18-4.10 (m, 1H), 3.98-3.89 (m, 1H), 3.83 (br dd, J=6.0, 10.3 Hz, 1H), 2.48-2.43 (m, 1H), 2.39-2.30 (m, 1H), 1.95 (s, 3H), 1.44-1.33 (m, 2H), 1.28-1.19 (m, 2H).

Example 223: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 391)

##STR01066##

Step 1: (S)-Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (223A-1)

[1516] To a solution of(S)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (250 mg, 745 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 18 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude product(S)-methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (250 mg, TFA salt) as a yellow oil. M+H.sup.+=236.2 (LCMS).

Step 2: (S)-Methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (223A-2)

[1517] To a solution of(S)-methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (250 mg, 1.06 mmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (172 mg, 2.10 mmol, 158 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 100/1 to 10/1. (S)-Methyl 2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzoate (160 mg, 642 mol, 60% yield) was obtained as a colorless oil. M+H.sup.+=250.1 (LCMS).

Step 3: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (223A-3)

[1518] A solution of(S)-methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (260 mg, 1.04 mmol, 1.0 eq) in HCl (2 M aqueous, 10 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V=10/1, 10 mL) then filtered. The filter cake was washed with MeOH/DCM (V/V=5.0 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (160 mg, crude) as a hydrophilic, colorless oil. M+H.sup.+=236.1 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 391)

[1519] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (80.0 mg, 340 mol, 1.0 eq) and 1-(quinolin-5-yl)cyclopropanamine (43.9 mg, 238 mmol, 0.7 eq) in ACN (5.0 mL) were added TCFH (95.4 mg, 340 mol, 1.0 eq) and NMI (27.9 mg, 340 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 10 m); flow rate: 25 mL/min; gradient: 5%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclo propyl)benzamide (16.6 mg, 34.6 mol, 10% yield, HCl salt) was obtained as a brown solid. M+H.sup.+=402.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.03 (br s, 1H), 9.83 (br d, J=8.5 Hz, 1H), 9.41-9.36 (m, 1H), 9.31 (d, J=4.6 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.21-8.06 (m, 3H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 4.70-4.57 (m, 1H), 4.42 (dd, J=8.3, 11.0 Hz, 1H), 4.22 (dd, J=3.2, 10.9 Hz, 1H), 4.06-3.92 (m, 1H), 3.84 (br dd, J=6.8, 9.4 Hz, 1H), 2.80 (d, J=5.0 Hz, 3H), 2.41-2.20 (m, 2H), 1.95 (s, 3H), 1.46 (br s, 2H), 1.34-1.27 (m, 2H).

Example 224: (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 390)

##STR01067##

Step 1: (R)-Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (224A-1)

[1520] To a stirred solution of (R)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-1-carboxylate (250 mg, 745 mol, 1.0 eq) in DCM (6.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product (R)-methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (250 mg, TFA salt) as a colorless oil. M+H.sup.+=236.2 (LCMS).

Step 2: (R)-Methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (224A-2)

[1521] To a solution of (R)-methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (250 mg, 716 mol, 1.0 eq) in MeOH (5.0 mL) was added TEA (99.6 L), followed by the addition of formaldehyde (116 mg, 1.43 mmol, 107 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (90.0 mg, 1.43 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.5). (R)-Methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (100 mg, 401 mol, 56% yield) was obtained as a colorless oil. M+H.sup.+=250.2 (LCMS).

Step 3: (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (224A-3)

[1522] A solution of (R)-methyl 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (90.0 mg, 361 mol, 1.0 eq) in HCl (2 M aqueous, 3.0 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with DCM/MeOH (V/V=10/1, 10 mL) then filtered. The filter cake was washed with DCM/MeOH (5.0 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give the crude product (R)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (40.0 mg) as a hydrophilic, colorless oil. M+H.sup.+=236.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.12 (d, J=2.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.76 (dd, J=2.8, 8.3 Hz, 1H), 3.90 (d, J=5.5 Hz, 2H), 3.39-3.22 (m, 3H), 2.78-2.65 (m, 1H), 2.36 (s, 3H), 2.25 (s, 3H), 2.03-1.92 (m, 1H).

Step 4: (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 390)

[1523] To a solution of (R)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (40.0 mg, 170 mol, 1.0 eq) and 1-(quinolin-5-yl)cyclopropanamine (31.3 mg, 170 mmol, 1.0 eq) in ACN (4.0 mL) were added TCFH (57.2 mg, 204 mol, 1.2 eq) and NMI (48.9 mg, 595 mol, 47.4 L, 3.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclo propyl)benzamide (19.8 mg, 45.2 mol, 27% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.07 (br s, 1H), 9.84-9.74 (m, 1H), 9.42-9.34 (m, 1H), 9.28 (d, J=4.1 Hz, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.18-8.14 (m, 1H), 8.14-8.05 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.76 (d, J=2.8 Hz, 1H), 4.69-4.57 (m, 1H), 4.42 (dd, J=8.2, 11.2 Hz, 1H), 4.22 (dd, J=3.3, 11.3 Hz, 1H), 4.03-3.93 (m, 1H), 3.84 (br dd, J=6.7, 9.6 Hz, 1H), 2.80 (d, J=5.0 Hz, 3H), 2.41-2.23 (m, 2H), 1.95 (s, 3H), 1.50-1.41 (m, 2H), 1.35-1.26 (m, 2H).

Example 225: (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 380)

##STR01068##

Step 1: (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (225A-1)

[1524] To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate (363 mg, 1.81 mmol, 1.0 eq) in toluene (15 mL) were added TMAD (933 mg, 5.42 mmol, 3.0 eq) and PPh.sub.3 (1.42 g, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/5. (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (600 mg, 1.72 mmol, 95% yield) was obtained as a yellow oil. M+H.sup.+=350.1 (LCMS).

Step 2: (S)-5-((1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (225A-2)

[1525] To a solution of(S)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (1.20 g, 3.43 mmol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (15 mL) was added NaOH (2 M aqueous, 7.0 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with MTBE (15 mL2). The aqueous layer was acidified to pH 5 using HCl (1 M aqueous). The product was extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product (S)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (1.10 g, 96% yield), which was used in the next step without any further purification. M56+H.sup.+=280.1 (LCMS).

Step 3: (S)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (225A-3)

[1526] To a solution of(S)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 596 mol, 1.0 eq) and 1-(quinolin-5-yl)cyclopropanamine (110 mg, 596 mol, 1.0 eq) in DMF (10 mL) were added TEA (181 mg, 1.79 mmol, 249 L, 3.0 eq), EDCI (286 mg, 1.49 mmol, 2.5 eq) and HOBt (201 mg, 1.49 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (S)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (180 mg, 359 mol, 60% yield) was obtained as a yellow oil. M+H.sup.+=502.2 (LCMS).

Step 4: (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 380)

[1527] To a stirred solution of(S)-tert-butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (180 mg, 359 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (27.2 mg, 62.1 mol, 17% yield, HCl salt) was obtained as a white solid. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.58-9.41 (m, 2H), 9.27 (s, 1H), 9.17 (br d, J=4.3 Hz, 1H), 8.98-8.84 (m, 1H), 8.16 (br d, J=8.5 Hz, 1H), 8.06 (br d, J=6.9 Hz, 1H), 8.00-7.89 (m, 2H), 7.09 (d, J=8.6 Hz, 1H), 6.90 (dd, J=2.6, 8.3 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.16 (dd, J=3.9, 10.6 Hz, 1H), 4.09-4.01 (m, 1H), 3.88-3.75 (m, 1H), 3.23-3.12 (m, 2H), 2.12-2.02 (m, 1H), 1.95 (s, 4H), 1.92-1.82 (m, 1H), 1.73-1.63 (m, 1H), 1.42 (br s, 2H), 1.31-1.22 (m, 2H).

Example 226: (S)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 379)

##STR01069##

Step 1: (S)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 379)

[1528] To a solution of(S)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (130 mg, 324 mol, 1.0 eq) in MeOH (10 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (52.6 mg, 648 mol, 48.2 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (40.7 mg, 648 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (26.2 mg, 57.7 mol, 18% yield, HCl salt) was obtained as a white solid. M+H.sup.+=416.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.76-10.57 (m, 1H), 9.73-9.57 (m, 1H), 9.33 (s, 1H), 9.23 (br s, 1H), 8.23 (br d, J=8.2 Hz, 1H), 8.16-7.95 (m, 3H), 7.09 (d, J=8.3 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.75 (br s, 1H), 4.31-4.20 (m, 2H), 3.73 (dt, J=3.0, 6.8 Hz, 1H), 3.59-3.48 (m, 1H), 3.15-2.99 (m, 1H), 2.88 (br d, J=4.8 Hz, 3H), 2.29-2.14 (m, 1H), 2.09-1.98 (m, 1H), 1.97-1.86 (m, 4H), 1.83-1.70 (m, 1H), 1.43 (br s, 2H), 1.29 (br s, 2H).

Example 227: (R)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 371)

##STR01070##

Step 1: (R)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (227A-1)

[1529] To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and (R)-tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate (363 mg, 1.81 mmol, 1.0 eq) in toluene (15 mL) were added TMAD (933 mg, 5.42 mmol, 3.0 eq) and PPh.sub.3 (1.42 g, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times, and then stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. (R)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (590 mg, 94% yield) was obtained as a white solid. M+H.sup.+=350.1 (LCMS).

Step 2: (R)-5-((1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (227A-2)

[1530] To a solution of (R)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (1.18 g, 3.38 mmol, 1.0 eq) in a mixture of MeOH (47 mL) and THF (24 mL) was added NaOH (2 M aqueous, 7.0 mL, 4.0 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The aqueous layer was acidified to pH 7 using HCl (1 M aqueous). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product (R)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (1.00 g, 88% yield) as a white solid, which was used in the next step without any further purification.

Step 3: (R)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (227A-3)

[1531] To a solution of (R)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 596 mol, 1.0 eq) and 1-(quinolin-5-yl)cyclopropanamine (109 mg, 596 mol, 1.0 eq) in DMF (10 mL) were added TEA (121 mg, 1.19 mmol, 166 L, 2.0 eq), EDCI (171 mg, 894 mol, 1.5 eq) and HOBt (121 mg, 894 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. (R)-tert-Butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (200 mg, 399 mol, 67% yield) was obtained as a yellow gum. M+H.sup.+=502.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13-9.10 (m, 1H), 9.10-9.06 (m, 1H), 8.92-8.89 (m, 1H), 7.95 (s, 1H), 7.89-7.85 (m, 1H), 7.74-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.05-7.00 (m, 1H), 6.89-6.84 (m, 1H), 6.69-6.57 (m, 1H), 3.99-3.91 (m, 2H), 3.82-3.73 (m, 1H), 3.27-3.21 (m, 2H), 1.95-1.78 (m, 7H), 1.45-1.31 (m, 9H), 1.30 (br s, 2H), 1.22-1.19 (m, 2H).

Step 4: (R)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 371)

[1532] To a stirred solution of (R)-tert-butyl 2-((4-methyl-3-((1-(quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (200 mg, 399 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (34.4 mg, 78.6 mol, 20% yield, HCl salt) was obtained as a white solid. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.92-9.72 (m, 2H), 9.40 (s, 1H), 9.30 (d, J=4.1 Hz, 1H), 9.24-9.12 (m, 1H), 8.35 (s, 1H), 8.16 (s, 3H), 7.07 (s, 1H), 6.95-6.86 (m, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.20-4.08 (m, 2H), 3.86-3.72 (m, 1H), 3.26-3.09 (m, 2H), 2.16-2.02 (m, 1H), 2.00-1.93 (m, 4H), 1.91-1.83 (m, 1H), 1.73-1.62 (m, 1H), 1.46 (s, 2H), 1.34-1.27 (m, 2H).

Example 228: (R)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 382)

##STR01071##

Step 1: (R)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 382)

[1533] To a solution of (R)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (140 mg, 349 mol, 1.0 eq) in MeOH (2.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (20.9 mg, 697 mol, 19.2 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The reaction mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (43.8 mg, 697 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (R)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (52.5 mg, 116 mol, 33% yield, HCl salt) was obtained as a white solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.06-10.82 (m, 1H), 9.89-9.66 (m, 1H), 9.37 (s, 1H), 9.31-9.23 (m, 1H), 8.37-8.27 (m, 1H), 8.21-7.99 (m, 3H), 7.07 (s, 1H), 6.98-6.85 (m, 1H), 6.76 (s, 1H), 4.38-4.21 (m, 2H), 3.82-3.65 (m, 1H), 3.63-3.45 (m, 1H), 3.16-3.00 (m, 1H), 2.87 (d, J=4.8 Hz, 3H), 2.29-2.15 (m, 1H), 1.95 (m, 5H), 1.83-1.66 (m, 1H), 1.45 (br s, 2H), 1.30 (br s, 2H).

Example 229: 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 299)

##STR01072##

Step 1: 1-(Isoquinolin-5-yl)cyclopropanamine (229A-2)

[1534] A mixture of isoquinoline-5-carbonitrile (300 mg, 1.95 mmol, 1.0 eq) in anhydrous Et.sub.2O (30 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (608 mg, 2.14 mmol, 632 L, 1.1 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 1.42 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (552 mg, 3.89 mmol, 480 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL) and extracted with MTBE (20 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. 1-(Isoquinolin-5-yl)cyclopropanamine (100 mg, 543 mol, 28% yield) was obtained as a yellow oil. M+H.sup.+=185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 299)

[1535] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (145 mg, 651 mol, 1.2 eq) in DCM (5.0 mL) were added TEA (165 mg, 1.63 mmol, 227 L, 3.0 eq), EDCI (156 mg, 814 mol, 1.5 eq), HOBt (110 mg, 814 mol, 1.5 eq) and 1-(isoquinolin-5-yl)cyclopropanamine (100 mg, 543 mol, 1.0 eq). The mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) at 25 C. and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (41.6 mg, 100 mol, 18% yield) was obtained as a yellow solid. M+H.sup.+=390.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.31 (s, 1H), 9.15 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.47 (d, J=6.0 Hz, 1H), 8.06-7.98 (m, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.89-6.79 (m, 1H), 6.61 (d, J=2.7 Hz, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.56-2.52 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.38-1.32 (m, 2H), 1.22-1.14 (m, 2H).

Example 230: N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 375)

##STR01073##

Step 1: tert-Butyl(2-(3-((1-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (230A-1)

[1536] To a solution of 1-(isoquinolin-5-yl)cyclopropanamine (50.0 mg, 231 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (71.4 mg, 231 mol, 1.0 eq) in acetonitrile (3.0 mL) were added TCFH (77.7 mg, 277 mol, 1.2 eq) and 1-methylimidazole (66.3 mg, 807 mol, 64.4 L, 3.5 eq). The mixture was stirred at 20 C. for 18 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R.sub.f=0.3). tert-Butyl(2-(3-((1-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (30.0 mg, 63.1 mol, 27% yield) was obtained as a white solid. M+H.sup.+=476.2 (LCMS).

Step 2: N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 375)

[1537] To a solution of tert-butyl(2-(3-((1-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (30.0 mg, 631 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 189 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (19.6 mg, 47.3 mol, 75% yield, HCl salt) was obtained as a white solid. M+H.sup.+=376.1 (LCMS); 1H NMR (400 MHZ, CD.sub.3OD) 9.83 (s, 1H), 9.22 (d, J=6.8 Hz, 1H), 8.69 (d, J=6.9 Hz, 1H), 8.63 (dd, J=0.9, 7.3 Hz, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.10-8.03 (m, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.95 (dd, J=2.8, 8.5 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.24-4.18 (m, 2H), 3.44-3.38 (m, 2H), 2.76 (s, 3H), 2.00 (s, 3H), 1.63-1.57 (m, 2H), 1.46-1.39 (m, 2H).

Example 231: N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 402)

##STR01074##

Step 1: N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 402)

[1538] To a solution of 1-(isoquinolin-5-yl)cyclopropanamine (40 mg, 217 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (91.9 mg, 391 mol, 1.8 eq) in DCM (2.0 mL) were added TEA (65.9 mg, 651 mmol, 90.6 L, 3.0 eq), EDCI (104 mg, 543 mol, 2.5 eq) and HOBt (73.3 mg, 543 mmol, 2.5 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (15.1 mg, 33.1 mol, 15% yield, FA salt) was obtained as a white solid. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.32 (s, 1H), 9.16 (s, 1H), 8.57 (d, J=6.0 Hz, 1H), 8.48 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J=7.6 Hz, 2H), 7.65 (t, J=7.7 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.7, 8.3 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 3.90 (d, J=4.9 Hz, 2H), 3.49-3.13 (m, 2H), 2.83 (q, J=8.2 Hz, 1H), 2.27 (s, 3H), 2.06-1.95 (m, 1H), 1.94 (s, 3H), 1.92-1.81 (m, 1H), 1.36 (s, 2H), 1.25-1.13 (m, 2H).

Example 232: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 333)

##STR01075##

Step 1: 1-(Isoquinolin-8-yl)cyclopropanamine (232A-2)

[1539] A mixture of isoquinoline-8-carbonitrile (100 mg, 649 mol, 1.0 eq) in anhydrous Et.sub.2O (7.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO)+ (203 mg, 714 mol, 211 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 476 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (185 mg, 1.30 mmol, 160 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that 40% starting material still remained and 13% desired compound was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (C18 column (25050 mm, 10 m); flow rate: 60 mL/min; gradient: 20%-40% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 1-(Isoquinolin-8-yl)cyclopropanamine (15 mg, 81.4 mol, 12% yield) was obtained as a white solid. M+H.sup.+=185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-8-yl)cyclopropyl)-2-methylbenzamide (Compound 333)

[1540] To a solution of 1-(isoquinolin-8-yl)cyclopropanamine (30.0 mg, 163 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (72.7 mg, 326 mol, 2.0 eq) in DCM (1.0 mL) were added TEA (49.4 mg, 488 mol, 67.9 L, 3.0 eq), EDCI (37.5 mg, 195 mol, 1.2 eq) and HOBt (26.4 mg, 195 mol, 1.2 eq). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-8-yl)cyclo propyl)-2-methylbenzamide (3.20 mg, 8.22 mol, 5% yield) was obtained as a white solid. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.04 (s, 1H), 9.24 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.04-7.79 (m, 3H), 7.77-7.59 (m, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.84 (dd, J=2.6, 8.7 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 3.95 (s, 2H), 2.60-2.54 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.39 (br s, 2H), 1.26 (br s, 2H).

Example 233: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-8-yl)cyclopropyl)benzamide (Compound 388)

##STR01076##

Step 1: 1-(Quinolin-8-yl)cyclopropanamine (233A-2)

[1541] To a mixture of quinoline-8-carbonitrile (300 mg, 1.95 mmol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (608 mg, 2.14 mmol, 630 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.43 mL, 2.2 eq) was added dropwise to maintain the temperature between-78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (552 mg, 3.89 mmol, 480 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 ml2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(Quinolin-8-yl)cyclopropanamine (60.0 mg, 330 mol, 17% yield) was obtained as a yellow oil. M+H.sup.+=185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-8-yl)cyclopropyl)benzamide (Compound 388)

[1542] To a solution of 1-(quinolin-8-yl)cyclopropanamine (40.0 mg, 217 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (48.5 mg, 217 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (44.0 mg, 430 mol, 60.4 L, 2.0 eq), EDCI (62.4 mg, 330 mol, 1.5 eq) and HOBt (44.0 mg, 330 mol, 1.5 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (2.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-45% B over 8 min; mobile phase A: 10 mM NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(quinolin-8-yl)cyclopropyl)benzamide (15.0 mg, 38.1 mol, 18% yield) was obtained as a white solid. M+H.sup.+=390.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.90-9.03 (m, 1H), 8.68 (s, 1H), 8.27-8.44 (m, 1H), 7.81-7.99 (m, 2H), 7.47-7.64 (m, 2H), 7.00 (br d, J=8.38 Hz, 1H), 6.75-6.86 (m, 1H), 6.61-6.71 (m, 1H), 3.95 (br t, J=5.50 Hz, 2H), 2.54-2.63 (m, 2H), 2.19 (br s, 6H), 1.97 (s, 3H), 1.33 (br d, J=8.63 Hz, 4H).

Example 234: 5-(2-Aminoethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 363)

##STR01077##

Step 1: tert-Butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)carbamate (234A-1)

[1543] To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (166 mg, 563 mol, 1.2 eq) and 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (100 mg, 469 mol, 1.0 eq) in DCM (1.0 mL) were added TEA (142 mg, 1.41 mmol, 196 L, 3.0 eq), EDCI (135 mg, 703 mol, 1.5 eq) and HOBt (95.0 mg, 703 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=2/1, R.sub.f=0.4) to give tert-butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)carbamate (200 mg, 408 mol, 87% yield) as a yellow oil. M+H.sup.+=491.2 (LCMS).

Step 2: 5-(2-Aminoethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 363)

[1544] To a stirred solution of tert-butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl) carbamoyl)-4-methyl phenoxy)ethyl)carbamate (200 mg, 408 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (150 mg, 383 mol, 94% yield, HCl salt) as a white solid. M+H.sup.+=391.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.12 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.04 (br s, 3H), 7.83 (d, J=7.9 Hz, 1H), 7.49-7.37 (m, 3H), 7.24 (d, J=2.5 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.6, 8.4 Hz, 1H), 6.66 (d, J=2.6 Hz, 1H), 4.08 (t, J=5.1 Hz, 2H), 3.87 (s, 3H), 3.19-3.08 (m, 2H), 1.98 (s, 3H), 1.33 (br s, 2H), 1.20-1.11 (m, 2H).

Example 235: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 320)

##STR01078##

Step 1:3-Methoxy-1-naphthonitrile (235A-2)

[1545] To a solution of 1-bromo-3-methoxynaphthalene (2.00 g, 8.44 mmol, 1.0 eq) in DMF (40 mL) were added Zn(CN).sub.2 (1.98 g, 16.9 mmol, 1.07 mL, 2.0 eq) and Pd(PPh.sub.3).sub.4 (975 mg, 844 mol, 0.1 eq). The mixture was stirred at 120 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (60 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. 3-Methoxy-1-naphthonitrile (1.50 g, 97% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.03-7.97 (m, 2H), 7.88 (d, J=2.6 Hz, 1H), 7.76 (d, J=2.5 Hz, 1H), 7.68-7.58 (m, 2H), 3.93 (s, 3H).

Step 2: 1-(3-Methoxynaphthalen-1-yl)cyclopropanamine (235A-3)

[1546] A mixture of 3-methoxynaphthalene-1-carbonitrile (1.40 g, 7.64 mmol, 1.0 eq) in anhydrous Et.sub.2O (100 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (2.39 g, 8.41 mmol, 2.48 mL, 1.1 eq) slowly, and then EtMgBr (3 M, in Et.sub.2O, 5.60 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (2.17 g, 15.3 mmol, 1.89 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (50 mL) and MTBE (50 mL), and extracted with MTBE (50 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 3-Methoxy-1-naphthonitrile (500 mg, 2.34 mmol, 31% yield) was obtained as a brown solid. M+H.sup.+=214.2 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.35 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.20 (d, J=2.3 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 3.93 (s, 3H), 2.04 (br s, 2H), 1.23-1.16 (m, 2H), 1.06-0.99 (m, 2H).

Step 3: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 320)

[1547] To a solution of 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (100 mg, 469 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (105 mg, 469 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (142 mg, 1.41 mmol, 196 L, 3.0 eq), EDCI (225 mg, 1.17 mmol, 2.5 eq) and HOBt (158 mg, 1.17 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-(2-(dimethylamino)ethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (57.5 mg, 124 mol, 26% yield, FA salt) as a white solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.49-7.35 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.95 (t, J=5.8 Hz, 2H), 3.87 (s, 3H), 2.58 (t, J=5.8 Hz, 2H), 2.19 (s, 6H), 1.97 (s, 3H), 1.33 (br s, 2H), 1.19-1.12 (m, 2H).

Example 236: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 345)

##STR01079##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)2-methylbenzamide (Compound 345)

[1548] To a solution of EtSH (1.05 g, 16.9 mmol, 1.25 mL, 141 eq) in DCM (5.0 mL) was added AlCl.sub.3 (95.6 mg, 717 mol, 39.2 L, 6.0 eq) at 0 C. To the resulting mixture was added 5-[2-(dimethylamino)ethoxy]-N-[1-(3-methoxy-1-naphthyl)cyclopropyl]-2-methyl-benzamide (50.0 mg, 119 mol, 1.0 eq) in DCM (0.5 mL) at 0 C. The resulting mixture was stirred at 0 C. for 10 min, then warmed to 20 C. and stirred at the same temperature for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (8.70 mg, 19.2 mol, 16% yield, FA salt) was obtained as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.18 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.08-7.00 (m, 2H), 6.83 (dd, J=2.6, 8.3 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 3.95 (br t, J=5.5 Hz, 2H), 2.58 (br t, J=5.5 Hz, 2H), 2.19 (s, 6H), 1.98 (s, 3H), 1.32 (br s, 2H), 1.13 (br s, 2H).

Example 237: N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 347)

##STR01080##

Step 1: tert-Butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (237A-1)

[1549] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (100 mg, 323 mol, 1.0 eq) and 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (68.9 mg, 323 mol, 1.0 eq) in DCM (10 mL) were added TEA (98.1 mg, 970 mol, 135 L, 3.0 eq), EDCI (155 mg, 808 mol, 2.5 eq) and HOBt (109 mg, 808 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (100 mg, 198 mol, 61% yield) was obtained as a yellow oil. M+H.sup.+=505.3 (LCMS).

Step 2: N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 347)

[1550] To a stirred solution of tert-butyl(2-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (100 mg, 198 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-70% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (48.3 mg, 109 mol, 55% yield, HCl salt) was obtained as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14 (br d, J=1.5 Hz, 1H), 8.87 (br d, J=1.0 Hz, 2H), 8.53 (br d, J=5.4 Hz, 1H), 7.91-7.77 (m, 1H), 7.53-7.33 (m, 3H), 7.24 (br s, 1H), 7.08 (br d, J=5.6 Hz, 1H), 6.97-6.84 (m, 1H), 6.67 (br s, 1H), 4.15 (br s, 2H), 3.87 (br s, 3H), 3.25 (br s, 2H), 2.57 (br s, 3H), 1.98 (br s, 3H), 1.33 (br s, 2H), 1.16 (br s, 2H).

Example 238: N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 384)

##STR01081##

Step 1: N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 384)

[1551] To a solution of 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (80.0 mg, 340 mol, 1.0 eq) and 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (72.5 mg, 340 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (103 mg, 1.02 mmol, 142 L, 3.0 eq), EDCI (163 mg, 850 mol, 2.5 eq) and HOBt (115 mg, 850 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (20040 mm, 10 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (38.2 mg, 80.2 mol, 24% yield, FA salt) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 3H), 7.23 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.91-3.86 (m, 5H), 3.36-3.25 (m, 2H), 2.84-2.76 (m, 1H), 2.25 (s, 3H), 2.02-1.81 (m, 5H), 1.33 (br s, 2H), 1.18-1.13 (m, 2H).

Example 239: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 401)

##STR01082##

Step 1:4-(1-(5-(2-(Dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (239A-1)

[1552] To a solution of 5-(2-(dimethylamino)ethoxy)-N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (110 mg, 272 mol, 1.0 eq) in DCM (5.0 mL) were added DIEA (105 mg, 816 mol, 142 L, 3.0 eq) and Tf.sub.2O (115 mg, 408 mol, 67.3 L, 1.5 eq) at 78 C. Then the mixture was stirred at 78 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=1/10, R.sub.f=0.4). 4-(1-(5-(2-(Dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (130 mg, 242 mol, 89% yield) was obtained as a brown solid. M+H.sup.+=537.2 (LCMS).

Step 2: 5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 401)

[1553] To a solution of 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl)naphthaen-2-yl trifluoromethanesulfonate (80.0 mg, 149 mol, 1.0 eq) in DMF (4.0 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (37.4 mg, 149 mol, 41.7 L, 50% purity, 1.0 eq), Cs.sub.2CO.sub.3 (160 mg, 492 mol, 3.3 eq) and Pd(dppf)Cl.sub.2.Math.DCM (12.2 mg, 14.9 mol, 0.1 eq). The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (20.8 mg, 49.3 mol, 33% yield, FA salt) was obtained as a gray solid. M+H.sup.+=403.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.05 (s, 1H), 8.63-8.56 (m, 1H), 7.85-7.79 (m, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.52-7.43 (m, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.8 Hz, 2H), 2.47 (s, 3H), 2.17 (s, 6H), 1.98 (s, 3H), 1.37-1.30 (m, 2H), 1.19-1.13 (m, 2H).

Example 240: 5-(2-Dimethylamino)ethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 319)

##STR01083##

Step 1: 6-Fluoronaphthalen-1-yl trifluoromethanesulfonate (240A-2)

[1554] To a solution of 6-fluoronaphthalen-1-ol (420 mg, 2.59 mmol, 1.0 eq) in DCM (12 mL) were added DIEA (669 mg, 5.18 mmol, 902 L, 2.0 eq) and Tf.sub.2O (730 mg, 2.59 mmol, 427 L, 1.0 eq) at 0 C. The mixture was stirred at 0 C. for 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to warm to room temperature, poured into H.sub.2O (20 mL) and extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 6-Fluoronaphthalen-1-yl trifluoromethanesulfonate (750 mg, 2.55 mmol, 90% purity) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.10 (br dd, J=5.3, 8.9 Hz, 1H), 7.83 (br d, J=8.2 Hz, 1H), 7.62-7.49 (m, 2H), 7.49-7.36 (m, 2H).

Step 2: 6-Fluoro-1-naphthonitrile (240A-3)

[1555] To a solution of 6-fluoronaphthalen-1-yl trifluoromethanesulfonate (750 mg, 2.55 mmol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN).sub.2 (598 mg, 5.10 mmol, 323 L, 2.0 eq) and Pd(PPh.sub.3).sub.4 (117 mg, 101 mol, 0.04 eq) under a N.sub.2 atmosphere. The mixture was stirred at 120 C. for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NH.sub.4Cl (16 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 6-Fluoro-1-naphthonitrile (390 mg, 2.28 mmol, 83% yield) was obtained as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.26 (dd, J=5.3, 9.2 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.90 (d, J=7.1 Hz, 1H), 7.62-7.54 (m, 2H), 7.49 (dt, J=2.5, 8.7 Hz, 1H).

Step 3: 1-(6-Fluoronaphthalen-1-yl)cyclopropanamine (240A-4)

[1556] A mixture of 6-fluoro-1-naphthonitrile (200 mg, 1.17 mmol, 1.0 eq) in anhydrous Et.sub.2O (35 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (365 mg, 1.29 mmol, 379 L, 1.1 eq) slowly at 78 C., and then EtMgBr (3 M in Et.sub.2O, 856 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (331 mg, 2.34 mmol, 288 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous) (20 mL) and MTBE (20 mL). The mixture was washed with MTBE (25 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (25 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=1/10, R.sub.f=0.5). 1-(6-Fluoro-1-naphthyl)cyclopropanamine (110 mg, 546 mol, 46% yield) was obtained as a white solid. M+H.sup.+=202.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47 (dd, J=5.6, 9.3 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (d, J=7.7 Hz, 1H), 7.40-7.32 (m, 1H), 1.24-1.17 (m, 2H), 1.07-1.00 (m, 2H).

Step 4: 5-(2-(Dimethylamino)ethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 319)

[1557] To a solution of 1-(6-fluoro-1-naphthyl)cyclopropanamine (80.0 mg, 397 mol, 1.0 eq) in DMF (4.0 mL) were added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (133 mg, 596 mol, 1.5 eq), TEA (120 mg, 1.19 mmol, 166 L, 3.0 eq), EDCI (91.4 mg, 477 mol, 1.2 eq) and HOBt (64.4 mg, 477 mol, 1.2 eq). The mixture was stirred at 25 C. for 6 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL3). The combined EtOAc layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (67.9 mg, 167 mol, 42% yield, FA salt) was obtained as a white solid. M+H.sup.+=407.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.59 (dd, J=5.6, 9.1 Hz, 1H), 8.43 (br s, 1H), 7.88 (d, J=7.0 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.59-7.43 (m, 2H), 7.34 (dt, J=2.6, 8.8 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.89-6.57 (m, 3H), 4.08 (t, J=5.3 Hz, 2H), 2.89 (t, J=5.3 Hz, 2H), 2.46 (s, 6H), 2.12 (s, 3H), 1.70-1.49 (m, 2H), 1.48-1.32 (m, 2H).

Example 241: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 392)

##STR01084##

Step 1: (S)-tert-butyl 2-((3-((1-(6-Fluoronaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (241A-1)

[1558] To a solution of 1-(6-fluoronaphthalen-1-yl)cyclopropanamine (31.3 mg, 156 mol, 1.0 eq) and (S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (50.0 mg, 155 mol, 1.0 eq) in DCM (2.0 mL) were added TEA (47.2 mg, 466 mol, 64.9 L, 3.0 eq), EDCI (44.7 mg, 233 mol, 1.5 eq) and HOBt (31.5 mg, 233 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R.sub.f=0.6). (S)-tert-Butyl 2-((3-((1-(6-fluoronaphthalen-1-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (70.0 mg, 139 mol, 89% yield) was obtained as a white solid. M56+H.sup.+=449.1 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 392)

[1559] To a solution of(S)-tert-butyl 2-((3-((1-(6-fluoronaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (70.0 mg, 139 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (2.16 g, 18.9 mmol, 1.40 mL, 136 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (C18-1 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 15%-60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (10.7 mg, 20.6 mol, 15% yield, TFA salt) as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.95-8.67 (m, 3H), 7.84 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.73 (dd, J=2.6, 10.3 Hz, 1H), 7.59-7.39 (m, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.8 Hz, 1H), 4.83-4.54 (m, 1H), 4.32-4.03 (m, 2H), 3.99-3.77 (m, 2H), 2.48-2.40 (m, 1H), 2.39-2.27 (m, 1H), 1.97 (s, 3H), 1.36 (s, 2H), 1.20 (br s, 2H).

Example 242: N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 377)

##STR01085##

Step 1: tert-Butyl(2-(3-((1-(6-fluoronaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (242A-1)

[1560] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (100 mg, 323 mol, 1.0 eq) and 1-(6-fluoronaphthalen-1-yl)cyclopropanamine (65.1 mg, 323 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (98.1 mg, 970 mol, 135 L, 3.0 eq), EDCI (155 mg, 808 mol, 2.5 eq) and HOBt (109 mg, 808 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.4). tert-Butyl(2-(3-((1-(6-fluoronaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (100 mg, 203 mol, 63% yield) was obtained as a colorless oil. M+H.sup.+=493.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.73 (dd, J=5.4, 9.2 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.72 (dd, J=2.4, 10.3 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.04 (br d, J=8.0 Hz, 1H), 6.84 (dd, J=2.5, 8.5 Hz, 1H), 6.60 (br s, 1H), 4.00-3.94 (m, 2H), 3.46 (t, J=5.6 Hz, 2H), 2.82 (br d, J=11.0 Hz, 3H), 1.95 (s, 3H), 1.42-1.23 (m, 13H).

Step 2: N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 377)

[1561] To a stirred solution of tert-butyl(2-(3-((1-(6-fluoronaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (100 mg, 203 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-(2-(methylamino) ethoxy)benzamide (40.7 mg, 94.9 mol, 47% yield, HCl salt) was obtained as a white solid. M+H.sup.+=393.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 9.01 (br s, 2H), 8.68 (br dd, J=5.9, 9.1 Hz, 1H), 7.75 (br dd, J=7.6, 18.0 Hz, 2H), 7.67 (dd, J=2.1, 10.2 Hz, 1H), 7.49-7.38 (m, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.2, 8.3 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 4.11 (br t, J=4.3 Hz, 2H), 3.18 (br s, 2H), 2.44 (br s, 3H), 1.89 (s, 3H), 1.30 (br s, 2H), 1.12 (br s, 2H).

Example 243: (S)N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 389)

##STR01086##

Step 1: (S)N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 389)

[1562] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(6-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (150 mg, 289 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (40.0 L), followed by the addition of formaldehyde (47.0 mg, 579 mmol, 43.1 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (36.4 mg, 579 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)N-(1-(6-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (10.7 mg, 13.0 mol, 8% yield, FA salt) was obtained as a white solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.74 (dd, J=5.8, 9.3 Hz, 1H), 8.22 (s, 1H), 7.87-7.66 (m, 3H), 7.56-7.40 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 3.86 (d, J=5.5 Hz, 2H), 3.27-3.18 (m, 3H), 2.71 (td, J=8.1, 16.0 Hz, 1H), 2.21 (s, 3H), 1.95 (s, 3H), 1.90-1.77 (m, 1H), 1.36 (s, 2H), 1.22-1.09 (m, 2H).

Example 244: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 365)

##STR01087##

Step 1: 7-Fluoronaphthalen-1-ol (244A-2)

[1563] To a solution of 7-fluoro-3,4-dihydronaphthalen-1 (2H)-one (1.00 g, 6.09 mmol, 1.0 eq) in DMA (10 mL) was added 10% palladium on carbon (100 mg, 1.83 mmol, 0.3 eq) and K.sub.2CO.sub.3 (2.53 g, 18.3 mmol, 3.0 eq). The mixture was stirred at 160 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was poured into H.sub.2O (50 mL) and extracted with EtOAc (25 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-Fluoronaphthalen-1-ol (900 mg, 5.55 mmol, 91% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.23-8.15 (m, 1H), 7.87-7.78 (m, 1H), 7.54-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.35-7.29 (m, 1H), 6.87-6.80 (m, 1H), 5.24-5.18 (m, 1H).

Step 2: 7-Fluoronaphthalen-1-yl trifluoromethanesulfonate (244A-3)

[1564] To a solution of 7-fluoronaphthalen-1-ol (350 mg, 2.16 mmol, 1.0 eq) in DCM (20 mL) were added Tf.sub.2O (670 mg, 2.37 mmol, 392 L, 1.0 eq) and pyridine (588 mg, 7.43 mmol, 0.6 mL, 3.4 eq) at 0 C. The mixture was stirred at 0 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (20 mL3). The combined layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-Fluoronaphthalen-1-yl trifluoromethane sulfonate (600 mg, 2.04 mmol, 94% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.97-7.87 (m, 2H), 7.72-7.66 (m, 1H), 7.55-7.45 (m, 2H), 7.43-7.36 (m, 1H).

Step 3: 7-Fluoro-1-naphthonitrile (244A-4)

[1565] To a solution of 7-fluoronaphthalen-1-yl trifluoromethanesulfonate (500 mg, 1.70 mmol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN).sub.2 (399 mg, 3.40 mmol, 216 L, 2.0 eq) and Pd(PPh.sub.3).sub.4 (196 mg, 170 mol, 0.1 eq). The mixture was stirred at 110 C. for 18 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NH.sub.4Cl (2.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-Fluoro-1-naphthonitrile (150 mg, 876 mol, 52% yield) was obtained as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13-8.07 (m, 1H), 7.99-7.92 (m, 2H), 7.91-7.84 (m, 1H), 7.56-7.49 (m, 1H), 7.46-7.38 (m, 1H).

Step 4: 1-(7-Fluoronaphthalen-1-yl)cyclopropanamine (244A-5)

[1566] A mixture of 7-fluoro-1-naphthonitrile (45.0 mg, 263 mol, 1.0 eq) in anhydrous Et.sub.2O (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (82.2 mg, 289 mol, 85.3 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 193 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (74.6 mg, 526 mol, 64.9 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL), and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R.sub.f=0.3). 1-(7-Fluoronaphthalen-1-yl)cyclopropane mine (30.0 mg, 149 mol, 57% yield) was obtained as a yellow oil. M+H.sup.+=202.1 (LCMS).

Step 5: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 365)

[1567] To a solution of 1-(7-fluoronaphthalen-1-yl)cyclopropanamine (20.0 mg, 49.7 mol, 1.0 eq) in DCM (1.0 mL) was added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (111 mg, 49.7 mol, 1.0 eq), TEA (15.1 mg, 149 mol, 20.8 L, 3.0 eq), EDCI (23.8 mg, 124 mol, 2.5 eq) and HOBt (16.8 mg, 124 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL5). The combined layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-fluoronaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (8.20 mg, 18.0 mol, 36% yield, FA salt) was obtained as a white solid. M+H.sup.+=407.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.43-8.40 (m, 1H), 8.12-8.07 (m, 1H), 8.02-7.96 (m, 1H), 7.92-7.85 (m, 1H), 7.82-7.76 (m, 1H), 7.47-7.42 (m, 1H), 7.32-7.28 (m, 1H), 7.04-6.99 (m, 1H), 6.83-6.74 (m, 2H), 6.59-6.56 (m, 1H), 4.08-4.00 (m, 2H), 2.84-2.76 (m, 2H), 2.42-2.38 (m, 6H), 2.19-2.10 (m, 3H), 1.61-1.52 (m, 2H), 1.43-1.33 (m, 2H).

Example 245: 5-(Azetidin-3-ylamino)-2-methyl-N-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 120)

##STR01088##

Step 1: tert-Butyl 3-(5-formylthiophen-2-yl)benzylcarbamate (245A-2)

[1568] A mixture of tert-butyl 3-bromobenzylcarbamate (300 mg, 1.05 mmol, 1.0 eq), (5-formylthiophen-2-yl) boronic acid (196 mg, 1.26 mmol, 1.2 eq) and KOAc (308 mg, 3.15 mmol, 3.0 eq) in DMSO (6.0 mL) was degassed and purged with N.sub.2 three times. To the mixture were added cataCXium A (70.6 mg, 210 mol, 0.2 eq) and Pd(OAc) 2 (23.5 mg, 105 mol, 0.1 eq). The resulting mixture was stirred at 80 C. for 6 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl 3-(5-formylthiophen-2-yl)benzylcarbamate (150 mg, 473 mol, 45% yield) was obtained as a brown oil. M+H.sup.+=318.3 (LCMS).

Step 2: tert-Butyl 3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (245A-3)

[1569] To a solution of tert-butyl 3-(5-formylthiophen-2-yl)benzylcarbamate (150 mg, 473 mol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of pyrrolidine (67.2 mg, 945 mol, 78.9 L, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (44.5 mg, 708 mol, 1.5 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl 3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (90.0 mg, 242 mol, 51% yield) was obtained as a yellow oil. M+H.sup.+=373.1 (LCMS).

Step 3: (3-(5-(Pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl) methanamine (245A-4)

[1570] To a stirred solution of tert-butyl 3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (90.0 mg, 242 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give (3-(5-(Pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl) methanamine (40.0 mg, 147 mol, 61% yield, HCl salt) as a yellow oil. M+H.sup.+=273.1 (LCMS).

Step 4: tert-Butyl 3-((4-methyl-3-((3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (245A-5)

[1571] To a solution of (3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl) methanamine (40.0 mg, 147 mol, 1.0 eq) and 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (45.0 mg, 147 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (44.6 mg, 441 mol, 61.3 L, 3 eq), EDCI (33.7 mg, 176 mol, 1.2 eq) and HOBt (23.8 mg, 176 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of MeOH/DCM from 0/1 to 1/50. tert-Butyl 3-((4-methyl-3-((3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)carbamoyl)phenyl)amino) azetidine-1-carboxylate (40.0 mg, 71.3 mol, 59% yield) was obtained as a yellow solid. M+H.sup.+=561.2 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-N-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 120)

[1572] To a stirred solution of tert-butyl 3-((4-methyl-3-((3-(5-(pyrrolidin-1-ylmethyl)thiophen-2yl)benzyl)carbamoyl)phenyl)amino) azetidine-1-carboxylate (40.0 mg, 71.3 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10040 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-N-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (9.20 mg, 19.9 mol, 28% yield, TFA salt) was obtained as a white solid. M+H.sup.+=461.0 (LCMS); .sup.1H NMR (400 MHz, CD.sub.3OD) 7.69 (s, 1H), 7.58-7.47 (m, 1H), 7.41-7.37 (m, 3H), 7.31-7.30 (m, 1H), 7.03-7.01 (m, 1H), 6.60-6.58 (m, 2H), 4.90-4.62 (m, 4H), 4.57-4.52 (m, 1H), 4.50-4.34 (m, 2H), 3.97-3.92 (m, 2H), 3.58 (s, 2H), 3.31-3.22 (m, 2H), 2.27 (s, 3H), 2.23-1.85 (m, 4H).

Example 246: (R)-5-Methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 126)

##STR01089##

Step 1: (R)-tert-Butyl(1-(3-bromophenyl)ethyl)carbamate (246A-2)

[1573] To a solution of (R)-1-(3-bromophenyl)ethanamine (1.00 g, 5.00 mmol, 1.0 eq) and TEA (759 mg, 7.50 mmol, 1.02 mL, 1.5 eq) in DCM (25 mL) was added Boc.sub.2O (1.09 g, 5.00 mmol, 1.23 mL, 1.0 eq). The mixture was stirred at 20 C. for 4 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. (R)-tert-Butyl(1-(3-bromophenyl)ethyl)carbamate (1.40 g, 4.66 mmol, 93% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.44 (s, 1H), 7.38 (td, J=1.8, 7.3 Hz, 1H), 7.26-7.16 (m, 2H), 4.78 (br s, 2H), 1.51-1.33 (m, 12H).

Step 2: (R)-tert-Butyl(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (246A-3)

[1574] To a mixture of (R)-tert-butyl(1-(3-bromophenyl)ethyl)carbamate (100 mg, 333 mol, 1.0 eq), (5-formyl-2-thienyl) boronic acid (52.0 mg, 333 mol, 1.0 eq), KOAc (98.1 mg, 999 mol, 3.0 eq), Pd(OAc) 2 (7.48 mg, 33.3 mol, 0.1 eq) and cataCXium A (23.9 mg, 66.6 mol, 0.2 eq) in DMSO (5.0 mL) was degassed and purged with N.sub.2 for three times. The mixture was stirred at 80 C. for 6 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.3). (R)-tert-Butyl(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (50.0 mg, 151 mol, 45% yield) was obtained as a yellow solid.

Step 3: (R)-tert-Butyl(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl)carbamate (246A-4)

[1575] To a mixture of (R)-tert-butyl(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (50.0 mg, 151 mol, 1.0 eq) and pyrrolidine (21.5 mg, 302 mol, 25.2 L, 2.0 eq) in MeOH (4.0 mL) was added NaBH.sub.3CN (28.4 mg, 453 mol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product (R)-tert-butyl(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl)carbamate (55.0 mg, 80% purity) as a brown oil, which was used in the next step without any further purification. M+H.sup.+=387.2 (LCMS).

Step 4: (R)-1-(3-(5-(Pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethanamine (246A-5)

[1576] To a mixture of (R)-tert-butyl(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl) carbamate (55.0 mg, 142 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product (R)-1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethanamine (50.0 mg, 80% purity) as a brown solid, which was used in the next step without any further purification. M+H.sup.+=287.3 (LCMS).

Step 5: (R)-5-Methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (Compound 126)

[1577] To a solution of (R)-1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethanamine (50.0 mg, 175 mol, 1.0 eq) and 5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (40.8 mg, 192 mol, 1.1 eq) in DCM (2.0 mL) were added TEA (88.3 mg, 873 mol, 122 L, 5.0 eq), EDCI (40.2 mg, 209 mol, 1.2 eq) and HOBt (28.3 mg, 209 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-5-Methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (9.10 mg, 20.0 mol, 12% yield) was obtained as a white solid. M+H.sup.+=445.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.18 (s, 1H), 7.70 (s, 1H), 7.56-7.49 (m, 1H), 7.41-7.34 (m, 3H), 7.28 (d, J=3.6 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 5.26 (q, J=7.0 Hz, 1H), 3.94 (s, 2H), 2.73 (br s, 4H), 2.47 (s, 3H), 1.86 (br s, 4H), 1.58 (d, J=7.0 Hz, 3H).

Example 247: N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (Compound 134)

##STR01090##

Step 1: (R)-5-(3-(1-Aminoethyl)phenyl)thiophene-2-carbaldehyde (247A-1)

[1578] To a stirred solution of (R)-tert-butyl(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (40.0 mg, 121 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (30 mg, 110 mol, 91% yield, HCl salt) as a white solid. M+H.sup.+=232.1 (LCMS).

Step 2: (R)N-(1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (247A-2)

[1579] To a solution of (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (100 mg, 432 mol, 1.0 eq) and 5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (101 mg, 476 mol, 1.1 eq) in DCM (5.0 mL) were added TEA (131 mg, 1.30 mmol, 181 L, 3 eq), EDCI (99.0 mg, 519 mol, 1.2 eq) and HOBt (70.1 mg, 519 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.5). (R)N-(1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (100 mg, 257 mol, 60% yield) was obtained as a yellow solid. M+H.sup.+=390.1 (LCMS).

Step 3: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (Compound 134)

[1580] To a solution of (1R,3S)-3-aminocyclopentanol (27.2 mg, 198 mol, 25.2 L, 1.1 eq) in MeOH (3.0 mL) was added TEA (10.0 L), followed by the addition of (R)N-(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (70.0 mg, 180 mol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (22.6 mg, 359 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10040 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (3.40 mg, 7.16 mol, 4% yield) was obtained as a colorless gum. M+H.sup.+=475.2 (LCMS); .sup.1HNMR (400 MHZ, CD.sub.3OD) 8.57-8.45 (m, 1H), 8.24-8.16 (m, 1H), 7.76-7.64 (m, 2H), 7.59-7.53 (m, 1H), 7.49-7.44 (m, 1H), 7.41 (dd, J=4.3, 11.4 Hz, 3H), 7.32-7.22 (m, 1H), 5.29-5.24 (m, 1H), 4.40 (s, 2H), 4.32 (td, J=4.1, 8.6 Hz, 1H), 3.68-3.58 (m, 1H), 2.54-2.42 (m, 3H), 2.30-2.09 (m, 2H), 2.01-1.76 (m, 4H), 1.66 (br d, J=6.9 Hz, 3H).

Example 248: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (Compound 137)

##STR01091##

Step 1: 2-Methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzoic acid (248A-1)

[1581] To a stirred solution of 5-amino-2-methylbenzoate (200 mg, 1.21 mmol, 1.0 eq) and 4-bromo-1-methyl-1H-pyrazole (234 mg, 1.45 mmol, 1.2 eq) in dioxane (8.0 mL) was added t-BuONa (582 mg, 6.05 mmol, 5.0 eq) and fBuXPhos Pd G3 (96.2 mg, 121 mol, 0.1 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with petroleum ether (3.0 mL5). The aqueous layer was treated with HCl (1 M aqueous) to adjust pH 4 and extracted with EtOAc (2.0 mL5). The combined organic layers dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the crude product 2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzoic acid (0.25 g) as a brown oil.

Step 2: (R)N-(1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (248A-2)

[1582] To a solution of 2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzoic acid (198 mg, 856 mol, 1.1 eq) and (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (180 mg, 778 mol, 1.0 eq) in DCM (6.0 mL) were added TEA (236 mg, 2.33 mmol, 325 L, 3.0 eq), EDCI (179 mg, 934 mol, 1.2 eq) and HOBt (126 mg, 934 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.6). (R)N-(1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (75.0 mg, 169 mol, 22% yield) was obtained as a yellow solid. M+H.sup.+=445.1 (LCMS).

Step 3: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (Compound 137)

[1583] To a solution of (1R,3S)-3-aminocyclopentanol (25.5 mg, 186 mol, 25 L, 1.1 eq) in MeOH (3.0 mL) was added TEA (10.0 L), followed by the addition of (R)N-(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (75.0 mg, 169 mol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (21.2 mg, 337 mol, 2.0 eq) was added. The result mixture was stirred at 20 C. for another 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-methyl-1H-pyrazol-4-yl)amino)benzamide (7.00 mg, 13.2 mol, 8% yield, TFA salt) was obtained as a white solid. M+H.sup.+=530.2 (LCMS); .sup.1HNMR (400 MHZ, CD.sub.3OD) 7.69-7.65 (m, 1H), 7.58-7.51 (m, 2H), 7.45-7.35 (m, 4H), 7.29-7.25 (m, 1H), 7.05-6.98 (m, 1H), 6.85-6.74 (m, 2H), 5.26-5.13 (m, 1H), 4.55-4.39 (m, 2H), 4.35-4.33 (m, 1H), 3.88-3.72 (m, 3H), 3.71-3.68 (m, 1H), 2.27-2.18 (m, 5H), 1.97-1.84 (m, 4H), 1.61-1.41 (m, 3H).

Example 249: 5-((1H-Pyrazol-4-yl)amino)-N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 140)

##STR01092##

Step 1: 2-Methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (249A-1)

[1584] To a mixture of methyl 5-amino-2-methylbenzoate (200 mg, 1.21 mmol, 1.0 eq) and 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (336 mg, 1.45 mmol, 1.2 eq) in anhydrous dioxane (8.0 mL) were added t-BuONa (582 mg, 6.05 mmol, 5.0 eq) and/BuXPhos Pd G3 (96.2 mg, 121 mol, 0.1 eq) degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (210 mg, 697 mol, 58% yield) as a yellow solid. M+H.sup.+=302.3 (LCMS).

Step 2: N((R)-1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (249A-2)

[1585] To a solution of 2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzoic acid (72.6 mg, 241 mol, 1.1 eq) and (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (50.7 mg, 219 mol, 1.0 eq) in DCM (3.0 mL) were added TEA (66.5 mg, 657 mol, 91.5 L, 3.0 eq), EDCI (50.4 mg, 263 mol, 1.2 eq) and HOBt (35.5 mg, 263 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.7). N((R)-1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (85.0 mg, 165 mol, 75% yield) was obtained as a yellow solid. M+H.sup.+=515.4 (LCMS).

Step 3: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (249A-3)

[1586] To a stirred solution of N((R)-1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (85.0 mg, 165 mol, 1.0 eq) and (1R,3S)-3-aminocyclopentanol (25.0 mg, 182 mol, 1.1 eq) in MeOH (3.0 mL). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then mixture NaBH.sub.3CN (20.8 mg, 330 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (20.0 mg, 33.4 mol, 20% yield) was obtained as a yellow solid. M+H.sup.+=600.3 (LCMS).

Step 4: 5-((1H-Pyrazol-4-yl)amino)-N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 140)

[1587] To a mixture of N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)benzamide (20.0 mg, 33.4 mol, 1.0 eq) in MeOH (2.0 mL) was added TsOH.Math.H.sub.2O (19.0 mg, 100 mol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-((1H-Pyrazol-4-yl)amino)-N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (4.12 mg, 6.54 mol, 20% yield, TFA salt) was obtained as a white solid. M+H.sup.+=516.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.65 (s, 1H), 7.57-7.52 (m, 3H), 7.43-7.35 (m, 3H), 7.27 (d, J=3.6 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.84-6.76 (m, 2H), 5.19 (q, J=7.0 Hz, 1H), 4.47 (s, 2H), 4.34 (quin, J=4.1 Hz, 1H), 3.74-3.66 (m, 1H), 2.30-2.23 (m, 1H), 2.22 (s, 3H), 2.20-2.14 (m, 1H), 2.04-1.79 (m, 4H), 1.53 (d, J=7.0 Hz, 3H).

Example 250: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (Compound 146)

##STR01093##

Step 1: (R)N-(1-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (250A-1)

[1588] To a solution of 5-methyl-1H-indazole-6-carboxylic acid (70.0 mg, 397 mol, 1.0 eq) and (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (91.9 mg, 397 mol, 20.0 L, 1.0 eq) in DCM (2.0 mL) were added TEA (80.4 mg, 795 mol, 111 L, 2.0 eq), EDCI (91.4 mg, 477 mol, 1.2 eq) and HOBt (64.4 mg, 477 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product (R)N-(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (130 mg) as a brown oil. M+H.sup.+=390.2 (LCMS).

Step 2: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (Compound 146)

[1589] To a solution of (1R,3S)-3-aminocyclopentanol (50.5 mg, 367 mol, 1.1 eq, HCl salt) in MeOH (2.0 mL) was added TEA (30.0 L), followed by the addition of (R)N-(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (130 mg, 334 mol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, and then NaBH.sub.3CN (62.9 mg, 1.00 mmol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-indazole-6-carboxamide (14.1 mg, 29.0 mol, 9% yield) was obtained as a white solid. M+H.sup.+=475.1 (LCMS); .sup.1H NMR (400 MHz, CD.sub.3OD) 8.27 (br s, 1H), 7.74 (s, 2H), 7.70 (s, 1H), 7.62 (s, 1H), 7.42 (dd, J=4.3, 7.8 Hz, 3H), 7.30 (d, J=3.7 Hz, 1H), 5.28 (q, J=7.0 Hz, 1H), 4.47 (s, 2H), 4.40-4.28 (m, 1H), 3.77-3.64 (m, 1H), 2.42 (s, 3H), 2.08-1.93 (m, 2H), 1.86 (br dd, J=3.7, 8.0 Hz, 4H), 1.60 (d, J=7.0 Hz, 3H).

Example 251: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 151)

##STR01094##

Step 1: (R)-tert-Butyl((6-((1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazol-2-yl)methyl)carbamat (251A-1)

[1590] To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 328 mol, 1.0 eq) and (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (75.8 mg, 328 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (66.3 mg, 655 mol, 91.2 L, 2.0 eq), EDCI (75.3 mg, 393 mol, 1.2 eq) and HOBt (23.1 mg, 393 mol, 1.2 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. (R)-tert-Butyl((6-((1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazole-2-yl)methyl)carbamate (70 mg, 135 mol, 41% yield) was obtained as a white solid. M+H.sup.+=519.3 (LCMS).

Step 2: tert-Butyl((6-(((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazol-2-yl)methyl) carbamate (251A-2)

[1591] To a solution of (1R,3S)-3-aminocyclopentanol (47.8 mg, 347 mol, 3.0 eq) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of (R)-tert-butyl((6-((1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazol-2-yl)methyl) carbamate (60.0 mg, 116 mol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (21.8 mg, 347 mol, 3.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl((6-(((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazol-2-yl)methyl)carbamate (70.0 mg). M+H.sup.+=604.4 (LCMS).

Step 3: 2-(Aminomethyl)-N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (Compound 151)

[1592] To a stirred solution of tert-butyl((6-(((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-1H-benzo[d]imidazol-2-yl)methyl) carbamate (50.0 mg, 82.8 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 82.8 L, 4.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 2-(aminomethyl)-N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-1H-benzo[d]imidazole-6-carboxamide (5.50 mg, 9.96 mol, 12% yield, HCl salt) as a white solid. M+H.sup.+=504.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.81 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.58 (dd, J=2.4, 6.2 Hz, 1H), 7.43 (t, J=4.8 Hz, 3H), 7.31 (d, J=3.7 Hz, 1H), 5.27 (d, J=7.1 Hz, 1H), 4.69 (s, 2H), 4.48 (s, 2H), 4.37-4.31 (m, 1H), 3.71 (br t, J=6.1 Hz, 1H), 2.50 (s, 3H), 2.34-2.13 (m, 2H), 2.07-1.94 (m, 1H), 1.91-1.82 (m, 3H), 1.60 (d, J=7.1 Hz, 3H).

Example 252: N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (Compound 154)

##STR01095##

Step 1: (R)N-(1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (252A-1)

[1593] To a solution of 6-methylquinoline-7-carboxylic acid (70.0 mg, 374 mol, 1.0 eq) in DCM (5 mL) were added (R)-5-(3-(1-aminoethyl)phenyl)thiophene-2-carbaldehyde (110 mg, 411 mol, 83 L, 1.1 eq, HCl salt), TEA (75.7 mg, 748 mol, 104 L, 2.0 eq), EDCI (108 mg, 561 mol, 1.5 eq) and HOBt (75.8 mg, 561 mol, 1.5 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (R)N-(1-(3-(5-Dormylthiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (130 mg, 325 mol, 87% yield) was obtained as a yellow oil. .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.93-9.83 (m, 1H), 8.88-8.78 (m, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.05-7.99 (m, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.68 (m, 1H), 7.64-7.61 (m, 1H), 7.59-7.48 (m, 3H), 5.33 (q, J=7.1 Hz, 1H), 2.57-2.49 (m, 3H), 1.66-1.59 (m, 3H).

Step 2: N((R)-1-(3-(5-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (Compound 154)

[1594] To a solution of (1R,3S)-3-aminocyclopentanol (179 mg, 1.30 mmol, 4.0 eq, HCl salt) in MeOH (5.0 mL) was added TEA (40.0 L), followed by the addition of (R)N-(1-(3-(5-dormylthiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (130 mg, 325 mol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N((R)-1-(3-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (39.0 mg, 80.3 mol, 25% yield, HCl salt) was obtained as a white solid. M+H.sup.+=486.1 (LCMS); HNMR: 1H NMR (400 MHZ, CD.sub.3OD) 9.23-9.19 (m, 1H), 9.14 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.12 (dd, J=5.4, 8.4 Hz, 1H), 7.76 (s, 1H), 7.60 (dt, J=1.8, 4.3 Hz, 1H), 7.50-7.39 (m, 2H), 7.31 (d, J=3.6 Hz, 1H), 7.30 (m, 1H), 5.38-5.28 (m, 1H), 4.50-4.44 (m, 2H), 4.38-4.30 (m, 1H), 3.76-3.64 (m, 1H), 2.59 (s, 3H), 2.32-2.13 (m, 2H), 2.07-1.95 (m, 1H), 1.92-1.81 (m, 3H), 1.64 (d, J=7.1 Hz, 3H).

Example 253: 5-(2-Aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 143)

##STR01096##

Step 1: tert-Butyl 3-(2-((3-fluorobenzyl)amino)-2-oxoethyl)azetidine-1-carboxylate (253A-2)

[1595] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl) acetic acid (500 mg, 2.32 mmol, 1.0 eq) in DCM (15 mL) were added (3-fluorophenyl) methanamine (436 mg, 3.48 mmol, 396 L, 1.5 eq), TEA (705 mg, 6.97 mmol, 970 L, 3.0 eq), EDCI (668 mg, 3.48 mmol, 1.5 eq) and HOBt (471 mg, 3.48 mmol, 1.5 eq). The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 3-(2-((3-fluorobenzyl)amino)-2-oxo ethyl)azetidine-1-carboxylate (700 mg, 2.17 mmol, 93% yield) was obtained as a colorless oil. M+H.sup.+=323.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.36-7.28 (m, 1H), 7.07-6.92 (m, 3H), 4.43 (br d, J=5.9 Hz, 2H), 4.21-4.01 (m, 2H), 3.72-3.49 (m, 2H), 3.07-2.87 (m, 1H), 2.55 (br d, J=7.9 Hz, 2H), 1.47-1.40 (m, 9H).

Step 2: 2-(Azetidin-3-yl)-N-(3-fluorobenzyl) acetamide (253A-3)

[1596] To a solution of tert-butyl 3-(2-((3-fluorobenzyl)amino)-2-oxoethyl)azetidine-1-carboxylate (300 mg, 936 mol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 30.0 mL) at 0 C. Then the mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product 2-(azetidin-3-yl)-N-(3-fluorobenzyl) acetamide (300 mg, HCl salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=223.3 (LCMS).

Step 3: N-(3-Fluorobenzyl)-2-(1-(1-(naphthalen-1-yl)ethyl)azetidin-3-yl)acetamide (Compound 143)

[1597] To a solution of 2-(azetidin-3-yl)-N-(3-fluorobenzyl) acetamide (300 mg, 1.16 mmol, 2.63 eq, HCl salt) in MeOH (15 mL) was added TEA (50.0 L), followed by the addition of 1-(1-naphthyl)ethanone (150 mg, 881 mol, 134 L, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (83.1 mg, 1.32 mmol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3; mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-2-(1-(1-(naphthalen-1-yl)ethyl)azetidin-3-yl) acetamide (7.82 mg, 20.8 mol, 5% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.20 (br d, J=8.3 Hz, 1H), 7.89-7.84 (m, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.58-7.41 (m, 4H), 7.29 (dt, J=6.0, 7.8 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.02-6.89 (m, 2H), 4.35-4.26 (m, 3H), 3.66-3.57 (m, 1H), 3.50-3.40 (m, 1H), 3.08 (t, J=7.1 Hz, 1H), 2.90-2.78 (m, 2H), 2.52 (d, J=7.0 Hz, 2H), 1.33 (d, J=6.6 Hz, 3H).

Example 254: N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)ethyl) pyrrolidine-3-carboxamide

##STR01097##

Step 1: tert-Butyl 3-((3-fluorobenzyl)carbamoyl) pyrrolidine-1-carboxylate (254A-2)

[1598] To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1.00 g, 4.65 mmol, 1.0 eq) and (3-fluorophenyl) methanamine (581 mg, 4.65 mmol, 0.53 mL, 1.0 eq) in DCM (15 mL) were added TEA (940 mg, 9.29 mmol, 1.30 mL, 2.0 eq), EDCI (1.07 g, 5.58 mmol, 1.2 eq) and HOBt (753 mg, 5.58 mmol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 3-((3-fluorobenzyl)carbamoyl) pyrrolidine-1-carboxylate (600 mg, 1.86 mmol, 40% yield) was obtained as a white solid. M56+H.sup.+=267.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.52 (br s, 1H), 7.36 (dt, J=6.4, 7.7 Hz, 1H), 7.14-6.94 (m, 3H), 4.29 (d, J=6.0 Hz, 2H), 3.45 (dd, J=8.0, 10.5 Hz, 1H), 3.40-3.33 (m, 1H), 3.31-3.26 (m, 1H), 3.25-3.15 (m, 1H), 3.06-2.90 (m, 1H), 2.05-1.89 (m, 2H), 1.39 (s, 9H).

Step 2: N-(3-Fluorobenzyl)pyrrolidine-3-carboxamide (254A-3)

[1599] To a stirred solution of tert-butyl 3-((3-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (200 mg, 434 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product N-(3-fluorobenzyl)pyrrolidine-3-carboxamide (200 mg), which was used in the next step without any further purification. M+H.sup.+=223.1 (LCMS).

Step 3: N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)ethyl)pyrrolidine-3-carboxamide (Compound 144)

[1600] To a solution of N-(3-fluorobenzyl)pyrrolidine-3-carboxamide (200 mg, 773 mol, 1.0 eq, HCl salt) in MeOH (10 mL) was added TEA (10.0 L), followed by the addition of 1-(naphthalen-1-yl)ethanone (132 mg, 773 mol, 120 L 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (146 mg, 2.32 mmol, 3.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 45%-75% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)ethyl)pyrrolidine-3-carboxamide (87.4 mg, 232 mol, 30% yield) was obtained as a colorless gum. M+H.sup.+=377.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.39 (br d, J=7.2 Hz, 1H), 7.89-7.82 (m, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.62 (dd, J=3.8, 6.7 Hz, 1H), 7.50-7.38 (m, 3H), 7.34-7.22 (m, 1H), 7.11-6.84 (m, 3H), 4.39-4.30 (m, 1H), 4.27 (d, J=8.7 Hz, 1H), 4.23-4.10 (m, 1H), 3.06-2.87 (m, 2H), 2.83-2.53 (m, 3H), 2.22-1.95 (m, 2H), 1.59-1.45 (m, 3H).

Example 255: (1R,5S,6r)-N-(3-Fluorobenzyl)-3-(1-(naphthalen-1-yl)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 149)

##STR01098##

Step 1: (1R,5S,6r)-tert-Butyl 6-((3-fluorobenzyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (255A-2)

[1601] To a solution of (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (500 mg, 2.20 mmol, 1.0 eq) and (3-fluorophenyl)methanamine (275 mg, 2.20 mmol, 1.0 eq) in DCM (10 mL) were added TEA (445 mg, 4.40 mmol, 612 L, 2.0 eq) and T.sub.3P (1.68 g, 2.64 mmol, 1.57 mL, 50% purity in EtOAc, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. (1R,5S,6r)-tert-Butyl 6-((3-fluorobenzyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 1.20 mmol, 54% yield) was obtained as a white solid. M+H.sup.+=335.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.56 (br t, J=5.9 Hz, 1H), 7.47-7.27 (m, 1H), 7.15-6.96 (m, 3H), 4.28 (br d, J=5.9 Hz, 2H), 3.48 (br dd, J=4.1, 10.8 Hz, 2H), 3.34-3.24 (m, 2H), 1.87 (br s, 2H), 1.43 (t, J=3.1 Hz, 1H), 1.37 (s, 9H).

Step 2: (1R,5S,6r)-N-(3-Fluorobenzyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (255A-3)

[1602] To a stirred solution of (1R,5S,6r)-tert-butyl 6-((3-fluorobenzyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 598 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude product (1R,5S,6r)-N-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (200 mg, HCl salt), which was used in the next step without any further purification. M+H.sup.+=235.2 (LCMS).

Step 3: (1R,5S,6r)-N-(3-Fluorobenzyl)-3-(1-(naphthalen-1-yl)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 149)

[1603] To a solution of (1R,5S,6r)-N-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (100 mg, 369 mol, 1.0 eq, HCl salt) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of 1-(naphthalen-1-yl)ethanone (62.9 mg, 369 mol, 56.1 L, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (69.6 mg, 1.11 mmol, 3.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 60%-90% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (1R,5S,6r)-N-(3-Fluorobenzyl)-3-(1-(naphthalen-1-yl)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (27.9 mg, 71.8 mol, 19% yield) was obtained as a white solid. M+H.sup.+=389.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.45 (br d, J=8.0 Hz, 1H), 7.87-7.82 (m, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.54 (d, J=6.9 Hz, 1H), 7.50-7.36 (m, 3H), 7.31 (dt, J=6.0, 7.9 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.04-6.92 (m, 2H), 4.35 (s, 2H), 4.07 (q, J=6.4 Hz, 1H), 3.39 (d, J=9.0 Hz, 1H), 2.77 (d, J=9.4 Hz, 1H), 2.63 (dd, J=3.4, 8.9 Hz, 1H), 2.28 (dd, J=3.5, 9.4 Hz, 1H), 2.13 (t, J=2.8 Hz, 1H), 2.01-1.95 (m, 1H), 1.84-1.79 (m, 1H), 1.45 (d, J=6.6 Hz, 3H).

Example 256: 2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-amine (Compound 135)

##STR01099##

Step 1: 2-(1-(Naphthalen-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (256A-1)

[1604] To a mixture of 1-(naphthalen-1-yl)ethanone (200 mg, 1.18 mmol, 178 L, 1.0 eq) and 7-nitro-1,2,3,4-tetrahydroisoquinoline (230 mg, 1.29 mmol, 1.1 eq) in MeOH (5.0 mL) was added Ti(i-PrO).sub.4 (668 mg, 2.35 mmol, 694 L, 2.0 eq). The mixture was stirred at 60 C. for 16 h. The mixture was cooled to 0 C. and NaBH.sub.4 (8.9 mg, 2.35 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (6.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 75%-98% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-(1-(Naphthalen-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (100 mg, 301 mol, 26% yield) was obtained as a white solid. M+H=333.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.42 (br s, 1H), 8.02-7.94 (m, 1H), 7.93-7.86 (m, 2H), 7.80 (br d, J=8.1 Hz, 1H), 7.66 (br d, J=6.4 Hz, 1H), 7.53-7.42 (m, 3H), 7.23 (d, J=8.4 Hz, 1H), 4.36 (br s, 1H), 4.01 (br d, J=14.6 Hz, 1H), 3.73 (br d, J=14.9 Hz, 1H), 3.05-2.64 (m, 4H), 1.62 (br d, J=6.5 Hz, 3H).

Step 2: 2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-amine (Compound 135)

[1605] To a solution of 2-(1-(naphthalen-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (70.0 mg, 211 mol, 1.0 eq) in a mixture of MeOH (2.5 mL) and H.sub.2O (0.5 mL) were added iron powder (58.8 mg, 1.05 mmol, 5.0 eq) and NH.sub.4Cl (56.3 mg, 1.05 mmol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then poured into H.sub.2O (6.0 mL). The product was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 60%-95% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-amine (3.40 mg, 10.3 mol, 5% yield) was obtained as a white gum. M+H.sup.+=303.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.48 (br s, 1H), 7.90-7.83 (m, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.69 (br d, J=7.3 Hz, 1H), 7.52-7.42 (m, 3H), 6.89 (d, J=8.2 Hz, 1H), 6.51 (br d, J=8.0 Hz, 1H), 6.36 (s, 1H), 4.25 (br d, J=6.0 Hz, 1H), 3.86 (br d, J=14.7 Hz, 1H), 3.56 (br d, J=15.1 Hz, 2H), 2.86-2.57 (m, 4H), 1.58 (br s, 3H).

Example 257: N-(2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-phenylacetamide (Compound 139)

##STR01100##

Step 1: N-(2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-phenylacetamide (Compound 139)

[1606] To a solution of 2-(1-(naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-amine (40.0 mg, 132 mol, 1.0 eq) and 2-phenylacetic acid (21.7 mg, 159 mol, 20.0 L, 1.2 eq) in DCM (2.0 mL) were added TEA (26.8 mg, 265 mol, 368 L, 2.0 eq), EDCI (30.4 mg, 159 mol, 1.2 eq) and HOBt (21.5 mg, 159 mol, 1.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 27%-57% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N-(2-(1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-phenylacetamide (7.04 mg, 12.9 mol, 10% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=421.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.16-7.97 (m, 2H), 7.85 (br s, 1H), 7.66 (br t, J=7.8 Hz, 4H), 7.32 (br s, 8H), 5.58 (br d, J=6.6 Hz, 1H), 4.77-3.94 (m, 2H), 3.86-3.38 (m, 4H), 3.29-2.66 (m, 2H), 1.95 (d, J=6.8 Hz, 3H).

Example 258: 5-((1,2-Dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 404)

##STR01101##

Step 1: tert-Butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (258A-1)

[1607] To a solution 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 945 mol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)-2-methylazetidine-1-carboxylate (190 mg, 945 mol, 1.0 eq) in toluene (18 mL) were added TMAD (488 mg, 2.84 mmol, 3.0 eq) and PPh.sub.3 (744 mg, 2.84 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times, then stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (370 mg, 740 mol, 79% yield) was obtained as a yellow solid. M+H.sup.+=501.3 (LCMS).

Step 2: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (258A-2)

[1608] To a solution of tert-butyl 2-methyl-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (180 mg, 360 mol, 1.0 eq) in DCM (10 mL) was added TFA (3.6 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the product 2-methyl-5-((2-methyl azetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (90.0 mg, TFA salt) as a brown oil, which was used in the next step without any further purification. M+H.sup.+=401.1 (LCMS).

Step 3: 5-((1,2-Dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 404)

[1609] To a solution of 2-methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (80.0 mg, 155 mol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (9.34 mg, 311 mol, 8.57 L, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6, then NaBH.sub.3CN (19.5 mg, 311 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (33.0 mg, 73.2 mol, 47% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=415.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.32-10.41 (m, 1H), 9.13 (s, 1H), 8.67 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.87-7.78 (m, 2H), 7.64-7.41 (m, 3H), 7.13-7.04 (m, 1H), 6.99-6.88 (m, 1H), 6.80-6.68 (m, 1H), 4.52-4.29 (m, 1H), 4.25-3.98 (m, 1H), 4.00-3.73 (m, 2H), 2.67-2.56 (m, 3H), 2.45-2.03 (m, 2H), 1.95 (s, 3H), 1.59 (s, 3H), 1.37 (br s, 2H), 1.18 (br s, 2H).

Example 259: rac-5-((1S,2R)-2-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 406)

##STR01102##

Step 1: rac-tert-Butyl((1R,2S)-2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)cyclobutyl)carbamate (259A-1)

[1610] To a solution of rac-tert-butyl((1S,2R)-2-hydroxycyclobutyl)carbamate (118 mg, 630 mol, 1.0 eq) and 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 630 mol, 1.0 eq) in toluene (12 mL) was added CMBP (228 mg, 945 mol, 1.5 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (8.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-85% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). rac-tert-Butyl((1R,2S)-2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)cyclobutyl)carbamate (46.0 mg, 94.53 mol, 5% yield) was obtained as a red solid. M+H.sup.+=487.3 (LCMS).

Step 2: rac-5-((1S,2R)-2-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 406)

[1611] To a solution of rac-tert-butyl((1R,2S)-2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)cyclobutyl)carbamate (46.0 mg, 94.5 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). rac-5-((1S,2R)-2-Aminocyclobutoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (10.1 mg, 23.7 mol, 25% yield, HCl salt) was obtained as a white solid. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18-9.08 (m, 1H), 8.71-8.61 (m, 1H), 8.30-8.15 (m, 3H), 7.98-7.91 (m, 1H), 7.87-7.78 (m, 2H), 7.62-7.42 (m, 3H), 7.10-7.03 (m, 1H), 6.84-6.77 (m, 1H), 6.60-6.54 (m, 1H), 4.86-4.74 (m, 1H), 4.03-3.90 (m, 1H), 2.38-2.23 (m, 1H), 2.20-2.07 (m, 2H), 2.02-1.95 (m, 3H), 1.94-1.87 (m, 1H), 1.40-1.32 (m, 2H), 1.23-1.14 (m, 2H).

Example 260: rac-5-(((2R,4R)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 416)

##STR01103## ##STR01104##

Step 1: 1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (260A-2)

[1612] To a solution of 1-ter-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (5.00 g, 20.6 mmol, 1.0 eq) in EtOH (50.0 mL) was added sodium tetrahydroborate (778 mg, 20.6 mmol, 1.0 eq) in portions at 0 C. The mixture was stirred at 0 C. for 30 min under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into cold H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of EtOAc/petroleum ether from 1/10 to 1/1. 1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (1.30 g, 5.30 mmol, 26% yield) was obtained as a white solid. M56+H.sup.+=190.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.38-4.35 (m, 1H), 3.79 (s, 3H), 3.75-3.57 (m, 3H), 3.52-3.46 (m, 1H), 2.11 (br d, J=7.8 Hz, 1H), 1.43 (s, 9H).

Step 2: 1-tert-Butyl2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (260A-3)

[1613] To a stirred solution of 1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (300 mg, 1.22 mmol, 1.0 eq) in DMF (3.0 mL) were added imidazole (167 mg, 2.45 mmol, 2.0 eq) and TBSCl (221 mg, 1.47 mmol, 1.2 eq) at 0 C. in portions. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of DCM. 1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (400 mg, 1.11 mmol, 91% yield, HCl salt) was obtained as a white solid. M+H.sup.+=360.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.40-4.25 (m, 2H), 3.71 (s, 3H), 3.67-3.56 (m, 1H), 3.39-3.24 (m, 1H), 2.37-2.22 (m, 1H), 2.15-2.06 (m, 1H), 1.43 (s, 9H), 0.92-0.86 (m, 9H), 0.07-0.03 (m, 6H).

Step 3: tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (260A-4)

[1614] To a solution of 1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (400 mg, 1.11 mmol, 1.0 eq) in THF (5.0 mL) was added lithium borohydride (60.6 mg, 2.78 mmol, 2.5 eq) in portions at 0 C. The mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of DCM to give tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (200 mg, 603 mol, 54% yield) as a yellow oil. M+H.sup.+=332.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.45-4.25 (m, 1H), 4.15-3.96 (m, 1H), 3.88-3.76 (m, 1H), 3.74-3.65 (m, 1H), 3.55 (br dd, J=7.4, 11.3 Hz, 1H), 3.36-3.20 (m, 1H), 3.17-3.04 (m, 1H), 2.34-2.14 (m, 1H), 1.65-1.56 (m, 1H), 1.48 (s, 9H), 0.90 (s, 9H), 0.09 (br s, 6H).

Step 4: tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (260A-5)

[1615] A mixture of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (190 mg, 573 mol, 1.0 eq), 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (182 mg, 573 mol, 1.0 eq) and PPh.sub.3 (4.34 g, 16.6 mmol, 1.1 eq) in toluene (2.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added TMAD (296 mg, 1.72 mmol, 3.0 eq) in portions at 20 C. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (150 mg, 238 mol, 41% yield) was obtained as a yellow oil. M+H.sup.+=631.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10-9.02 (m, 1H), 8.65 (br d, J=8.3 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.88-7.75 (m, 2H), 7.59-7.39 (m, 3H), 7.02 (d, J=8.3 Hz, 1H), 6.83 (br dd, J=2.3, 8.3 Hz, 1H), 6.61 (br d, J=12.0 Hz, 1H), 4.48-4.33 (m, 1H), 4.13-4.05 (m, 1H), 3.97-3.91 (m, 1H), 3.50 (dd, J=5.1, 11.6 Hz, 1H), 3.31-3.22 (m, 1H), 3.15-3.00 (m, 1H), 2.15-2.02 (m, 1H), 1.95 (s, 3H), 1.91-1.80 (m, 1H), 1.45-1.29 (m, 11H), 1.17-1.13 (m, 2H), 0.74 (br d, J=8.0 Hz, 9H), 0.06-0.08 (m, 6H).

Step 5: rac-(2R,4R)-tert-Butyl-4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclo propyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (260A-6)

[1616] A solution of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (150 mg, 238 mol, 1.0 eq) in THF (2.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added tetrabutylammonium fluoride (1 M in THF, 713 mol, 3.0 eq) dropwise at 0 C. The resulting mixture was stirred at 20 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.6). rac-(2R,4R)-tert-Butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (80.0 mg, 155 mol, 65% yield) was obtained as a white solid. M+H.sup.+=517.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.65 (br d, J=8.5 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.82 (t, J=7.8 Hz, 2H), 7.60-7.42 (m, 3H), 7.02 (d, J=8.5 Hz, 1H), 6.89-6.81 (m, 1H), 6.62 (br d, J=14.5 Hz, 1H), 5.01 (br s, 1H), 4.24 (br s, 1H), 4.10 (br s, 1H), 3.96 (br d, J=4.9 Hz, 2H), 3.44 (dd, J=4.8, 11.4 Hz, 1H), 3.19-3.07 (m, 1H), 2.09-2.01 (m, 1H), 1.94 (s, 3H), 1.87 (br d, J=13.5 Hz, 1H), 1.48-1.30 (m, 9H), 1.30 (br s, 2H), 1.17-1.15 (m, 2H).

Step 6: rac-5-(((2R,4R)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 416)

[1617] To a stirred solution of rac-(2R,4R)-tert-butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (80.0 mg, 155 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). rac-5-(((2R,4R)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (140 mg, 334 mol, 77% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.61-9.45 (m, 1H), 9.12 (s, 1H), 9.10-8.97 (m, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.87-7.77 (m, 2H), 7.61-7.42 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.6, 8.4 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 5.46 (br s, 1H), 4.39 (br s, 1H), 4.21-4.13 (m, 1H), 4.07 (t, J=9.9 Hz, 1H), 3.89 (br d, J=3.9 Hz, 1H), 3.22-3.11 (m, 1H), 3.10-3.01 (m, 1H), 2.32-2.22 (m, 1H), 1.97 (s, 3H), 1.72-1.59 (m, 1H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 261: 5-(((2R,4S)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 414)

##STR01105##

Step 1: rac-(2R,4S)-tert-Butyl4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclo propyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (261A-1)

[1618] A solution of tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (150 mg, 238 mol, 1.0 eq) in THF (2.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added tetrabutylammonium fluoride (1 M in THF, 713 mol, 3.0 eq) dropwise at 0 C. The resulting mixture was stirred at 20 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/2, R.sub.f=0.6). rac-(2R,4S)-tert-Butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy) methyl)pyrrolidine-1-carboxylate (40.0 mg, 77.4 mol, 33% yield) was obtained as a white solid. M+H.sup.+=517.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.65 (br d, J=8.1 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.82 (t, J=7.6 Hz, 2H), 7.59-7.43 (m, 3H), 7.02 (br d, J=7.8 Hz, 1H), 6.83 (dd, J=2.4, 8.3 Hz, 1H), 6.61 (br s, 1H), 4.91 (br s, 1H), 4.25 (br s, 1H), 4.00 (br d, J=3.8 Hz, 1H), 3.96-3.81 (m, 1H), 3.31-3.19 (m, 2H), 1.94 (br s, 5H), 1.45-1.31 (m, 9H), 1.30 (br s, 2H), 1.16 (br s, 2H).

Step 2: rac-5-(((2R,4S)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 414)

[1619] To a stirred solution of rac-(2R,4S)-tert-Butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (40.0 mg, 77.4 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). rac-5-(((2R,4S)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (5.70 mg, 13.5 mol, 17% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.55-9.36 (m, 1H), 9.10 (s, 1H), 8.91-8.74 (m, 1H), 8.65 (d, J=7.9 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.87-7.79 (m, 2H), 7.60-7.45 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.7, 8.2 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 5.45-5.43 (m, 1H), 4.42 (br s, 1H), 4.18 (br d, J=7.3 Hz, 1H), 4.06-3.94 (m, 2H), 3.26-3.20 (m, 1H), 3.12-2.97 (m, 1H), 2.13-2.01 (m, 1H), 1.97 (s, 3H), 1.86-1.76 (m, 1H), 1.39-1.31 (m, 2H), 1.19 (br s, 2H).

Example 262: 5-((2-Aminoethyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 412)

##STR01106##

Step 1: 5-((2-Aminoethyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 412)

[1620] To a stirred solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 263 mol, 1.0 eq) and ethane-1,2-diamine (23.7 mg, 394 mol, 26.4 L, 1.5 eq) in dioxane (1.0 mL) were added K.sub.2CO.sub.3 (36.3 mg, 263 mol, 1.0 eq), CuI (5.01 mg, 26.3 mol, 0.1 eq) and DMEDA (4.64 mg, 52.6 mol, 5.66 L, 0.2 eq) in one portion. The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3).

[1621] The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-((2-Aminoethyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (44.0 mg, 122 mol, 47% yield, HCl salt) was obtained as a white solid. M+H.sup.+=360.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.99 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.87-7.71 (m, 5H), 7.61-7.42 (m, 3H), 6.87 (d, J=8.4 Hz, 1H), 6.51 (dd, J=2.4, 8.2 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 3.18 (t, J=6.3 Hz, 2H), 2.95-2.76 (m, 2H), 1.88 (s, 3H), 1.41-1.27 (m, 2H), 1.21-1.11 (m, 2H).

Example 263: 5-((2-Aminoethyl)(methyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 421)

##STR01107##

Step 1: tert-Butyl(2-(methyl(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)amino)ethyl)carbamate (263A-1)

[1622] A mixture of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 394 mol, 1.0 eq) and tert-butyl(2-(methylamino)ethyl)carbamate (103 mg, 592 mol, 1.5 eq) in dioxane (7.5 mL) was degassed and purged with N.sub.2 three times. To the mixture were added K.sub.2CO.sub.3 (54.5 mg, 394 mol, 1.0 eq), DMEDA (6.96 mg, 78.9 mol, 8.49 L, 0.2 eq) and CuI (7.50 mg, 39.5 mol, 0.1 eq) at 20 C. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.3). tert-Butyl(2-(methyl(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)amino)ethyl)carbamate (150 mg, 317 mol, 80% yield) was obtained as a colorless oil. M+H.sup.+=474.2 (LCMS).

Step 2: 5-((2-aminoethyl)(methyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 421)

[1623] To a stirred solution of tert-butyl(2-(methyl(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenyl)amino)ethyl)carbamate (100 mg, 211 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-((2-Aminoethyl)(methyl)amino)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (25.8 mg, 60.2 mol, 29% yield, HCl salt) was obtained as a white solid. M+H.sup.+=374.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.99 (s, 1H), 8.60-8.71 (m, 3H), 7.93 (d, J=7.8 Hz, 1H), 7.86-7.78 (m, 2H), 7.60-7.43 (m, 3H), 6.87 (d, J=8.3 Hz, 1H), 6.54 (dd, J=2.5, 8.3 Hz, 1H), 6.32 (d, J=2.5 Hz, 1H), 3.27-3.19 (m, 2H), 3.02-2.91 (m, 2H), 2.53 (br d, J=3.9 Hz, 3H), 1.88 (s, 3H), 1.40-1.30 (m, 2H), 1.20-1.12 (m, 2H).

Example 264: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-3-yl)benzamide (Compound 413)

##STR01108##

Step 1: tert-Butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (264A-1)

[1624] To a solution of tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (150 mg, 288 mol, 1.0 eq) in MeOH (2 mL) was added 10% palladium on carbon (10.0 mg). The mixture was stirred at 20 C. for 2 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give the crude product tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (70.0 mg, 147 mol, 51% yield) as a yellow oil, which was used in the next step without any further purification. M56+H.sup.+=415.2 (LCMS).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-3-yl)benzamide (Compound 413)

[1625] To a stirred solution of tert-butyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (70.0 mg, 134 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(pyrrolidin-3-yl)benzamide (20.2 mg, 54.0 mol, 40% yield, HCl salt) was obtained as a white solid. M+H.sup.+=371.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 9.03-8.86 (m, 1H), 8.65 (d, J=8.4 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.83 (dd, J=4.6, 7.4 Hz, 2H), 7.62-7.43 (m, 3H), 7.22 (dd, J=1.5, 7.8 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.02 (s, 1H), 3.56-3.47 (m, 1H), 3.37 (br s, 2H), 3.22-3.11 (m, 1H), 2.96 (br t, J=10.4 Hz, 1H), 2.30-2.20 (m, 1H), 1.99 (s, 3H), 1.90-1.77 (m, 1H), 1.36 (s, 2H), 1.24-1.14 (m, 2H).

Example 265: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-4-yl)benzamide (Compound 407)

##STR01109##

Step 1: tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)piperidine-1-carboxylate (265A-1)

[1626] To a solution of tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (150 mg, 280 mol, 1.0 eq) in MeOH (2 mL) was added 10% palladium on carbon (10.0 mg). The mixture was stirred at 20 C. for 2 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) piperidine-1-carboxylate (70.0 mg, 142 mol, 51% yield) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=485.3 (LCMS).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-4-yl)benzamide (Compound 407)

[1627] To a stirred solution of tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) piperidine-1-carboxylate (70.0 mg, 130 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperidin-4-yl)benzamide (47.7 mg, 122 mol, 94% yield, HCl salt) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11 (s, 1H), 8.81-8.69 (m, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.53-8.35 (m, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.86-7.79 (m, 2H), 7.62-7.43 (m, 3H), 7.09 (s, 2H), 6.88 (s, 1H), 3.29 (br s, 2H), 2.99-2.85 (m, 2H), 2.79-2.69 (m, 1H), 1.98 (s, 3H), 1.88-1.78 (m, 2H), 1.76-1.63 (m, 2H), 1.40-1.32 (m, 2H), 1.23-1.13 (m, 2H).

Example 266: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperazin-1-yl)benzamide (Compound 410)

##STR01110##

Step 1: 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperazin-1-yl)benzamide (Compound 410)

[1628] To a solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (200 mg, 526 mol, 1.0 eq) and piperazine (68.0 mg, 789 mol, 4.38 L, 1.5 eq) in THF (10 mL) were added 1-BuONa (151.6 mg, 1.58 mmol, 3.0 eq) and/BuXPhos Pd G3 (41.8 mg, 52.6 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times and then the mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-45% B over 8 min; mobile phase A: 0.05% aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperazin-1-yl)benzamide was obtained as a white solid. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.03 (s, 1H), 8.67 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.7, 12.3 Hz, 2H), 7.58-7.43 (m, 3H), 6.94 (d, J=8.6 Hz, 1H), 6.80 (dd, J=2.5, 8.4 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 2.94-2.85 (m, 4H), 2.81-2.73 (m, 4H), 1.91 (s, 3H), 1.37-1.32 (m, 2H), 1.16 (br s, 2H).

Example 267: 2-Methyl-5-(4-methylpiperazin-1-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 418)

##STR01111##

Step 1: 2-Methyl-5-(4-methylpiperazin-1-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 418)

[1629] To a solution of 2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-5-(piperazin-1-yl)benzamide (60.0 mg, 156 mol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 L), followed by the addition of formaldehyde (25.3 mg, 300 mol, 23.2 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (19.6 mg, 311 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(4-methylpiperazin-1-yl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (17.9 mg, 40.59 mol, 16% yield, HCl salt) was obtained as a white solid. M+H.sup.+=400.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.21 (s, 1H), 9.06 (s, 1H), 8.68-8.62 (m, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.82 (t, J=8.6 Hz, 2H), 7.58-7.44 (m, 3H), 7.01 (d, J=8.2 Hz, 1H), 6.90 (dd, J=2.5, 8.7 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 3.68 (br d, J=11.9 Hz, 2H), 3.45 (br d, J=12.3 Hz, 2H), 3.13-3.02 (m, 2H), 2.90 (br t, J=12.7 Hz, 2H), 2.80 (d, J=4.8 Hz, 3H), 1.92 (s, 3H), 1.38-1.32 (m, 2H), 1.21-1.15 (m, 2H).

Example 268: 5-(1,4-Diazepan-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 411)

##STR01112##

Step 1: tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-1,4-diazepane-1-carboxylate (268A-1)

[1630] To a solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (120 mg, 316 mol, 1.0 eq) and tert-butyl 1,4-diazepane-1-carboxylate (94.8 mg, 473 mol, 92.9 L, 1.5 eq) in THF (10 mL) were added t-BuONa (91.0 mg, 947 mol, 3.0 eq), tBuXPhos Pd G3 (25.1 mg, 31.6 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times and then the mixture was stirred at 80 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (4 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-1,4-diazepane-1-carboxylate (80.0 mg, 160 mol, 51% yield) was obtained as a yellow oil. M+H.sup.+=500.3 (LCMS); 1H NMR (400 MHZ, CDCl.sub.3) 8.67 (d, J=8.6 Hz, 1H), 7.97 (d, J=6.4 Hz, 1H), 7.89 (br d, J=7.6 Hz, 2H), 7.81-7.75 (m, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.60 (dd, J=2.8, 8.4 Hz, 1H), 6.33 (d, J=1.6 Hz, 1H), 3.74-3.66 (m, 2H), 3.50 (br t, J=5.8 Hz, 2H), 3.45-3.41 (m, 3H), 1.79-1.69 (m, 2H), 1.50 (br d, J=0.6 Hz, 2H), 1.41-1.34 (m, 6H), 1.22 (s, 9H).

Step 2: 5-(1,4-Diazepan-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 411)

[1631] To a solution of tert-butyl 4-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)-1,4-diazepane-1-carboxylate (80.0 mg, 160 mol, 51% yield) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(1,4-Diazepan-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (13.9 mg, 31.9 mol, 20% yield, HCl salt) was obtained as a white solid. M+H.sup.+=400.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (s, 3H), 8.67 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.86-7.75 (m, 2H), 7.59-7.43 (m, 3H), 6.93 (d, J=8.6 Hz, 1H), 6.67 (dd, J=2.6, 8.4 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 3.64-3.55 (m, 2H), 3.39 (t, J=6.1 Hz, 2H), 3.10 (br s, 2H), 3.00 (br s, 2H), 2.04-1.95 (m, 2H), 1.91 (s, 3H), 1.35 (s, 2H), 1.21-1.12 (m, 2H).

Example 269: 5-(2-(Dimethylamino)ethoxy)-2,4-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 405)

##STR01113##

Step 1: Methyl 5-hydroxy-2,4-dimethylbenzoate (269A-1)

[1632] To a solution of methyl 5-hydroxy-4-iodo-2-methylbenzoate (600 mg, 2.05 mmol, 1.0 eq) in DMF (20 mL) were added methylboronic acid (738 mg, 12.3 mmol, 6.0 eq), Cs.sub.2CO.sub.3 (2.34 g, 7.19 mmol, 3.5 eq) and Pd.sub.2 (dba) 3 (94.1 mg, 103 mol, 0.05 eq). The resulting mixture was degassed and purged with N.sub.2 three times and then was stirred at 130 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-hydroxy-2,4-dimethylbenzoate (200 mg, 333 mol, 54% yield) was obtained as a yellow oil.

[1633] M+H.sup.+=181.1 (LCMS).

Step 2: Methyl 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoate (269A-2)

[1634] To a solution of 2-chloro-N,N-dimethylethanamine (95.9 mg, 666 mol, 2.0 eq, HCl salt) in DMF (10 mL) was added K.sub.2CO.sub.3 (230 mg, 1.66 mmol, 5.0 eq). The mixture was stirred at 20 C. for 30 min. To the resulting mixture were added methyl 5-hydroxy-2,4-dimethylbenzoate (200 mg, 333 mol, 1.0 eq), 18-crown-6 (139 mg, 532 mol, 1.6 eq) and KI (92.9 mg, 566 mol, 1.7 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 5-(2-(dimethylamino)ethoxy)-2,4-dimethyl benzoate (180 mg, 716 mol, 50% yield) was obtained as a white solid. M+H.sup.+=252.1 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (269A-3)

[1635] To a solution of methyl 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoate (90.0 mg, 358 mol, 1.0 eq) in a mixture of MeOH (7.0 mL) and THF (3.5 mL) was added NaOH (2 M aqueous, 2.26 mL, 12.7 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and treated with HCl (1 M aqueous) to adjust the pH to 6 and the product was extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (70.0 mg, 82% yield) as a yellow solid, which was used in the next step without any further purification. M+H.sup.+=238.1 (LCMS).

Step 4: 5-(2-(Dimethylamino)ethoxy)-2,4-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 405)

[1636] To a solution of 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (70.0 mg, 295 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (54.1 mg, 295 mol, 1.0 eq) in DMF (3.5 mL) were added EDCI (84.8 mg, 442 mol, 1.5 eq), HOBt (59.8 mg, 442 mol, 1.5 eq) and TEA (59.7 mg, 590 mol, 82.1 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2,4-dimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (27.1 mg, 60.8 mol, 21% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=403.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.92-10.67 (m, 1H), 9.11-9.01 (m, 1H), 8.74-8.62 (m, 1H), 8.01-7.88 (m, 1H), 7.81 (s, 2H), 7.62-7.42 (m, 3H), 6.94-6.88 (m, 1H), 6.74-6.67 (m, 1H), 4.30-4.21 (m, 2H), 3.50-3.40 (m, 2H), 2.81 (d, J=4.9 Hz, 6H), 2.12 (s, 3H), 1.99-1.88 (m, 3H), 1.44-1.34 (m, 2H), 1.21-1.11 (m, 2H).

Example 270: 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-4-yl)cyclopropyl)-2-methylbenzamide (Compound 409)

##STR01114##

Step 1: 1-(Isoquinolin-4-yl)cyclopropanamine (270A-2)

[1637] A mixture of isoquinoline-4-carbonitrile (200 mg, 1.30 mmol, 1.2 eq) in anhydrous Et.sub.2O (12 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (553 mg, 1.95 mmol, 574 L, 1.5 eq) slowly, and then EtMgBr (3 M, 951 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (368 mg, 2.59 mmol, 320 L, 2.0 eq) was added slowly with no obvious temperature change.

[1638] The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.25). 1-(Isoquinolin-4-yl)cyclopropanamine (60.0 mg, 25% yield) was obtained as a yellow oil. M+H.sup.+=185.0 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-4-yl)cyclopropyl)-2-methylbenz amide (Compound 409)

[1639] To a solution of 1-(isoquinolin-4-yl)cyclopropanamine (70.0 mg, 380 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (84.8 mg, 380 mol, 1.0 eq) in DCM (4 mL) were added TEA (115 mg, 1.14 mmol, 159 L, 3.0 eq), EDCI (182 mg, 950 mol, 2.5 eq) and HOBt (128 mg, 950 mol, 2.5 eq). The mixture was stirred at 20 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(isoquinolin-4-yl)cyclopropyl)-2-methylbenzamide (38.3 mg, 85.6 mol, 23% yield, FA salt) was obtained as a pink solid. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (s, 1H), 9.14 (s, 1H), 8.75 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.19-8.09 (m, 2H), 7.85 (ddd, J=1.3, 7.0, 8.4 Hz, 1H), 7.73-7.62 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 3.97 (t, J=5.8 Hz, 2H), 2.62 (t, J=5.7 Hz, 2H), 2.22 (s, 6H), 1.94 (s, 3H), 1.40-1.33 (m, 2H), 1.26-1.19 (m, 2H).

Example 271: N-(1-(9H-Carbazol-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 415)

##STR01115##

Step 1: 9H-Carbazole-4-carbonitrile (271A-2)

[1640] To a solution of 4-bromo-9H-carbazole (1.00 g, 4.06 mmol, 1.0 eq) in DMF (10 mL) was added CuCN (582 mg, 6.50 mmol, 1.42 mL, 1.6 eq) at 20 C. The mixture was stirred at 150 C. for 18 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 9H-Carbazole-4-carbonitrile (600 mg, 3.12 mmol, 77% yield) was obtained as a white solid. MH.sup.+=191.0 (LCMS).

Step 2: tert-Butyl 4-cyano-9H-carbazole-9-carboxylate (271A-3)

[1641] To a solution of 9H-carbazole-4-carbonitrile (400 mg, 2.08 mmol, 1.0 eq) in THF (5.0 mL) were added DMAP (280 mg, 2.29 mmol, 1.1 eq) and Boc.sub.2O (500 mg, 2.29 mmol, 526 L, 1.1 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 4-cyano-9H-carbazole-9-carboxylate (400 mg, 1.37 mmol, 66% yield) was obtained as a white solid. M+H.sup.+=293.1 (LCMS).

Step 3: tert-Butyl 4-(1-aminocyclopropyl)-9H-carbazole-9-carboxylate (271A-4)

[1642] A mixture of tert-butyl 4-cyano-9H-carbazole-9-carboxylate (100 mg, 342 mol, 1.0 eq) in anhydrous Et.sub.2O (7.5 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (146 mg, 513 mol, 151 L, 1.5 eq) slowly and then EtMgBr (3 M in Et.sub.2O, 251 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (97.1 mg, 684 mol, 84.4 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (8.0 mL) and MTBE (8.0 mL) and the mixture was extracted with MTBE (8.0 mL4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 4-(1-aminocyclopropyl)-9H-carbazole-9-carboxylate (30.0 mg, 93.1 mol, 27% yield) was obtained as a white solid. M+H.sup.+=323.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.49 (d, J=7.7 Hz, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.21-8.17 (m, 1H), 7.57-7.52 (m, 1H), 7.48-7.42 (m, 2H), 7.40-7.35 (m, 1H), 1.71 (s, 9H), 1.11 (br s, 2H), 0.97 (br s, 2H).

Step 4: tert-Butyl 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl)-9H-carbazole-9-carboxylate (271A-5)

[1643] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (49.9 mg, 223 mol, 1.2 eq) in DCM (2.0 mL) were added TEA (56.5 mg, 558 mol, 77.7 L, 3.0 eq), EDCI (53.5 mg, 279 mol, 1.5 eq), HOBt (37.7 mg, 279 mol, 1.5 eq) and tert-butyl 4-(1-aminocyclopropyl)-9H-carbazole-9-carboxylate (60.0 mg, 186 mol, 1.0 eq). The mixture was stirred at 20 C. for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.4). tert-Butyl 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl)-9H-carbazole-9-carboxylate (30.0 mg, 56.9 mol, 31% yield) was obtained as a white solid. M+H.sup.+=528.2 (LCMS).

Step 5: N-(1-(9H-Carbazol-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenz amide (Compound 415)

[1644] To a solution of tert-butyl 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl)-9H-carbazole-9-carboxylate (30.0 mg, 56.9 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(9H-Carbazol-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (6.50 mg, 15.2 mol, 27% yield, HCl salt) was obtained as a white solid. M+H.sup.+=428.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.32 (s, 1H), 10.14-10.03 (m, 1H), 8.96 (s, 1H), 8.62 (d, J=7.9 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.50-7.46 (m, 1H), 7.42-7.36 (m, 2H), 7.34-7.29 (m, 1H), 7.16 (t, J=7.3 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.90-6.85 (m, 1H), 6.62 (d, J=2.6 Hz, 1H), 4.15 (br t, J=4.8 Hz, 2H), 3.42-3.36 (m, 2H), 2.78-2.73 (m, 6H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.23 (br s, 2H).

Example 272: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 417)

##STR01116##

Step 1: 7-((tert-Butyldimethylsilyl)oxy)-1-naphthonitrile (272A-2)

[1645] To a solution of 7-hydroxy-1-naphthonitrile (500 mg, 2.96 mmol, 1.0 eq) in DMF (5.0 mL) were added TBSCl (535 mg, 3.55 mmol, 435 L, 1.2 eq) and imidazole (402 mg, 5.91 mmol, 2.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL4). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 7-((tert-Butyldimethylsilyl)oxy)-1-naphthonitrile (770 mg, 2.72 mmol, 92% yield) was obtained as a yellow gum. M+H.sup.+=284.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.00 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.1 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.21 (dd, J=2.3, 8.8 Hz, 1H), 1.04 (s, 9H), 0.31 (s, 6H).

Step 2: 1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (272A-3)

[1646] A mixture of 7-((tert-butyldimethylsilyl)oxy)-1-naphthonitrile (300 mg, 1.06 mmol, 1.0 eq) in Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (451 mg, 1.59 mmol, 469 L, 1.5 eq) slowly at 78 C. and then EtMgBr (3 M in Et.sub.2O, 776 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. Then BF.sub.3.Math.Et.sub.2O (300 mg, 2.12 mmol, 261 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (220 mg, 702 mol, 66% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.75 (br d, J=8.9 Hz, 2H), 7.68 (br d, J=7.0 Hz, 1H), 7.60 (s, 1H), 7.32-7.28 (m, 1H), 7.10 (dd, J=1.8, 8.8 Hz, 1H), 1.10 (s, 2H), 1.05-0.76 (m, 11H), 0.24 (s, 6H). [1647] Step 3: N-(1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (272A-4)

[1648] To a solution of 1-(7-((tert-butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (220 mg, 702 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (157 mg, 702 mol, 1.0 eq) in DMF (10 mL) were added TEA (213 mg, 2.11 mmol, 293 L, 3.0 eq), EDCI (161 mg, 842 mol, 1.2 eq) and HOBt (114 mg, 842 mol, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL5). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. N-(1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (140 mg, 270 mol, 38% yield) was obtained as a yellow gum.

Step 4: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 417)

[1649] To a solution of N-(1-(7-((tert-butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (130 mg, 251 mol, 1.0 eq) in THF (10 mL) was added TBAF (1 M in THF, 752 L, 3.0 eq) at 0 C. The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL5), concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-hydroxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (17.9 mg, 40.6 mol, 16% yield, HCl salt) was obtained as a brown solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.08-9.89 (m, 1H), 9.77-9.51 (m, 1H), 9.05 (s, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.79-7.61 (m, 3H), 7.27-7.04 (m, 3H), 6.90 (dd, J=2.7, 8.3 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.25 (br t, J=4.9 Hz, 2H), 3.44 (q, J=5.0 Hz, 2H), 2.80 (d, J=4.9 Hz, 6H), 2.00 (s, 3H), 1.32 (br s, 2H), 1.12 (br s, 2H).

Example 273: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 408)

##STR01117##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 408)

[1650] To a solution of EtSH (5.04 g, 81.1 mmol, 6.0 mL, 67.9 eq) in DCM (25 mL) was added AlCl.sub.3 (956 mg, 7.17 mmol, 392 L, 6.0 eq) at 0 C., then 5-(2-(dimethylamino)ethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (500 mg, 1.19 mmol, 1.0 eq) in DCM (5.0 mL) was added at 0 C. dropwise. The resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. The resulting mixture was stirred at the same temperature for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (20040 mm, 10 m); flow rate: 50 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methyl benzamide (250 mg, 535 mol, 45% yield) was obtained as a brown gum. M+H.sup.+=449.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.09 (s, 1H), 8.58 (dd, J=3.4, 6.2 Hz, 1H), 8.19 (s, 1H), 7.94-7.79 (m, 1H), 7.75-7.66 (m, 2H), 7.56-7.39 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.6, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.97 (t, J=5.7 Hz, 2H), 3.10 (q, J=7.3 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.23 (s, 6H), 1.97 (s, 3H), 1.39-1.28 (m, 5H), 1.18 (br s, 2H).

Example 274: (S)N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 419)

##STR01118##

Step 1: (S)-tert-Butyl 2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (274A-1)

[1651] To a solution of 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (63.6 mg, 298 mol, 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (100 mg, 298 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (90.5 mg, 894 mol, 125 L, 3.0 eq), EDCI (143 mg, 745 mol, 2.5 eq) and HOBt (101 mg, 745 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/10 to 1/2. (S)-tert-Butyl 2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) pyrrolidine-1-carboxylate (150 mg, 283 mol, 95% yield) was obtained as a colorless oil. M+H.sup.+=531.3 (LCMS).

Step 2: (S)N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 419)

[1652] To a solution of(S)-tert-butyl 2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (150 mg, 283 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(3-Methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (80.3 mg, 172 mol, 61% yield, HCl salt) was obtained as a white solid. M+H.sup.+=431.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.55 (br d, J=4.0 Hz, 1H), 9.14 (s, 1H), 8.97 (br d, J=3.9 Hz, 1H), 8.54 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.51-7.35 (m, 3H), 7.24 (d, J=2.3 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (dd, J=2.6, 8.4 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 4.20-4.11 (m, 1H), 4.09-4.00 (m, 1H), 3.87 (s, 4H), 3.23-3.11 (m, 2H), 2.12-2.01 (m, 1H), 1.99-1.96 (m, 3H), 1.95-1.82 (m, 2H), 1.72-1.61 (m, 1H), 1.33 (br s, 2H), 1.16 (br s, 2H).

Example 275: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 420)

##STR01119##

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 420)

[1653] To a solution of 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (50.0 mg, 93.2 mol, 1.0 eq) and thiophen-2-ylboronic acid (14.3 mg, 112 mol, 1.2 eq) in DMSO (5.0 mL) were added Pd(OAc) 2 (2.09 mg, 9.32 mol, 0.1 eq), KOAc (27.4 mg, 280 mol, 3.0 eq) and bis(1-adamantyl)-butyl-phosphane (6.68 mg, 18.6 mol, 0.2 eq). The mixture was degassed and purged with N.sub.2 three times, and then the mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 25%-55% B over 10 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (7.10 mg, 14.0 mol, 15% yield, HCl salt) was obtained as a white solid. M+H.sup.+=371.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.16-10.05 (m, 1H), 9.19 (s, 1H), 8.66-8.58 (m, 1H), 8.14-8.07 (m, 2H), 8.03-7.95 (m, 1H), 7.68-7.65 (m, 1H), 7.63 (d, J=5.0 Hz, 1H), 7.60-7.50 (m, 2H), 7.21 (dd, J=3.7, 5.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.6, 8.3 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.24 (t, J=4.8 Hz, 2H), 3.47-3.39 (m, 2H), 2.79 (d, J=4.9 Hz, 6H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H).

Example 276: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl)benzamide (Compound 459)

##STR01120##

Step 1: (E)-2-Methyl-N-(naphthalen-1-ylmethylene) propane-2-sulfinamide (276A-1)

[1654] To a mixture of naphthalene-1-carbaldehyde (2.00 g, 12.8 mmol, 1.74 mL, 1.0 eq) and 2-methylpropane-2-sulfinamide (2.33 g, 19.2 mmol, 1.5 eq) in THF (80 mL) was added Ti(OEt).sub.4 (5.26 g, 23.0 mmol, 4.78 mL, 1.8 eq) at 25 C., the reaction mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (50 ml) and the mixture was filtered. The filtrate was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 3/1. (E)-2-Methyl-N-(1-naphthylmethylene) propane-2-sulfinamide (3.00 g, 11.6 mmol, 90% yield) was obtained as a yellow oil. M+H.sup.+=260.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.12 (s, 1H), 9.03 (d, J=8.4 Hz, 1H), 8.16-8.07 (m, 2H), 8.01 (d, J=7.6 Hz, 1H), 7.74-7.56 (m, 3H), 1.33 (s, 9H).

Step 2: 2-Methyl-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl) propane-2-sulfinamide (276A-2)

[1655] To a mixture of (E)-2-methyl-N-(1-naphthylmethylene) propane-2-sulfinamide (3.00 g, 11.6 mmol, 1.0 eq) in THF (60 mL) was added bromo (ethynyl)magnesium (0.5 M in THF, 46.3 mL, 2.0 eq) at 0 C. The reaction mixture was stirred at 25 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (100 mL3). The combined organic layers were concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/1. 2-Methyl-N-[1-(1-naphthyl) prop-2-ynyl]propane-2-sulfinamide (1.00 g, 3.50 mmol, 30% yield) was obtained as a brown oil. M+H.sup.+=286.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.24 (d, J=8.0 Hz, 1H), 7.99-7.84 (m, 4H), 7.65-7.47 (m, 4H), 5.92 (dd, J=2.0, 6.8 Hz, 1H), 2.75 (d, J=2.4 Hz, 1H), 1.22 (s, 9H).

Step 3: 1-(Naphthalen-1-yl) prop-2-yn-1-amine (276A-3)

[1656] To a mixture of 2-methyl-N-[1-(1-naphthyl) prop-2-ynyl]propane-2-sulfinamide (500 mg, 1.75 mmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a crude product 1-(1-naphthyl) prop-2-yn-1-amine (250 mg, HCl salt) as a brown solid. M+H.sup.+=182.2 (LCMS).

Step 4: 2-Methyl-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl)-5-nitrobenzamide (276A-4)

[1657] To a solution of 1-(1-naphthyl) prop-2-yn-1-amine (100 mg, 459 mol, 1.0 eq, HCl salt) and 2-methyl-5-nitro-benzoic acid (83.2 mg, 459 mol, 1.0 eq) in DMF (2.0 mL) were added HATU (262 mg, 689 mol, 1.5 eq) and DIEA (178 mg, 1.38 mmol, 240 L, 3.0 eq) at 25 C., the reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (50 ml) and the mixture was filtered. The filter cake was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.2). 2-Methyl-N-[1-(1-naphthyl) prop-2-ynyl]-5-nitro-benzamide (60.0 mg, 174 mol, 38% yield) was obtained as a white solid. M+H.sup.+=182.2 (LCMS).

Step 5: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl)benzamide (Compound 459)

[1658] To a mixture of 2-methyl-N-[1-(1-naphthyl) prop-2-ynyl]-5-nitro-benzamide (45.0 mg, 130 mol, 1.0 eq) in a mixture of THF (600 L), EtOH (600 L) and H.sub.2O (200 L) were added Fe (36.5 mg, 653 mol, 5.0 eq) and NH.sub.4Cl (34.9 mg, 653 mol, 5.0 eq) at 25 C. The reaction mixture was stirred at 80 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-[1-(1-naphthyl) prop-2-ynyl]benzamide (9.80 mg, 31.2 mol, 24% yield) was obtained as a brown solid. M+H.sup.+=315.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.12 (d, J=8.4 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.81 (dd, J=8.4, 12.0 Hz, 2H), 7.55-7.37 (m, 3H), 6.88 (d, J=8.0 Hz, 1H), 6.81-6.72 (m, 1H), 6.63-6.52 (m, 2H), 6.23-5.98 (m, 1H), 2.55 (d, J=2.4 Hz, 1H), 2.22 (s, 3H).

Example 277: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl)benzamide (Compound 448)

##STR01121##

Step 1: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl) prop-2-yn-1-yl)benzamide (Compound 448)

[1659] To a mixture of 1-(1-naphthyl) prop-2-yn-1-amine (50.0 mg, 229 mol, 1.0 eq, HCl salt) and 2-methyl-5-[(1-methylazetidin-2-yl)methoxy]benzoic acid (54.0 mg, 229 mol, 1.0 eq) in DMF (1.0 mL) were added DIEA (89.1 mg, 689 mol, 120 L, 3.0 eq) and HATU (131 mg, 345 mol, 1.5 eq) at 25 C., the reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-[(1-methylazetidin-2-yl)methoxy]-N-[1-(1-naphthyl) prop-2-ynyl]benzamide (34.7 mg, 84.1 mol, 37% yield) was obtained as a brown solid. M+H.sup.+=399.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.13 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.86-7.76 (m, 2H), 7.55-7.38 (m, 3H), 6.99 (d, J=8.4 Hz, 1H), 6.83-6.69 (m, 3H), 6.09 (br d, J=8.8 Hz, 1H), 3.87-3.77 (m, 2H), 3.33 (quin, J=5.6 Hz, 1H), 3.27-3.18 (m, 1H), 2.74 (q, J=8.2 Hz, 1H), 2.56 (d, J=2.4 Hz, 1H), 2.28 (d, J=3.6 Hz, 3H), 2.26 (d, J=2.0 Hz, 3H), 1.99-1.86 (m, 2H).

Example 278: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)azetidin-3-yl)benzamide (Compound 453)

##STR01122##

Step 1: tert-Butyl 3-hydroxy-3-(naphthalen-1-yl)azetidine-1-carboxylate (278A-1)

[1660] To a solution of 1-bromonaphthalene (5.00 g, 24.2 mmol, 3.36 mL, 1.0 eq) in THF (30 mL) was added n-BuLi (2.5 M in hexane, 29.0 mL, 3.0 eq) dropwise at 78 C. under a N.sub.2 atmosphere. The mixture was stirred at 78 C. for 1 h. To the mixture was added dropwise the solution of tert-butyl 3-oxoazetidine-1-carboxylate (6.20 g, 36.2 mmol, 1.5 eq) in THF (30 mL) at 78 C. The mixture was stirred at 78 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (40 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl 3-hydroxy-3-(naphthalen-1-yl)azetidine-1-carboxylate (3.80 g, 8.89 mmol, 37% yield) was obtained as a yellow oil. M56+H.sup.+=244.0 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00-7.86 (m, 3H), 7.63-7.43 (m, 4H), 4.46 (d, J=9.1 Hz, 2H), 4.33-4.15 (m, 2H), 1.37 (s, 9H).

Step 2: tert-Butyl 3-chloro-3-(naphthalen-1-yl)azetidine-1-carboxylate (278A-2)

[1661] To a solution of tert-butyl 3-hydroxy-3-(naphthalen-1-yl)azetidine-1-carboxylate (1.00 g, 3.34 mmol, 1.0 eq) in DCM (10 mL) was added TEA (676 mg, 6.68 mmol, 930 L, 2.0 eq), followed by MsCl (765 mg, 6.68 mmol, 517 L, 2.0 eq) dropwise at 0 C. The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. tert-Butyl 3-chloro-3-(naphthalen-1-yl)azetidine-1-carboxylate (520 mg, 1.64 mmol, 50% yield) was obtained as a colourless oil. M56+H.sup.+=262.1 (LCMS).

Step 3: tert-Butyl 3-azido-3-(naphthalen-1-yl)azetidine-1-carboxylate (278A-3)

[1662] To a solution of tert-butyl 3-chloro-3-(naphthalen-1-yl)azetidine-1-carboxylate (500 mg, 1.57 mmol, 1.0 eq) in DMF (6.0 mL) was added NaN.sub.3 (205 mg, 3.15 mmol, 2.0 eq) in portions at 0 C. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using pure DCM. tert-Butyl 3-azido-3-(naphthalen-1-yl)azetidine-1-carboxylate (400 mg, 1.23 mmol, 78% yield) was obtained as a yellow oil. M56+H.sup.+=269.1 (LCMS).

Step 4: tert-Butyl 3-amino-3-(naphthalen-1-yl)azetidine-1-carboxylate (278A-4)

[1663] To a solution of tert-butyl 3-azido-3-(naphthalen-1-yl)azetidine-1-carboxylate (400 mg, 1.23 mmol, 1.0 eq) in TFE (6.0 mL) was added 10% palladium on carbon (40.0 mg) under a N.sub.2 atmosphere. The resulting mixture was stirred at 20 C. under a H.sub.2 (15 psi) atmosphere for 2 h.

[1664] LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give the crude product tert-butyl 3-amino-3-(naphthalen-1-yl)azetidine-1-carboxylate (330 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=299.2 (LCMS).

Step 5: tert-Butyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methyl benzamido)-3-(naphthalen-1-yl)azetidine-1-carboxylate (278A-5)

[1665] To a solution of tert-butyl 3-amino-3-(naphthalen-1-yl)azetidine-1-carboxylate (150 mg, 503 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (171 mg, 553 mol, 1.1 eq) in DMF (1.0 mL) were added HATU (287 mg, 754 mol, 1.5 eq) and DIEA (195 mg, 1.51 mmol, 263 L, 3.0 eq). The mixture was stirred at 20 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude tert-butyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzamido)-3-(naphthalen-1-yl)azetidine-1-carboxylate (160 mg, 271 mol, 54% yield) as a yellow oil. M+H.sup.+=590.6 (LCMS).

Step 6: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)azetidin-3-yl)benzamide (Compound 453)

[1666] To a solution of tert-butyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methyl benzamido)-3-(naphthalen-1-yl)azetidine-1-carboxylate (160 mg, 244 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (1.06 g, 9.26 mmol, 686 L, 38 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)azetidin-3-yl)benzamide (86.4 mg, 222 mol, 91% yield, TFA salt) was obtained as a white solid. M+H.sup.+=390.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.65 (s, 1H), 9.58-9.44 (m, 1H), 9.01-8.84 (m, 1H), 8.63 (br s, 2H), 8.06-8.01 (m, 1H), 7.96 (br d, J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.80 (br d, J=7.1 Hz, 1H), 7.63-7.55 (m, 3H), 7.13 (d, J=8.6 Hz, 1H), 6.94 (dd, J=2.2, 8.3 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 4.84 (br s, 2H), 4.79-4.67 (m, 2H), 4.12 (br t, J=4.6 Hz, 2H), 3.29 (br s, 2H), 2.61 (br s, 3H), 2.06 (s, 3H).

Example 279: 2-Methyl-N-(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)-5-(2-(methylamino)ethoxy)benzamide (Compound 499)

##STR01123## ##STR01124##

Step 1: tert-Butyl 3-(((benzyloxy) carbonyl)amino)-3-(naphthalen-1-yl)azetidine-1-carboxylate (279A-1)

[1667] To a solution of tert-butyl 3-amino-3-(naphthalen-1-yl)azetidine-1-carboxylate (180 mg, 603 mol, 1.0 eq) in DCM (1.0 mL) were added DIEA (85.8 mg, 664 mol, 116 L, 1.1 eq) and Cb.sub.2Cl (226 mg, 1.33 mmol, 189 UL, 2.2 eq) at 0 C. The mixture was stirred at 20 C. for 2 h.

[1668] LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/5, R.sub.f=0.5). tert-Butyl 3-(((benzyloxy) carbonyl)amino)-3-(naphthalen-1-yl)azetidine-1-carboxylate (80.0 mg, 185 mol, 31% yield) was obtained as a yellow oil. M+H.sup.+=433.3 (LCMS).

Step 2: Benzyl(3-(naphthalen-1-yl)azetidin-3-yl)carbamate (279A-2)

[1669] To a solution of tert-butyl 3-(((benzyloxy) carbonyl)amino)-3-(naphthalen-1-yl)azetidine-1-carboxylate (80.0 mg, 166 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude product benzyl(3-(naphthalen-1-yl)azetidin-3-yl)carbamate (50.0 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=333.1 (LCMS).

Step 3: Benzyl(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamate (279A-3)

[1670] To a solution of benzyl(3-(naphthalen-1-yl)azetidin-3-yl)carbamate (50.0 mg, 150 mol, 1.0 eq) in MeOH (1.0 mL) was added formaldehyde (6.77 mg, 226 mol, 6.22 L, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (56.7 mg, 903 mol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/10, R.sub.f=0.3). Benzyl(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamate (50.0 mg, 144 mol, 96% yield) was obtained as a white solid. M+H.sup.+=347.2 (LCMS).

Step 4: 1-Methyl-3-(naphthalen-1-yl)azetidin-3-amine (279A-4)

[1671] To a solution of benzyl(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamate (50.0 mg, 130 mol, 1.0 eq) in DCM (500 L) was added TMSI (130 mg, 450 mol, 8.4 L, 5.0 eq) in portions at 0 C. The resulting mixture was stirred at 20 C. for 8 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was poured into saturated aqueous NH.sub.4Cl (5.0 mL) and extracted with DCM (10 mL3). But the desired compound was hydrophilic. The aqueous layer was lyophilized to give the crude product 1-methyl-3-(naphthalen-1-yl)azetidin-3-amine (25.0 mg), which was used in the next step without any further purification. M+H.sup.+=213.1 (LCMS).

Step 5: tert-Butylmethyl(2-(4-methyl-3-((1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamoyl)phenoxy)ethyl)carbamate (279A-5)

[1672] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (32.1 mg, 104 mol, 1.1 eq) in acetonitrile (1.0 mL) were added TCFH (31.7 mg, 113 mol, 1.2 eq), 1-methylimidazole (23.2 mg, 283 mol, 22.5 L, 3.0 eq) and 1-methyl-3-(naphthalen-1-yl)azetidin-3-amine (20.0 mg, 94.2 mol, 1.0 eq). The resulting mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (5.0 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.5). tert-Butylmethyl(2-(4-methyl-3-((1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamoyl) phenoxy)ethyl)carbamate (40.0 mg, 79.4 mol, 84% yield) was obtained as a yellow oil. M+H.sup.+=504.3 (LCMS).

Step 6: 2-Methyl-N-(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)-5-(2-(methylamino)ethoxy)benzamide (Compound 499)

[1673] To a solution of tert-butylmethyl(2-(4-methyl-3-((1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)carbamoyl)phenoxy)ethyl)carbamate (35.0 mg, 62.6 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (875 L) at 0 C. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m)); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-N-(1-methyl-3-(naphthalen-1-yl)azetidin-3-yl)-5-(2-(methylamino)ethoxy)benzamide (7.50 mg, 18.0 mol, 29% yield, TFA salt) was obtained as a white solid. M+H.sup.+=404.1 (LCMS), .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.40 (br s, 1H), 8.81-8.34 (m, 1H), 8.05-7.99 (m, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.90-7.83 (m, 1H), 7.74 (br s, 1H), 7.60-7.55 (m, 3H), 7.12 (d, J=8.4 Hz, 1H), 6.94 (dd, J=2.8, 8.4 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 5.17-4.69 (m, 4H), 4.16 (t, J=5.2 Hz, 2H), 3.29 (t, J=5.2 Hz, 2H), 2.95 (br s, 3H), 2.64 (s, 3H), 2.07 (s, 3H).

Example 280: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 451)

##STR01125##

Step 1: 5-Hydroxy-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (280A-1)

[1674] To a solution of 3-(naphthalen-1-yl)oxetan-3-amine (250 mg, 1.25 mmol, 0.80 eq) and 5-hydroxy-2-methylbenzoic acid (239 mg, 1.57 mmol, 1.0 eq) in DMF (8.0 mL) were added TEA (159 mg, 1.57 mmol, 218 L, 1.0 eq), EDCI (316 mg, 1.65 mmol, 1.0 eq) and HOBt (42.4 mg, 314 mol, 0.20 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Hydroxy-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benz amide (80.0 mg, 216 mol, 14% yield, HCl salt) was obtained as a white solid. M+H.sup.+=334.1 (LCMS).

Step 2: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (Compound 451)

[1675] To a solution of 5-hydroxy-2-methyl-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (70.0 mg, 210 mol, 1.0 eq) and 2-(methylamino)ethanol (15.8 mg, 210 mol, 16.9 L, 1.0 eq) in toluene (6.0 mL) were added TMAD (108 mg, 630 mol, 3.0 eq) and PPh.sub.3 (165 mg, 630 mol, 3.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(3-(naphthalen-1-yl)oxetan-3-yl)benzamide (6.00 mg, 15.4 mol, 7% yield, HCl salt) was obtained as a white solid. M+H.sup.+=391.1 (LCMS); 1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.01-7.96 (m, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.78 (br d, J=6.6 Hz, 2H), 7.57-7.49 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.6, 8.3 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 5.28-5.18 (m, 4H), 3.91 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.29 (s, 3H), 1.93 (s, 3H).

Example 281: N-(3-(3-Methoxynaphthalen-1-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 450)

##STR01126##

Step 1: N-(3-(3-Methoxynaphthalen-1-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (281A-2)

[1676] To a solution of 1-bromo-3-methoxynaphthalene (500 mg, 2.11 mmol, 1.0 eq) in THF (5.0 mL) was added n-BuLi (2.5 M in hexane, 1.01 mL, 1.2 eq) dropwise at 78 C. under a N.sub.2 atmosphere, the resulting mixture was stirred at 78 C. for 1 h, then a solution of 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (554 mg, 3.16 mmol, 1.5 eq) in THF (5.0 mL) was added dropwise at 78 C. The mixture was stirred at 78 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by addition of saturated aqueous NH.sub.4Cl (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. N-(3-(3-Methoxynaphthalen-1-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (252 mg, 740 mol, 35% yield) was obtained as a yellow oil. M+H.sup.+=334.2 (LCMS).

Step 2:3-(3-Methoxynaphthalen-1-yl)oxetan-3-amine (281A-3)

[1677] To a solution of N-(3-(3-methoxynaphthalen-1-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (252 mg, 756 mol, 1.0 eq) in MeOH (3.0 mL) was added HCl/dioxane (4 M, 1.51 mL, 8.0 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a crude product 3-(3-methoxynaphthalen-1-yl)oxetan-3-amine (200 mg, HCl salt) as a yellow solid. M+H.sup.+=230.2 (LCMS).

Step 3: N-(3-(3-Methoxynaphthalen-1-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 450)

[1678] To a solution of 3-(3-methoxynaphthalen-1-yl)oxetan-3-amine (40.0 mg, 151 mol, 1.0 eq, HCl salt) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (40.9 mg, 151 mol, 1.0 eq, HCl salt) in DMF (2.0 mL) were added HBTU (143 mg, 376 mol, 2.5 eq) and DIEA (97.3 mg, 753 mol, 131 L, 5.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 50 mL/min; gradient: 15%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(3-(3-Methoxynaphthalen-1-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (5.60 mg, 12.5 mol, 8% yield) was obtained as an off-white gum. M+H.sup.+==447.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.85 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 1H), 7.27-7.21 (m, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.89-6.80 (m, 1H), 6.69 (d, J=2.6 Hz, 1H), 5.57-5.11 (m, 4H), 3.98-3.85 (m, 5H), 3.54-3.35 (m, 2H), 2.99-2.89 (m, 1H), 2.47-2.32 (m, 3H), 2.15-1.91 (m, 5H).

Example 282: 5-(2-Acetamidoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 425)

##STR01127##

Step 1: 5-(2-Acetamidoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 425)

[1679] To a solution of 5-(2-aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 277 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (112 mg, 1.11 mmol, 154 L, 4.0 eq) and acetic anhydride (56.6 mg, 555 mol, 52.0 L, 2.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (5-(2-Acetamidoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (21.2 mg, 52.4 mol, 19% yield) was obtained as a white solid. M+H.sup.+=403.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.66 (br d, J=8.3 Hz, 1H), 8.06 (br s, 1H), 7.93 (br d, J=7.6 Hz, 1H), 7.86-7.77 (m, 2H), 7.61-7.41 (m, 3H), 7.03 (br d, J=7.9 Hz, 1H), 6.99-6.99 (m, 1H), 6.83 (br d, J=7.8 Hz, 1H), 6.62 (br s, 1H), 3.87 (br s, 2H), 3.34 (br d, J=5.0 Hz, 2H), 1.96 (s, 3H), 1.80 (s, 3H), 1.35 (br s, 2H), 1.23-1.07 (m, 2H).

Example 283: 2-Methyl-5-(2-(methylsulfonamido) ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 424)

##STR01128##

Step 1: 2-Methyl-5-(2-(methylsulfonamido) ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 424)

[1680] To a solution of 5-(2-aminoethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 277 mol, 1.0 eq) in DCM (4.0 mL) were added TEA (28.1 mg, 277 mol, 38.6 L, 1.0 eq) and MsCl (25.4 mg, 222 mol, 17.2 L, 0.8 eq) at 0 C. The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 45%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylsulfonamido) ethoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (37.2 mg, 84.8 mol, 30% yield, HCl salt) was obtained as a white solid. M+H.sup.+=439.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.81 (t, J=7.8 Hz, 2H), 7.62-7.42 (m, 3H), 7.25 (t, J=5.9 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.7, 8.3 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 3.93 (t, J=5.5 Hz, 2H), 3.29-3.23 (m, 2H), 2.91 (s, 3H), 1.95 (s, 3H), 1.35 (s, 2H), 1.20-1.13 (m, 2H).

Example 284: 5-(((2R,4S)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 439)

##STR01129##

Step 1: 5-(((2R,4S)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 439)

[1681] To a solution of (5-(((2R,4S)-4-hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (60.0 mg, 144 mol, 1.0 eq) in MeOH (6.0 mL) was added TEA (20 L), followed by the addition of formaldehyde (16.1 L, 216 mol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (54.3 mg, 864 mol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4S)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (35.6 mg, 81.6 mol, 57% yield) was obtained as a white solid. M+H.sup.+=431.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.21 (br d, J=5.1 Hz, 1H), 9.10 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.83 (t, J=6.6 Hz, 2H), 7.59-7.44 (m, 3H), 7.08 (d, J=8.6 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 5.66-5.48 (m, 1H), 4.46-4.34 (m, 1H), 4.32-4.23 (m, 1H), 4.18 (dd, J=7.6, 10.9 Hz, 1H), 4.00-3.88 (m, 1H), 3.69 (td, J=5.9, 11.5 Hz, 1H), 3.08-3.00 (m, 1H), 2.96 (d, J=4.8 Hz, 3H), 2.14-2.07 (m, 1H), 1.99-1.91 (m, 4H), 1.36 (br s, 2H), 1.20-1.15 (m, 2H).

Example 285: 5-(((2R,4R)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 440)

##STR01130##

Step 1: 5-(((2R,4R)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 440)

[1682] To a solution of 5-(((2R,4R)-4-hydroxypyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 360 mol, 1.0 eq) in MeOH (2.0 mL) was added TEA (50 L), followed by the addition of formaldehyde (40.2 L, 540 mol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (136 mg, 2.16 mmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4R)-4-Hydroxy-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (86.5 mg, 201 mol, 56% yield, HCl salt) was obtained as a white solid. M+H.sup.+=431.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.10 (br d, J=5.1 Hz, 1H), 9.10 (s, 1H), 8.66 (br d, J=7.8 Hz, 1H), 7.93 (br d, J=7.8 Hz, 1H), 7.83 (br t, J=6.9 Hz, 2H), 7.62-7.42 (m, 3H), 7.08 (br d, J=8.1 Hz, 1H), 6.95-6.85 (m, 1H), 6.69 (br s, 1H), 5.55 (br s, 1H), 4.41 (br s, 1H), 4.30-4.21 (m, 1H), 4.20-4.11 (m, 1H), 3.89-3.75 (m, 1H), 3.46-3.36 (m, 2H), 3.21-3.16 (m, 1H), 2.91 (br d, J=2.3 Hz, 3H), 1.96 (s, 3H), 1.73-1.62 (m, 1H), 1.36 (br s, 2H), 1.19 (br s, 2H).

Example 286: 5-(((2R,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 438)

##STR01131##

Step 1: (2R,4R)-tert-Butyl 4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (286A-1)

[1683] A solution of (2R,4S)-tert-butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (130 mg, 352 mol, 1.0 eq) in DCM (2.0 mL) was degassed and purged with N.sub.2 three times. To this solution was added DAST (101 mg, 629 mol, 83.1 L, 2.5 eq) dropwise at 78 C. The mixture was warmed to room temperature and stirred under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude (2R,4R)-tert-butyl 4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (120 mg, 231 mol, 92% yield) as a white solid, which was used in the next step without any further purification. M+H.sup.+=519.3 (LCMS).

Step 2: 5-(((2R,4R)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 438)

[1684] To a solution of (2R,4R)-tert-butyl 4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (120 mg, 208 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.6 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (16.2 mg, 37.0 mol, 18% yield, HCl salt) was obtained as a white solid. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.08-9.85 (m, 1H), 9.47-9.25 (m, 1H), 9.12 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.83 (t, J=6.6 Hz, 2H), 7.61-7.43 (m, 3H), 7.08 (d, J=8.5 Hz, 1H), 6.89 (dd, J=2.8, 8.3 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 5.58-5.31 (m, 1H), 4.25-4.13 (m, 1H), 4.08-3.93 (m, 2H), 3.63-3.47 (m, 1H), 3.47-3.35 (m, 1H), 2.63-2.54 (m, 1H), 2.10-1.99 (m, 1H), 1.97 (s, 3H), 1.36 (s, 2H), 1.22-1.13 (m, 2H).

Example 287: 5-(((2R,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 437)

##STR01132##

Step 1: 5-(((2R,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalene-1-yl)cyclopropyl)benzamide (Compound 437)

[1685] To a solution of 5-(((2R,4R)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 95.6 mol, 1.0 eq) in MeOH (6.0 mL) was added TEA (13 L), followed by the addition of formaldehyde (10.7 L, 143 mol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (36.0 mg, 573 mol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalene-1-yl)cyclopropyl)benzamide (15.3 mg, 34.1 mol, 36% yield) was obtained as a white solid. M+H.sup.+=433.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.55-10.26 (m, 1H), 9.10 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.87-7.79 (m, 2H), 7.60-7.43 (m, 3H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.70 (br d, J=2.4 Hz, 1H), 5.59-5.30 (m, 1H), 4.36-4.23 (m, 1H), 4.15 (br d, J=9.8 Hz, 1H), 3.99-3.75 (m, 2H), 3.55-3.39 (m, 1H), 2.96 (br s, 3H), 2.82-2.72 (m, 1H), 2.14-1.98 (m, 1H), 1.96 (s, 3H), 1.36 (s, 2H), 1.18 (br s, 2H).

Example 288: 5-(((2R,4S)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 442)

##STR01133##

Step 1: (2R,4S)-tert-Butyl4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (288A-1)

[1686] A solution of (2R,4R)-tert-butyl 4-hydroxy-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (400 mg, 774 mol, 1.0 eq) in DCM (10 mL) was degassed and purged with N.sub.2 three times. To this solution was added DAST (312 mg, 1.94 mmol, 256 L, 2.5 eq) dropwise at 78 C. The mixture was warmed to 20 C. and stirred another 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude (2R,4S)-tert-butyl 4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (350 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=519.2 (LCMS).

Step 2: 5-(((2R,4S)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 442)

[1687] To a solution of (2R,4S)-tert-butyl 4-fluoro-2-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (350 mg, 675 mol, 1.0 eq) in EtOAc (7.0 mL) was added HCl/EtOAc (4 M, 14 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4S)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300 mg, 659 mol, 98% yield, HCl salt) was obtained as a white solid. M+H.sup.+=419.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.98 (br d, J=2.2 Hz, 1H), 9.68-9.40 (m, 1H), 9.18-9.12 (m, 1H), 8.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.87-7.78 (m, 2H), 7.62-7.44 (m, 3H), 7.11-7.05 (m, 1H), 6.92-6.86 (m, 1H), 6.67 (d, J=2.6 Hz, 1H), 5.65-5.30 (m, 1H), 4.28-4.00 (m, 3H), 3.47 (br d, J=8.6 Hz, 2H), 2.47-2.18 (m, 2H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.23-1.13 (m, 2H).

Example 289: 5-(((2R,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 441)

##STR01134##

Step 1: 5-(((2R,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 441)

[1688] To a solution of 5-(((2R,4S)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (240 mg, 573 mol, 1.0 eq) in MeOH (9.0 mL) was added TEA (80.0 L), followed by the addition of HCHO (93.1 mg, 1.15 mmol, 85.4 L, 37% purity in water, 2.0 eq). The resulting mixture was treated with a small amount of AcOH (34.4 mg, 573 mol, 32.8 L, 1.0 eq) to adjust the pH to 6. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (72.1 mg, 1.15 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2R,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-methyl-N-(1-(naphthaalen-1-yl)cyclopropyl)benzamide (72.7 mg, 144 mol, 25% yield, HCl salt) was obtained as a white solid. M+H.sup.+=433.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.43-11.24 (m, 1H), 9.14 (s, 1H), 8.66 (br d, J=8.3 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.86-7.77 (m, 2H), 7.63-7.41 (m, 3H), 7.08 (d, J=8.5 Hz, 1H), 6.96-6.83 (m, 1H), 6.77-6.66 (m, 1H), 5.61-5.26 (m, 1H), 4.47-4.18 (m, 3H), 4.08-3.97 (m, 1H), 3.56-3.35 (m, 1H), 2.96 (br d, J=4.8 Hz, 3H), 2.78-2.65 (m, 1H), 2.22-2.03 (m, 1H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.18 (br s, 2H).

Example 290: 5-((1-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 492) and 5-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 491)

##STR01135## ##STR01136##

Step 1: 2-(Benzylamino)-2-methylpropan-1-ol (290A-2)

[1689] To a solution of benzaldehyde (11.9 g, 112 mmol, 11.3 mL, 1.0 eq) and 2-amino-2-methylpropan-1-ol (10.0 g, 112 mmol, 10.7 mL, 1.0 eq) in DCM (100 mL) was added 4 molecular sieve (15.0 g). The mixture was stirred at 20 C. for 16 h. Then the mixture was filtered through a pad of cotton and concentrated under vacuum to give a residue. To this residue was added MeOH (50 mL), followed by NaBH.sub.4 (5.09 g, 135 mmol, 1.2 eq) at 0 C. After the addition, the mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(Benzylamino)-2-methylpropan-1-ol (3.00 g, 16.7 mmol, 15% yield) was obtained as a white solid. M+H.sup.+=180.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.39-7.22 (m, 5H), 3.68 (s, 2H), 3.34 (s, 2H), 1.15 (s, 6H).

Step 2: 2-(Benzyl(1-hydroxy-2-methylpropan-2-yl)amino) acetonitrile (290A-3)

[1690] To a solution of 2-(benzylamino)-2-methylpropan-1-ol (3.00 g, 16.7 mmol, 1.0 eq) in acetonitrile (50 mL) were added 2-bromoacetonitrile (5.62 g, 46.9 mmol, 3.12 mL, 2.8 eq) and K.sub.2CO.sub.3 (3.47 g, 25.1 mmol, 1.5 eq). The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (40 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(Benzyl(1-hydroxy-2-methylpropan-2-yl)amino) acetonitrile (3.50 g, 16.0 mmol, 96% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.44-7.16 (m, 5H), 4.75 (t, J=5.2 Hz, 1H), 3.81 (s, 2H), 3.52 (s, 2H), 3.42 (d, J=5.1 Hz, 2H), 1.14 (s, 6H).

Step 3: 1-Benzyl-4,4-dimethylazetidine-2-carbonitrile (290A-4)

[1691] To a solution of 2-(benzyl(1-hydroxy-2-methylpropan-2-yl)amino) acetonitrile (1.70 g, 7.79 mmol, 1.0 eq) in THF (17 mL) was added dimethyl phosphorochloridate (2.25 g, 15.6 mmol, 1.68 mL, 2.0 eq) at 20 C. under a N.sub.2 atmosphere, then KHMDS (1 M in THF, 19.5 mL, 2.5 eq) was added dropwise keeping the temperature below 15 C. The mixture was stirred at 20 C. for 1 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-Benzyl-4,4-dimethylazetidine-2-carbonitrile (640 mg, 3.20 mmol, 41% yield) was obtained as a colorless oil. M+H.sup.+=201.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.39-7.20 (m, 5H), 4.13 (dd, J=6.9, 8.1 Hz, 1H), 3.73-3.65 (m, 1H), 3.61-3.53 (m, 1H), 2.26-2.19 (m, 1H), 2.16-2.09 (m, 1H), 1.20 (d, J=8.3 Hz, 6H).

Step 4: 1-Benzyl-4,4-dimethylazetidine-2-carboxylic acid (290A-5)

[1692] To a solution of 1-benzyl-4,4-dimethylazetidine-2-carbonitrile (300 mg, 1.50 mmol, 1.0 eq) in EtOH (1.5 mL) and H.sub.2O (0.8 mL) was added NaOH (120 mg, 3.00 mmol, 2.0 eq) at room temperature. The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with MTBE (3.0 mL3). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V=10/1, 10 mL) then filtered. The filter cake was washed with MeOH/DCM (3.0 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give 1-benzyl-4,4-dimethylazetidine-2-carboxylic acid (200 mg, 912 mol, 61% yield) as a white solid. M+H.sup.+=220.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.40 (d, J=7.1 Hz, 2H), 7.32-7.17 (m, 3H), 3.86-3.70 (m, 3H), 2.06 (t, J=9.6 Hz, 1H), 2.01-1.88 (m, 1H), 1.28 (s, 3H), 1.05 (s, 3H).

Step 5: (1-Benzyl-4,4-dimethylazetidin-2-yl)methanol (290A-6)

[1693] To a solution of 1-benzyl-4,4-dimethylazetidine-2-carboxylic acid (150 mg, 684 mol, 1.0 eq) in THF (3.0 mL) was added LiAlH.sub.4 (1 M in THF, 1.37 mL, 2.0 eq) dropwise at 0 C. under a N.sub.2 atmosphere. The reaction mixture was stirred at 0 C. for 10 min, then warmed to room temperature and stirred another 15 min at this temperature. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (10 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude (1-benzyl-4,4-dimethylazetidin-2-yl)methanol (75.0 mg, 365 mol, 53% yield) as a yellow gum. M+H.sup.+=206.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.35-7.16 (m, 5H), 4.18-4.03 (m, 1H), 3.66 (d, J=13.6 Hz, 1H), 3.49 (d, J=13.5 Hz, 1H), 3.23-3.06 (m, 3H), 1.78 (dd, J=7.4, 10.1 Hz, 1H), 1.66-1.56 (m, 1H), 1.19 (s, 3H), 0.98 (s, 3H).

Step 6: 5-((1-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 492) and 5-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 491)

[1694] A mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 315 mol, 1.0 eq), (1-benzyl-4,4-dimethylazetidin-2-yl)methanol (64.7 mg, 315 mol, 1.0 eq), and CMBP (114 mg, 473 mol, 1.5 eq) in toluene (5.0 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 50%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-((1-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (16.2 mg, 31.8 mol, 10% yield) was obtained as a white solid. M+H.sup.+=505.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.82 (t, J=6.6 Hz, 2H), 7.59-7.43 (m, 3H), 7.26 (d, J=7.1 Hz, 2H), 7.13 (t, J=7.4 Hz, 2H), 7.08-7.01 (m, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.65 (dd, J=2.6, 8.4 Hz, 1H), 6.42 (d, J=2.8 Hz, 1H), 3.74-3.63 (m, 2H), 3.60-3.40 (m, 3H), 1.94 (s, 3H), 1.86 (dd, J=7.6, 10.1 Hz, 1H), 1.67 (dd, J=8.2, 9.8 Hz, 1H), 1.34 (br s, 2H), 1.23-1.13 (m, 5H), 1.00 (s, 3H). 5-((1-Benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (6.50 mg, 12.8 mol, 4% yield) was obtained as a yellow solid. M+H.sup.+=505.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04 (s, 1H), 8.63 (br d, J=7.9 Hz, 1H), 7.93 (br d, J=7.1 Hz, 1H), 7.86-7.72 (m, 2H), 7.62-7.38 (m, 3H), 7.36-7.12 (m, 5H), 6.97 (br d, J=8.3 Hz, 1H), 6.71 (br dd, J=2.1, 8.3 Hz, 1H), 6.46 (br d, J=2.1 Hz, 1H), 4.72 (br s, 1H), 3.57 (br d, J=13.0 Hz, 1H), 3.46-3.35 (m, 1H), 3.32 (s, 2H), 2.96-2.76 (m, 1H), 2.10 (br dd, J=8.0, 12.8 Hz, 1H), 1.93 (s, 3H), 1.71 (br dd, J=2.9, 13.0 Hz, 1H), 1.33 (br s, 2H), 1.16 (s, 4H), 1.05 (s, 3H).

Example 291: 5-((4,4-Dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 534)

##STR01137##

Step 1: 5-((4,4-Dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclo propyl)benzamide (Compound 534)

[1695] To a solution of 5-((1-benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (110 mg, 218 mol, 1.0 eq) in TFE (20 mL) was added 10% palladium on carbon (100 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 several times. The mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-((4,4-Dimethylazetidin-2-yl)methoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (7.20 mg, 17.4 mol, 8% yield) was obtained as a white solid. M+H.sup.+=415.1 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.66 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.82 (t, J=8.3 Hz, 2H), 7.60-7.42 (m, 3H), 7.01 (d, J=8.4 Hz, 1H), 6.81 (dd, J=2.7, 8.3 Hz, 1H), 6.59 (d, J=2.6 Hz, 1H), 3.90-3.72 (m, 3H), 2.03 (dd, J=7.9, 10.7 Hz, 1H), 1.96 (s, 3H), 1.76 (dd, J=7.3, 10.8 Hz, 1H), 1.38-1.33 (m, 2H), 1.30 (s, 3H), 1.17 (br t, J=5.4 Hz, 2H), 1.13 (s, 3H).

Example 292: 5-((5,5-Dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 533)

##STR01138##

Step 1: 5-((5,5-Dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 533)

[1696] To a solution of 5-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 198 mol, 1.0 eq) in TFE (20 mL) was added 10% palladium on carbon (100 mg) under a N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL3). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-((5,5-Dimethylpyrrolidin-3-yl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (21.8 mg, 52.2 mol, 26% yield) was obtained as a white solid. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.66 (br d, J=8.0 Hz, 1H), 7.93 (br d, J=7.9 Hz, 1H), 7.81 (br dd, J=7.7, 11.2 Hz, 2H), 7.60-7.42 (m, 3H), 7.01 (br d, J=8.6 Hz, 1H), 6.76 (br d, J=7.8 Hz, 1H), 6.51 (br s, 1H), 4.75 (br s, 1H), 3.19-3.11 (m, 1H), 2.87-2.78 (m, 1H), 1.96 (s, 3H), 1.84 (br dd, J=7.4, 13.4 Hz, 1H), 1.54 (br d, J=13.3 Hz, 1H), 1.35 (br s, 2H), 1.17 (br s, 2H), 1.12 (s, 3H), 1.06 (s, 3H).

Example 293:4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 487)

##STR01139##

Step 1: 5-Hydroxy-2-methyl-4-nitrobenzoic acid (293A-1)

[1697] A solution of 5-hydroxy-2-methylbenzoic acid (5.00 g, 32.9 mmol, 1.0 eq) in H.sub.2SO.sub.4 (50 mL, 98% purity) was cooled to 0 C. and to this mixture was added KNO.sub.3 (3.49 g, 34.5 mmol, 1.1 eq) at 0 C. The mixture was stirred at 20 C. for 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The mixture was treated with ice water (40 mL) slowly and extracted with DCM (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 5-Hydroxy-2-methyl-4-nitrobenzoic acid (640 mg, 3.25 mmol, 10% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.29-10.19 (m, 1H), 8.07-7.99 (m, 1H), 7.90-7.80 (m, 1H), 2.67-2.58 (m, 3H).

Step 2: 5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (293A-2)

[1698] To a solution of 5-hydroxy-2-methyl-4-nitrobenzoic acid (600 mg, 3.04 mmol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropanamine (502 mg, 2.74 mmol, 0.90 eq) in DMF (30 mL) were added TEA (308 mg, 3.04 mmol, 424 L, 1.0 eq), EDCI (613 mg, 3.20 mmol, 1.1 eq) and HOBt (82.3 mg, 609 mol, 0.20 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into brine (50 mL) and extracted with EtOAc (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-Hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (460 mg, 1.27 mmol, 42% yield) was obtained as a yellow solid. M+H.sup.+=363.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.41-10.24 (m, 1H), 8.48-8.40 (m, 1H), 7.96-7.89 (m, 2H), 7.86-7.80 (m, 2H), 7.64-7.44 (m, 3H), 6.93-6.89 (m, 1H), 6.53-6.44 (m, 1H), 2.14-2.09 (m, 3H), 1.63-1.57 (m, 2H), 1.47-1.40 (m, 2H).

Step 3: tert-Butyl 2-((4-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2-nitrophenoxy)methyl)azetidine-1-carboxylate (293A-3)

[1699] To a mixture of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (140 mg, 386 mol, 1.0 eq) and ter-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (72.3 mg, 386 mol, 1.0 eq) in toluene (8.0 mL) was added CMBP (933 mg, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 2-((4-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2-nitrophenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 169 mol, 44% yield) was obtained as a yellow oil. M+H.sup.+=532.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.28 (s, 1H), 8.61 (d, J=8.3 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.83 (dd, J=7.7, 11.7 Hz, 2H), 7.69 (s, 1H), 7.61-7.43 (m, 3H), 7.04 (s, 1H), 4.45-4.32 (m, 2H), 4.11 (br d, J=8.3 Hz, 1H), 3.70 (br s, 2H), 2.34-2.21 (m, 1H), 2.17-2.05 (m, 1H), 1.92 (s, 3H), 1.43-1.21 (m, 13H).

Step 4: 5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitro benzamide (293A-4)

[1700] To a solution of tert-butyl 2-((4-methyl-5-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)-2-nitrophenoxy)methyl)azetidine-1-carboxylate (70.0 mg, 132 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.08 g, 9.45 mmol, 700 L, 72 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude product 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamid (90.0 mg, TFA salt) as a yellow oil. M+H.sup.+=432.1 (LCMS).

Step 5: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (293A-5)

[1701] To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (90.0 mg, 165 mol, 1.0 eq) in MeOH (4.0 mL) was added TEA (23.0 L), followed by the addition of formaldehyde (26.8 mg, 330 mol, 24.6 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (20.7 mg, 330 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for another 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.4). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (60.0 mg, 135 mol, 82% yield) was obtained as a yellow solid. M+H.sup.+=446.1 (LCMS).

Step 6:4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 487)

[1702] To a stirred solution of 2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenzamide (60.0 mg, 135 mol, 1.0 eq) in a mixture of MeOH (6.0 mL) and H.sub.2O (1.2 mL) was added iron powder (37.6 mg, 673 mol, 5.0 eq), followed by NH.sub.4Cl (36.0 mg, 673 mol, 5.0 eq). The mixture was stirred at 70 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, filtered through a pad of Celite. The filtrate was poured into H.sub.2O (10 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (24.0 mg, 52.3 mol, 39% yield, HCl salt) was obtained as a white solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.93 (br s, 1H), 8.67 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.85-7.80 (m, 2H), 7.60-7.43 (m, 3H), 6.84-6.70 (m, 2H), 4.71-4.60 (m, 1H), 4.31-4.18 (m, 2H), 4.05 (dt, J=4.4, 9.7 Hz, 1H), 3.90-3.82 (m, 1H), 2.83 (s, 3H), 2.48-2.30 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 294: 5-((Azetidin-3-yloxy)methyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 435)

##STR01140##

Step 1: 5-(Bromomethyl)-2-methylbenzoic acid (294A-2)

[1703] To a solution of 2-methylbenzoic acid (4.00 g, 29.4 mmol, 3.77 mL, 1.0 eq) in phosphoric acid (0.5 mL) were added paraformaldehyde (2.50 g) and HBr (19.4 g, 79.0 mmol, 13.0 mL, 33% purity in HOAc, 2.7 eq) at 20 C. The mixture was stirred at 115 C. for 15 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL). The resulting solid was collected by filtration, washed with H.sub.2O (20 mL) and dried under vacuum to give a crude product 5-(bromomethyl)-2-methylbenzoic acid (6.00 g) as a white solid. M+H.sup.+=229.0 (LCMS).

Step 2: 5-(((1-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)methyl)-2-methylbenzoic acid (294A-3)

[1704] To a solution of 5-(bromomethyl)-2-methylbenzoic acid (300 mg, 1.31 mmol, 1.0 eq) in THF (10 mL) was added NaH (105 mg, 2.62 mmol, 60% purity, 2.0 eq). The mixture was stirred at 0 C. for 30 min, then tert-butyl 3-hydroxyazetidine-1-carboxylate (340 mg, 1.96 mmol, 1.5 eq) was added at 0 C. The mixture was stirred at 0 C. for 2 h. LCMS indicated that 3% of the starting material was remaining and 66% of desired compound was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with DCM (10 mL2). The organic phase was discarded. The aqueous layer was acidified to pH 5 by using HCl (1 M aqueous) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give residue which was purified by preparative HPLC (C18-1 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 35%-80%, B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (((1-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)methyl)-2-methylbenzoic acid (1.10 g, 3.22 mmol, 49% yield) was obtained as a white solid. M100+H.sup.+=222.2 (LCMS).

Step 3: tert-Butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzyl)oxy)azetidine-1-carboxylate (294A-4)

[1705] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (214 mg, 1.17 mmol, 1.5 eq) in DCM (10 mL) were added HOBt (263 mg, 1.94 mmol, 2.5 eq), TEA (236 mg, 2.33 mmol, 325 L, 3.0 eq), EDCI (373 mg, 1.94 mmol, 2.5 eq) and 5-(((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-2-methylbenzoic acid (250 mg, 778 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (15030 mm, 5 m); flow rate: 25 mL/min;

[1706] gradient: 35%-80% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). tert-Butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzyl)oxy)azetidine-1-carboxylate (250 mg, 488 mol, 63% yield) was obtained as a white amorphous solid. M100+H.sup.+=387.2 (LCMS).

Step 4: 5-((Azetidin-3-yloxy)methyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 435)

[1707] To a solution of tert-butyl 3-((4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)benzyl)oxy)azetidine-1-carboxylate (100 mg, 206 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (23.4 mg, 206 mol, 15.2 L, 1.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-((Azetidin-3-yloxy)methyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (23.5 mg, 46.9 mol, 23% yield, TFA salt) was obtained as a white solid. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.23-9.07 (m, 1H), 8.71-8.52 (m, 2H), 7.99-7.80 (m, 3H), 7.65-7.44 (m, 3H), 7.34-6.79 (m, 3H), 4.47-4.32 (m, 3H), 4.15-4.03 (m, 2H), 3.79 (m, 2H), 2.03 (m, 1H), 1.98-1.94 (m, 1H), 2.09-1.93 (m, 1H), 1.37 (m, 2H), 1.26-1.12 (m, 2H).

Example 295: 2-Methyl-5-(((1-methylazetidin-3-yl)oxy)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 447)

##STR01141##

Step 1: 2-Methyl-5-(((1-methylazetidin-3-yl)oxy)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 447)

[1708] To a solution of 5-((azetidin-3-yloxy)methyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (80.0 mg, 207 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) were added formaldehyde (16.8 mg, 207 mol, 15.4 L, 37% purity in water, 1.0 eq), TEA (20.9 mg, 207 mol, 28.8 L, 1.0 eq) and HOAc (1.24 mg, 20.7 mol, 1.18 L, 0.10 eq). The mixture was stirred at 20 C. for 1 h. Then NaBH.sub.3CN (32.5 mg, 517 mol, 2.5 eq) was added to the mixture. The resulting mixture was stirred at 20 C. for 11 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-(((1-methylazetidin-3-yl)oxy)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (16.3 mg, 40.7 mol, 20% yield) was obtained as a white solid. M+H.sup.+=401.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.64-7.55 (m, 1H), 7.54-7.44 (m, 2H), 7.21-7.13 (m, 1H), 7.13-7.03 (m, 2H), 6.50 (m, 1H), 4.32-4.31 (m, 1H), 4.33-4.25 (m, 2H), 4.16-4.03 (m, 1H), 3.63-3.50 (m, 2H), 2.87 (m, 2H), 2.34 (m, 3H), 2.17 (m, 3H), 1.63-1.52 (m, 2H), 1.45-1.34 (m, 2H).

Example 296: 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 449)

##STR01142##

Step 1: tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenyl) ethynyl)azetidine-1-carboxylate (296A-2)

[1709] To a solution of tert-butyl 2-ethynylazetidine-1-carboxylate (270 mg, 1.49 mmol, 1.0 eq) in TEA (5.0 mL) were added methyl 5-iodo-2-methylbenzoate (411 mg, 1.49 mmol, 1.0 eq), CuI (5.67 mg, 29.8 mol, 0.02 eq), and Pd(PPh.sub.3).sub.2Cl.sub.2 (20.9 mg, 29.8 mol, 0.02 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. tert-Butyl 2-((3-(methoxycarbonyl)-4-methyl phenyl) ethynyl)azetidine-1-carboxylate (220 mg, 655 mol, 44% yield) was obtained as a colorless oil. M100+H.sup.+=230.1 (LCMS).

Step 2: tert-Butyl 2-(3-(methoxycarbonyl)-4-methylphenethyl)azetidine-1-carboxylate (296A-3)

[1710] To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenyl) ethynyl)azetidine-1-carboxylate (200 mg, 607 mol, 1.0 eq) in MeOH (10 mL) was added 10% palladium on carbon (30.0 mg). The mixture was stirred at 50 C. for 2 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product tert-butyl 2-(3-(methoxycarbonyl)-4-methylphenethyl)azetidine-1-carboxylate (200 mg) as a colorless oil. M100+H.sup.+=234.1 (LCMS).

Step 3: 5-(2-(1-(tert-Butoxycarbonyl)azetidin-2-yl)ethyl)-2-methylbenzoic acid (296A-4)

[1711] To a solution of tert-butyl 2-(3-(methoxycarbonyl)-4-methylphenethyl)azetidine-1-carboxy late (200 mg, 599 mol, 1.0 eq) in THF (1.0 mL) were added LiOH.Math.H.sub.2O (176 mg, 4.20 mmol, 7.0 eq), MeOH (500 L) and H.sub.2O (500 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL2). The organic phase was discarded. The aqueous layer was acidified to pH 5 by using HCl (1 M aqueous) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product 5-(2-(1-(tert-butoxycarbonyl)azetidin-2-yl)ethyl)-2-methylbenzoic acid (200 mg) as a colorless oil. M100+H.sup.+=220.1 (LCMS).

Step 4: tert-Butyl 2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenethyl)azetidine-1-carboxylate (296A-5)

[1712] To a solution of 1-(naphthalen-1-yl)cyclopropanamine (86.1 mg, 469 mol, 1.0 eq) in DCM (2.0 mL) were added HOBt (159 mg, 1.17 mmol, 2.5 eq), TEA (143 mg, 1.41 mmol, 196 L, 3.0 eq), EDCI (225 mg, 1.17 mmol, 2.5 eq) and 5-(2-(1-(tert-butoxycarbonyl)azetidin-2-yl)ethyl)-2-methylbenzoic acid (150 mg, 469 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product tert-butyl 2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenethyl)azetidine-1-carboxylate (400 mg) as a yellow oil. M100+H.sup.+=385.2 (LCMS).

Step 5: 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benz amide (Compound 449)

[1713] To a solution of tert-butyl 2-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl) phenethyl)azetidine-1-carboxylate (300 mg, 619 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (70.6 mg, 619 mol, 45.8 L, 1.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 15%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (66.0 mg, 130 mol, 21% yield, TFA salt) was obtained as a white solid. M+H.sup.+=385.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11-9.04 (m, 1H), 8.68-8.63 (m, 1H), 7.97-7.91 (m, 1H), 7.87-7.81 (m, 2H), 7.61-7.43 (m, 3H), 7.12-7.04 (m, 2H), 6.97-6.88 (m, 1H), 4.28-4.16 (m, 1H), 3.96-3.80 (m, 1H), 3.76-3.65 (m, 1H), 2.47-2.28 (m, 4H), 2.21-2.09 (m, 1H), 2.08 (m, 1H), 1.99 (m, 3H), 1.96-1.85 (m, 1H), 1.39-1.32 (m, 2H).

Example 297: 2-Methyl-5-(2-(1-methylazetidin-2-yl)ethyl)-N-(1-(naphthalen-1-yl)cyclo

[1714] propyl)benzamide (Compound 455)

##STR01143##

Step 1: 2-Methyl-5-(2-(1-methylazetidin-2-yl)ethyl)-N-(1-(naphthalen-1-yl)cyclo propyl)benzamide (Compound 455)

[1715] To a solution of 5-(2-(azetidin-2-yl)ethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 104 mol, 1.0 eq, TFA salt) in MeOH (1.0 mL) were added formaldehyde (8.44 mg, 104 mol, 7.74 L, 37% purity in water, 1.0 eq), TEA (10.5 mg, 104 mol, 14.5 L, 1.0 eq) and HOAc (624 g, 10.4 mol, 0.1 eq). The mixture was stirred at 20 C. for 1 h. Then NaBH.sub.3CN (16.3 mg, 260 mol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 2-Methyl-5-(2-(1-methylazetidin-2-yl)ethyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (20.8 mg, 52.2 mol, 50% yield) was obtained as a white solid. M+H.sup.+=399.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.52-8.44 (m, 1H), 7.98-7.88 (m, 2H), 7.84-7.77 (m, 1H), 7.61-7.43 (m, 3H), 7.08-6.94 (m, 3H), 6.53-6.44 (m, 1H), 3.42-3.33 (m, 1H), 2.95-2.83 (m, 1H), 2.76-2.67 (m, 1H), 2.51-2.42 (m, 2H), 2.27 (m, 3H), 2.15 (m, 3H), 2.00-1.91 (m, 1H), 1.88-1.74 (m, 2H), 1.73-1.62 (m, 1H), 1.62-1.55 (m, 2H), 1.44-1.37 (m, 2H).

Example 298: Methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) propanoate (Compound 431)

##STR01144##

Step 1: (E)-Methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)acrylate (298A-1)

[1716] To a solution of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (120 mg, 316 mol, 1.0 eq), Pd(OAc) 2 (708 mg, 3.16 mol, 0.01 eq) and PPh.sub.3 (1.66 mg, 6.31 mol, 0.02 eq) in DMF (6.0 mL) was added methyl acrylate (272 mg, 3.16 mmol, 284 l, 10 eq), followed by TEA (63.9 mg, 631 mol, 87.8 L, 2.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. (E)-Methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) acrylate (104 mg, 270 mol, 29% yield) was obtained as a yellow oil. M+H.sup.+=386.1 (LCMS).

Step 2: Methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)propanoate (Compound 431)

[1717] To a solution of (E)-methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) acrylate (90.0 mg, 234 mol, 1.0 eq) in EtOAc (10 mL) was added 10% palladium on carbon (10 mg). The mixture was degassed and purged with H.sub.2 three times, and then the mixture was stirred at 20 C. for 2 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (2.0 mL3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-65% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). Methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) propanoate (21.5 mg, 54.2 mol, 24% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=388.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10-9.01 (m, 1H), 8.70-8.60 (m, 1H), 7.97-7.89 (m, 1H), 7.87-7.77 (m, 2H), 7.61-7.42 (m, 3H), 7.13-7.07 (m, 1H), 7.06-6.99 (m, 1H), 6.91 (d, J=1.3 Hz, 1H), 3.52 (s, 3H), 2.79-2.70 (m, 2H), 2.56 (s, 2H), 2.01-1.93 (m, 3H), 1.40-1.31 (m, 2H), 1.21-1.12 (m, 2H).

Example 299: 5-(3-Amino-3-oxopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 452)

##STR01145##

Step 1: 5-(3-Amino-3-oxopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 452)

[1718] To a solution of methyl 3-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) propanoate (320 mg, 826 mol, 1.0 eq) in MeOH (3.0 mL) was added NH.sub.3/MeOH (7 M, 32 mL, 271 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10025 mm, 5 m); flow rate: 40 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(3-Amino-3-oxopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (25.9 mg, 69.5 mol, 8% yield) was obtained as a white solid. M+H.sup.+=373.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.71-8.60 (m, 1H), 7.98-7.90 (m, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.63-7.42 (m, 3H), 7.27-7.18 (m, 1H), 7.05 (br d, J=17.9 Hz, 2H), 6.90 (s, 1H), 6.77-6.64 (m, 1H), 2.76-2.63 (m, 2H), 2.32-2.20 (m, 2H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.23-1.11 (m, 2H).

Example 300: 5-(3-Aminopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 472)

##STR01146##

Step 1: 5-(2-Cyanoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (300A-1)

[1719] A mixture of 5-(3-amino-3-oxopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benz amide (68.0 mg, 183 mol, 1.0 eq) in DMF (5.0 mL) was degassed and purged with N.sub.2 three times, and to this solution was added (COCl).sub.2 (69.5 mg, 548 mol, 47.9 L, 3.0 eq) at 0 C. The mixture was stirred at 0 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). Crude 5-(2-cyanoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (76.0 mg) was obtained as a yellow oil. M+H.sup.+=355.2 (LCMS).

Step 2: 5-(3-Aminopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 472)

[1720] To a solution of 5-(2-cyanoethyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (61.0 mg, 172 mol, 1.0 eq) in THF (20 mL) was added Raney-Ni (14.7 mg), followed by NH.sub.3.Math.H.sub.2O (24.1 mg, 172 mol, 26.5 L, 25% purity 1.0 eq). The mixture was degassed and purged with H.sub.2 three times. The mixture was stirred at 30 C. for 16 h under a H.sub.2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(3-Aminopropyl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (9.00 mg, 22.7 mol, 13% yield, HCl salt) was obtained as a white solid. M+H.sup.+=359.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.09 (s, 1H), 8.71-8.61 (m, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.87-7.80 (m, 2H), 7.73 (br s, 3H), 7.48 (d, J=7.5 Hz, 3H), 7.12-7.04 (m, 2H), 6.93-6.88 (m, 1H), 2.77-2.63 (m, 2H), 2.58-2.52 (m, 2H), 1.99 (s, 3H), 1.80-1.69 (m, 2H), 1.35 (br d, J=1.5 Hz, 2H), 1.18 (br d, J=1.4 Hz, 2H).

Example 301: 5-(4-Aminopiperidin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 463)

##STR01147##

Step 1: tert-Butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl)piperidin-4-yl)carbamate (301A-1)

[1721] A mixture of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 263 mol, 1.0 eq) and tert-butyl piperidin-4-ylcarbamate (79.0 mg, 394 mol, 4.38 L, 1.5 eq) in THF (4.0 mL) was degassed and purged with N.sub.2 three times. To this mixture were added t-BuONa (75.8 mg, 789 mol, 3.0 eq) and t-BuXPhos Pd G3 (20.9 mg, 26.3 mol, 0.1 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5 tert-Butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) piperidin-4-yl)carbamate (80.0 mg, 160 mol, 20% yield) was obtained as a brown solid. M+H.sup.+=500.3 (LCMS).

Step 2: 5-(4-Aminopiperidin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benz amide (Compound 463)

[1722] To a solution of tert-butyl(1-(4-methyl-3-((1-(naphthalen-1-yl)cyclopropyl)carbamoyl)phenyl) piperidin-4-yl)carbamate (75.0 mg, 150 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 7.5 mL). The resulting mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(4-Aminopiperidin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (13.0 mg, 32.5 mol, 22% yield, HCl salt) was obtained as a white solid. M+H.sup.+=400.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (br s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.09-7.98 (m, 3H), 7.93 (d, J=8.4 Hz, 1H), 7.82 (dd, J=7.9, 11.1 Hz, 2H), 7.63-7.39 (m, 3H), 7.02 (br d, J=3.9 Hz, 1H), 6.92-6.57 (m, 1H), 3.58 (br d, J=12.5 Hz, 2H), 3.25-3.08 (m, 1H), 2.94-2.63 (m, 2H), 1.93 (s, 5H), 1.77-1.44 (m, 2H), 1.35 (br s, 2H), 1.18 (br s, 2H).

Example 302: 5-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 505)

##STR01148##

Step 1: 5-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 505)

[1723] A mixture of 5-bromo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (150 mg, 394 mol, 1.0 eq) and 2-(piperazin-1-yl)ethanol (61.6 mg, 473 mol, 58.0 L, 1.2 eq) in tert-amylalcohol (3.0 mL) was degassed and purged with N.sub.2 three times. To the mixture were added XPhos Pd G3 (33.4 mg, 39.4 mol, 0.1 eq) and Cs.sub.2CO.sub.3 (257 mg, 788 mol, 2.0 eq). The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (3.30 mg, 2.92 mol, HCl salt) was obtained as a white solid. M+H.sup.+=430.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.68-9.55 (m, 1H), 9.03 (s, 1H), 8.66 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.60-7.43 (m, 3H), 7.02 (d, J=8.0 Hz, 1H), 6.93-6.86 (m, 1H), 6.64 (d, J=2.8 Hz, 1H), 3.80-3.72 (m, 2H), 3.70-3.64 (m, 2H), 3.57-3.53 (m, 2H), 3.24-3.20 (m, 2H), 3.16-3.07 (m, 2H), 3.01-2.90 (m, 2H), 1.93 (s, 3H), 1.38-1.32 (m, 2H), 1.21-1.14 (m, 2H).

Example 303: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (Compound 426)

##STR01149##

Step 1:4-Amino-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (301A-1)

[1724] To a stirred solution of 5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-nitrobenz amide (230 mg, 635 mol, 1.0 eq) in a mixture of MeOH (8.0 mL) and H.sub.2O (1.6 mL) was added iron powder (355 mg, 6.35 mmol, 10 eq) in one portion, followed by NH.sub.4Cl (340 mg, 6.35 mmol, 10 eq). The mixture was stirred at 70 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL), filtered, and the filtrate was extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 4-Amino-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (130 mg, 391 mol, 31% yield) was obtained as a yellow solid. M+H.sup.+=333.1 (LCMS).

Step 2:4-(2-Chloroacetamido)-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (301A-2)

[1725] To a solution of 4-amino-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (120 mg, 361 mol, 1.0 eq) in DCM (4.0 mL) was added TEA (110 mg, 1.08 mmol, 151 L, 3.0 eq) at 0 C., followed by 2-chloroacetyl chloride (28.5 mg, 253 mol, 20.1 L, 0.7 eq) in DCM (1.0 mL). The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.4). 4-(2-Chloroacetamido)-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (40.0 mg, 97.8 mol, 27% yield) was obtained as a yellow solid. M+H.sup.+=409.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.52-8.41 (m, 1H), 7.96-7.79 (m, 3H), 7.64-7.41 (m, 4H), 7.10-7.04 (m, 1H), 6.87-6.77 (m, 1H), 6.63-6.47 (m, 1H), 5.39-5.25 (m, 1H), 4.26-4.19 (m, 2H), 2.14 (br d, J=2.1 Hz, 3H), 1.40-1.39 (m, 2H), 1.30-1.29 (m, 2H).

Step 3: 2-(Chloromethyl)-5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (301A-3)

[1726] To a solution of 4-(2-chloroacetamido)-5-hydroxy-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (60.0 mg, 147 mol, 1.0 eq) in toluene (6.0 mL) was added TsOH.Math.H.sub.2O (12.6 mg, 73.4 mol, 0.5 eq). The resulting mixture was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.5). 2-(Chloromethyl)-5-methyl-N-(1-(naphthaalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (20.0 mg, 51.2 mol, 35% yield) was obtained as a yellow solid. M+H.sup.+=391.1 (LCMS).

Step 4: 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (Compound 426)

[1727] To a solution of 2-(chloromethyl)-5-methyl-N-(1-(naphthaalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (20.0 mg, 51.2 mol, 1.0 eq) in acetonitrile (2.0 mL) was added methanamine hydrochloride (13.8 mg, 205 mol, 4.0 eq), followed by KI (1.70 mg, 10.2 mol, 0.20 eq) and K.sub.2CO.sub.3 (14.1 mg, 102 mol, 2.0 eq). The mixture was stirred at 80 C. for 16 h.

[1728] LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A:

[1729] 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-N-(1-(naphthalen-1-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (3.20 mg, 7.20 mol, 14% yield, FA salt) was obtained as a white solid. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20-9.14 (m, 1H), 8.68-8.61 (m, 1H), 7.98-7.89 (m, 1H), 7.87-7.78 (m, 2H), 7.62-7.43 (m, 4H), 7.38-7.34 (m, 1H), 3.91-3.86 (m, 2H), 2.30-2.26 (m, 3H), 2.13-2.09 (m, 3H), 1.42-1.36 (m, 2H), 1.23-1.17 (m, 2H).

Example 304: N-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 432)

##STR01150##

Step 1:2,3-Dihydrobenzo[b][1,4]dioxine-5-carboxamide (304A-2)

[1730] To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (2.00 g, 11.1 mmol, 1.0 eq) in THF (50 mL) were added NMM (1.24 g, 12.2 mmol, 1.34 mL 1.1 eq) and isobutyl chloroformate (1.67 g, 12.2 mmol, 1.60 mL, 1.1 eq) at 0 C. under a N.sub.2 atmosphere. The mixture was stirred at 0 C. for 30 min. NH.sub.3/MeOH (7 M, 10 mL, 6.3 eq) was added slowly. The mixture was stirred at 20 C. for 1 h. TLC indicated that the starting material was completely consumed. The mixture was treated with H.sub.2O (40 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. 2,3-Dihydrobenzo[b][1,4]dioxine-5-carboxamide (1.80 g, 10.1 mmol, 90% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.52 (br s, 2H), 7.29 (dd, J=1.7, 7.7 Hz, 1H), 6.97 (dd, J=1.7, 7.9 Hz, 1H), 6.91-6.82 (m, 1H), 4.38-4.32 (m, 2H), 4.30-4.24 (m, 2H).

Step 2:2,3-Dihydrobenzo[b][1,4]dioxine-5-carbonitrile (304A-3)

[1731] A solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (500 mg, 2.79 mmol, 1.0 eq) in SOCl.sub.2 (2.5 mL) was stirred at 80 C. for 6 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give crude product which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. 2,3-Dihydrobenzo[b][1,4]dioxine-5-carbonitrile (300 mg, 1.86 mmol, 67% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.32-7.15 (m, 2H), 7.03-6.92 (m, 1H), 4.47-4.38 (m, 2H), 4.37-4.29 (m, 2H).

Step 3: 1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropanamine (304A-4)

[1732] A mixture of 2,3-dihydrobenzo[b][1,4]dioxine-5-carbonitrile (150 mg, 931 mol, 1.0 eq) in anhydrous Et.sub.2O (15 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (291 mg, 1.02 mmol, 302 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 683 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (264 mg, 1.86 mmol, 230 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (5 mL) and extracted with MTBE (5.0 mL3). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.6). 1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropane amine (90.0 mg, 471 mol, 51% yield) was obtained as a brown oil. M+H.sup.+=192.0 (LCMS).

Step 4: N-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (Compound 432)

[1733] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropanamine (50.0 mg, 261 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (61.5 mg, 261 mol, 1.0 eq) in DMF (5.0 mL) were added DIEA (101 mg, 784 mol, 137 L, 3.0 eq) and HBTU (99.2 mg, 261 mol, 1.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (29.2 mg, 65.6 mol, 25% yield, HCl salt) was obtained as a white solid. M+H.sup.+=409.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.54-10.40 (m, 1H), 8.66-8.57 (m, 1H), 7.15-7.09 (m, 1H), 7.03 (dd, J=3.0, 6.3 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 6.76-6.69 (m, 2H), 4.64 (dt, J=2.5, 6.9 Hz, 1H), 4.41-4.32 (m, 1H), 4.30-4.27 (m, 2H), 4.25-4.21 (m, 2H), 4.19-4.10 (m, 1H), 4.09-3.97 (m, 1H), 3.93-3.81 (m, 1H), 2.85 (d, J=5.1 Hz, 3H), 2.40-2.30 (m, 2H), 2.13 (s, 3H), 1.09 (br d, J=6.5 Hz, 4H).

Example 305: N-(1-(2-Isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 457)

##STR01151##

Step 1: 2-Isopropylnaphthalene (305A-2)

[1734] To a mixture of 2-isopropenylnaphthalene (3.00 g, 17.8 mmol, 1.0 eq) in MeOH (20 mL) was added 10% palladium on carbon (3.00 g) at 25 C., the reaction mixture was stirred at 25 C. for 3 h under a H.sub.2 (15 psi) atmosphere. HPLC indicated that the starting material was completely consumed. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product 2-isopropylnaphthalene (3.00 g) as a yellow oil.

Step 2: 1-Bromo-2-isopropylnaphthalene (305A-3)

[1735] To a mixture of 2-isopropylnaphthalene (3.00 g, 17.6 mmol, 1.0 eq) in CH.sub.3CN (60 mL) was added NBS (3.45 g, 19.3 mmol, 1.1 eq) at 0 C., the reaction mixture was stirred at 60 C. for 2 h. HPLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous Na.sub.2SO.sub.3 (50 ml), extracted with EtOAc (100 mL3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (7530 mm, 3 mm); flow rate: 25 mL/min; gradient: 40%-90% B over 10 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 1-Bromo-2-isopropyl-naphthalene (1.20 g, 4.82 mmol, 27% yield) was obtained as a yellow oil.

Step 3: 2-Isopropyl-1-naphthonitrile (305A-4)

[1736] To a mixture of 1-bromo-2-isopropyl-naphthalene (1.15 g, 4.62 mmol, 1.0 eq) in DMF (40 mL) were added Pd(PPh.sub.3).sub.4 (533 mg, 461 mol, 0.1 eq) and Zn(CN).sub.2 (2.17 g, 18.4 mmol, 1.17 mL, 4.0 eq) at 25 C. The reaction mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (50 ml) and extracted with EtOAc (50 mL3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 35%-75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Isopropylnaphthalene-1-carbonitrile (800 mg, 4.10 mmol, 8% yield) was obtained as a yellow oil. M+H.sup.+=196.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.10 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.52 (dt, J=1.1, 7.6 Hz, 1H), 7.46-7.33 (m, 2H), 3.55 (td, J=6.8, 13.6 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).

Step 4: 1-(2-Isopropylnaphthalen-1-yl)cyclopropanamine (305A-5)

[1737] A mixture of 2-isopropylnaphthalene-1-carbonitrile (200 mg, 1.02 mmol, 1.0 eq) in anhydrous Et.sub.2O (30 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (320 mg, 1.13 mmol, 332 L, 1.1 eq) slowly, and then EtMgBr (3 M, 751 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was completed, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (290 mg, 2.05 mmol, 252 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (50 mL) and MTBE (30 mL) and extracted with MTBE (30 mL2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (1030 mm, 10 m); flow rate: 25 mL/min; gradient: 45%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 1-(2-Isopropyl-1-naphthyl)cyclopropanamine (50.0 mg, 222 mol, 10% yield) was obtained as a yellow solid. M+H.sup.+=226.2 (LCMS).

Step 5: N-(1-(2-Isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 457)

[1738] To a mixture of 1-(2-isopropyl-1-naphthyl)cyclopropanamine (45.0 mg, 200 mol, 1.0 eq) and 2-methyl-5-[(1-methylazetidin-2-yl)methoxy]benzoic acid (47.0 mg, 200 mol, 1.0 eq) in DMF (1.0 mL) were added HATU (114 mg, 299 mol, 1.5 eq) and DIEA (77.4 mg, 599 mol, 104 L, 3.0 eq) at 25 C. The reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex Luna C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-50% B over 8 min;

[1739] mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give N-(1-(2-isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (16.5 mg, 36.1 mol, 18% yield, HCl salt) as a brown solid. M+H.sup.+=443.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.38 (br s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.87 (dd, J=8.4, 16.0 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.53-7.42 (m, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.03-6.92 (m, 2H), 6.84 (q, J=7.2 Hz, 1H), 4.76-4.67 (m, 1H), 4.41-4.30 (m, 1H), 4.28-4.16 (m, 2H), 3.99 (d, J=10.0 Hz, 1H), 3.52-3.43 (m, 1H), 2.98 (s, 3H), 2.65-2.52 (m, 2H), 2.34 (s, 3H), 1.44-1.30 (m, 10H).

Example 306: 5-(2-Aminopropoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 445)

##STR01152##

Step 1: Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (306A-1)

[1740] To a solution of methyl 5-hydroxy-2-methylbenzoate (1.05 g, 6.02 mmol, 1.0 eq) in toluene (20 mL) was added tert-butyl(1-hydroxypropan-2-yl)carbamate (1.00 g, 6.02 mmol, 1.0 eq), followed by TMAD (3.11 g, 18.1 mmol, 3.0 eq) and PPh.sub.3 (4.74 g, 18.1 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool room temperature, poured into water (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 6/100. Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (500 mg, 1.39 mmol, 23% yield) was obtained as a white solid. M100+H.sup.+=224.1 (LCMS).

Step 2: 5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (306A-2)

[1741] To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (618 mg, 1.91 mmol, 1.0 eq) in a mixture of THF (5.0 mL), MeOH (3.5 mL) and H.sub.2O (2.5 mL) was added LiOH.Math.H.sub.2O (246 mg, 5.73 mmol, 3.0 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (250 50 mm, 10 m); flow rate: 60 mL/min; gradient: 40%-80% B over 10 min; mobile phase A: 0.1% TFA, mobile aqueous phase B: acetonitrile). 5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (98.0 mg, 317 mol, 17% yield, TFA salt) was obtained as a white solid. M100+H.sup.+=210.2 (LCMS).

Step 3: tert-Butyl(1-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (306A-3)

[1742] To a solution of 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (20.0 mg, 93.8 mol, 1.0 eq, TFA salt) in DMF (2.0 mL) was added 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (34.8 mg, 113 mol, 1.2 eq), followed by HBTU (107 mg, 218 mmol, 3.0 eq) and DIEA (121 mg, 938 mmol, 163 L, 10 eq). The mixture was stirred at 20 C. for 16 h.

[1743] LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a crude product tert-butyl(1-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (47.0 mg) as a yellow oil. M56+H.sup.+=449.2 (LCMS).

Step 4: 5-(2-Aminopropoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 445)

[1744] To a solution of tert-butyl(1-(3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (47.0 mg, 93.1 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (775 mg, 6.80 mmol, 503 L, 73 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-Aminopropoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (33.4 mg, 64.4 mmol, 41% yield, TFA salt) was obtained as a white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ppm 9.10 (s, 1H), 8.53 (d, J=8.41 Hz, 1H), 7.94 (br s, 2H), 7.83 (d, J=8.16 Hz, 1H), 7.50-7.36 (m, 3H), 7.24 (d, J=2.26 Hz, 1H), 7.08 (d, J=8.41 Hz, 1H), 6.90 (br d, J=2.51 Hz, 1H), 6.67 (d, J=2.51 Hz, 1H), 4.02 (dd, J=10.23, 3.70 Hz, 1H), 3.87 (s, 3H), 3.86-3.81 (m, 1H), 3.54 (br d, J=1.25 Hz, 1H), 1.98 (s, 3H), 1.32 (br s, 2H), 1.22 (d, J=6.65 Hz, 3H), 1.17 (br s, 2H).

Example 307: 5-(((2S,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(3-methoxy

[1745] naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 490)

##STR01153##

Step 1: (2S,4R)-tert-Butyl4-fluoro-2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (307A-1)

[1746] To a solution of methyl 5-hydroxy-2-methylbenzoate (1.17 g, 7.02 mmol, 1.1 eq) and (2S,4R)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.40 g, 6.39 mmol, 1.0 eq) in toluene (14 mL) were added TMAD (3.30 g, 19.2 mmol, 3.0 eq) and PPh.sub.3 (5.02 g, 19.2 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times and then was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. (2S,4R)-tert-Butyl 4-fluoro-2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 3.27 mmol, 51% yield) was obtained as a yellow oil. M+H.sup.+=368.1 (LCMS); 1HNMR (400 MHZ, DMSO-d.sub.6) 7.34 (d, J=2.9 Hz, 1H), 7.23 (br d, J=8.4 Hz, 1H), 7.09 (dd, J=2.3, 8.3 Hz, 1H), 5.41-5.18 (m, 1H), 4.22-4.09 (m, 3H), 3.83-3.62 (m, 4H), 3.32 (s, 2H), 2.42 (s, 3H), 1.38 (s, 9H), 1.24-1.14 (m, 1H).

Step 2: 5-(((2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl benzoic acid (307A-2)

[1747] To a solution of (2S,4R)-tert-butyl 4-fluoro-2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 3.27 mmol, 1.0 eq) in a mixture of THF (15 mL) and MeOH (5.0 mL) was added NaOH (2 M in aqueous, 2.0 mL, 1.2 eq). The mixture was stirred at 70 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with MTBE (5 mL3). The aqueous was basified to pH 5 by using HCl (1 M, aqueous). The product was extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude 5-(((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (1.10 g, 3.11 mmol, 95% yield) as a yellow oil. M100+H.sup.+=254.1 (LCMS).

Step 3: (2S,4R)-tert-Butyl 4-fluoro-2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (307A-3)

[1748] To a solution of 5-(((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 565 mol, 1.0 eq) and 1-(3-methoxynaphthalen-1-yl)cyclopropanamine (121 mg, 566 mol, 1.0 eq) in DMF (2.0 mL) were added DIEA (219 mg, 1.70 mmol, 296 L, 3.0 eq) and HATU (323 mg, 849 mol, 1.5 eq). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. (2S,4R)-tert-Butyl 4-fluoro-2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 364 mol, 64% yield) was obtained as a yellow oil. M+H.sup.+=549.1 (LCMS).

Step 4: 5-(((2S,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 490)

[1749] To a solution of (2S,4R)-tert-butyl 4-fluoro-2-((3-((1-(3-methoxynaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 364 mol, 1.0 eq) in EtOAc (3.0 mL) was added EtOAc/HCl (4 M, 3.0 mL). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2S,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (110 mg, 245 mol, 67% yield, HCl salt) was obtained as a white solid. M+H.sup.+=449.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.12-9.90 (m, 1H), 9.66-9.40 (m, 1H), 9.13 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.63-7.32 (m, 3H), 7.24 (d, J=2.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.89 (dd, J=2.6, 8.4 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 5.57-5.37 (m, 1H), 4.27-4.19 (m, 1H), 4.17-4.09 (m, 1H), 4.08-4.00 (m, 1H), 3.87 (s, 3H), 3.45 (br s, 2H), 2.44-2.30 (m, 1H), 2.07 (s, 1H), 1.98 (s, 3H), 1.34 (br s, 2H), 1.16 (br s, 2H).

Example 308: 5-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(3-methoxy

[1750] naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 489)

##STR01154##

Step 1: 5-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(3-methoxy naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 489)

[1751] To a solution of 5-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (60.0 mg, 133 mol, 1.0 eq) in MeOH (1.0 mL) was added TEA (20.1 L), followed by formaldehyde (16.3 mg, 200 mol, 14.5 L, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (50.4 mg, 803 mol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (50.0 mg, 108 mol, 81% yield, HCl salt) was obtained as a white solid. M+H.sup.+=463.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.1-10.9 (m, 1H), 9.11 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.49-7.37 (m, 3H), 7.25-7.23 (m, 1H), 7.10-7.07 (m, 1H), 6.93-6.89 (m, 1H), 6.70 (d, J=2.5 Hz, 1H), 5.53-5.36 (m, 1H), 4.35-4.25 (m, 2H), 3.94 (br s, 2H), 3.87 (s, 3H), 3.53-3.42 (m, 1H), 2.96 (br s, 3H), 2.46-2.19 (m, 1H), 2.07 (s, 1H), 1.96 (s, 3H), 1.33 (br s, 2H), 1.19-1.14 (m, 2H).

Example 309: N-(1-(3-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 433)

##STR01155##

Step 1: N-(1-(3-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 433)

[1752] To a mixture of N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (70.0 mg, 163 mol, 1.0 eq) in DCM (5.0 mL) was added dropwise the solution of BBr.sub.3 (326 mg, 1.30 mmol, 125 L, 8.0 eq) in DCM (500 L) at 78 C. under a N.sub.2 atmosphere. The mixture was stirred at 78 C. for 1 h then stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was diluted with MeOH (3.0 mL) and then acidified to pH 8 by using ammonium hydroxide (25% aqueous). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (5.30 mg, 11.2 mol, 8% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.52-8.48 (m, 1H), 8.46-8.41 (m, 1H), 7.67 (br d, J=7.6 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.40-7.31 (m, 2H), 7.09-7.05 (m, 2H), 6.89 (br dd, J=2.5, 8.4 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 4.27-4.03 (m, 3H), 3.90-3.81 (m, 1H), 3.65-3.47 (m, 1H), 2.72 (s, 3H), 2.41-2.32 (m, 2H), 2.03 (s, 3H), 1.43-1.28 (m, 4H).

Example 310: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-propoxynaphthalen-1-yl)cyclopropyl)benzamide (Compound 474)

##STR01156##

Step 1: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-propoxynaphthalen-1-yl)cyclopropyl)benzamide (Compound 474)

[1753] A mixture of N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (100 mg, 240 mol, 1.0 eq), propan-1-ol (15.9 mg, 264 mol, 19.8 L, 1.1 eq) and PPh.sub.3 (189 mg, 720 mol, 3.0 eq) in toluene (5.0 mL) was degassed and purged with N.sub.2 three times. To the mixture was added TMAD (124 mg, 720 mol, 3.0 eq) at 20 C. The resulting mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (20040 mm, 10 m); flow rate: 75 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-propoxynaphthalen-1-yl)cyclopropyl)benzamide (14.9 mg, 32.0 mol, 13% yield, FA salt) was obtained as a white solid. M+H.sup.+=459.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.17-8.98 (m, 1H), 8.57-8.49 (m, 1H), 8.20-8.17 (m, 1H), 7.84-7.78 (m, 1H), 7.48-7.34 (m, 3H), 7.24-7.20 (m, 1H), 7.05-6.99 (m, 1H), 6.88-6.80 (m, 1H), 6.61-6.57 (m, 1H), 4.06-4.00 (m, 2H), 3.89-3.84 (m, 2H), 3.30-3.24 (m, 2H), 2.81-2.70 (m, 1H), 2.25-2.21 (m, 3H), 2.00-1.77 (m, 7H), 1.36-1.30 (m, 2H), 1.19-1.13 (m, 2H), 1.07-1.00 (m, 3H).

Example 311: N-(1-(3-Bromonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 461)

##STR01157##

Step 1:3-Bromo-1-naphthamide (311A-2)

[1754] To a solution of 3-bromo-1-naphthoic acid (3.00 g, 12.0 mmol, 1.0 eq) in THF (30 mL) was added CDI (2.90 g, 17.9 mmol, 1.5 eq) at 0 C. The mixture was stirred at 20 C. for 1.5 h. Then NH.sub.3.Math.H.sub.2O (9.10 g, 64.9 mmol, 10.0 mL, 25% purity, 5.4 eq) was added to the mixture, the resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue. The residue was triturated in H.sub.2O (15 mL) at 20 C. for 15 min. The mixture was filtered and the filter cake was washed subsequently by H.sub.2O (8.0 mL2) and HCl (1 M aqueous) (10 mL1). The filter cake was then concentrated under vacuum to give a crude product 3-bromo-1-naphthamide (2.92 g) as a white solid. M+H.sup.+=250.1 (LCMS).

Step 2:3-Bromo-1-naphthonitrile (311A-3)

[1755] To a solution of 3-bromo-1-naphthamide (240 mg, 960 mol, 1.0 eq) in DMF (5.0 mL) were added TEA (400 mg, 3.95 mmol, 550 L, 4.1 eq) and TFAA (410 mg, 1.95 mmol, 271 L, 2.0 eq) at 0 C. The mixture was stirred at 20 C. for 6 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 8/100 to give 3-bromo-1-naphthonitrile (188 mg, 810 mol, 84% yield) as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.38-8.14 (m, 2H), 8.07-7.94 (m, 1H), 7.93-7.81 (m, 1H), 7.79-7.60 (m, 2H).

Step 3: 1-(3-Bomonaphthalen-1-yl)cyclopropanamine (311A-4)

[1756] A mixture of 3-bromo-1-naphthonitrile (180 mg, 776 mmol, 1.0 eq) in anhydrous Et.sub.2O (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (331 mg, 1.16 mmol, 343 L, 1.5 eq) slowly, and then EtMgBr (3 M, 595 L, 2.3 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (220 mg, 1.55 mmol, 191 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was poured into HCl (1 M aqueous) (7.0 mL), and the mixture was extracted with EtOAc (5.0 mL3). The organic phase was discarded. The aqueous layer was basified to pH 8 by using saturated Na.sub.2CO.sub.3 aqueous solution and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with EtOAc several times. The combined filtrate was extracted with EtOAc (8.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product 1-(3-bomonaphthalen-1-yl)cyclopropanamine (80.0 mg) as a yellow oil. M+H.sup.+=262.4 (LCMS).

Step 4: N-(1-(3-Bromonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 461)

[1757] To a solution of 1-(3-bromonaphthalen-1-yl)cyclopropanamine (111 mg, 425 mol, 1.0 eq) in DMF (2.0 mL) was added 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (100 mg, 425 mol, 1.0 eq), followed by HBTU (322 mg, 850 mol, 2.0 eq) and DIEA (164 mg, 1.28 mmol, 222 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that 8% starting material remained and 37% desired compound was detected. The mixture was filtered and the filtrate was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (95.0 mg, 156 mol, 38% yield, TFA salt) as a yellow solid. M+H.sup.+=479.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) ppm 13.35-12.45 (m, 1H), 8.67-8.43 (m, 1H), 8.11-8.02 (m, 1H), 8.00-7.92 (m, 1H), 7.83-7.75 (m, 1H), 7.61-7.48 (m, 2H), 7.40 (br s, 1H), 7.09-6.90 (m, 1H), 6.81-6.53 (m, 2H), 4.36-4.31 (m, 2H), 4.27-4.08 (m, 1H), 3.97-3.83 (m, 1H), 3.75-3.57 (m, 1H), 2.94-2.71 (m, 3H), 2.63-2.38 (m, 2H), 2.15 (s, 3H), 1.63-1.51 (m, 2H), 1.45-1.29 (m, 2H).

Example 312: (S)-5-(2-Aminopropoxy)-N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 541)

##STR01158##

Step 1: (S)-Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (312A-1)

[1758] To a solution of methyl 5-hydroxy-2-methylbenzoate (10.5 g, 60.2 mmol, 1.0 eq) in toluene (200 mL) was added(S)-tert-butyl(1-hydroxypropan-2-yl)carbamate (1.00 g, 6.02 mmol, 1.0 eq), followed by TMAD (31.1 g, 180 mmol, 3.0 eq) and PPh.sub.3 (47.4 g, 181 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into water (30 mL), and then extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. (S)-Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (4.30 g, 12.5 mmol, 21% yield) was obtained as a white solid. M100+H.sup.+=224.1 (LCMS).

Step 2: (S)-5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (312A-2)

[1759] To a solution of(S)-methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (3.50 g, 10.8 mmol, 1.0 eq) in a mixture of THF (16 mL), MeOH (12 mL) and H.sub.2O (8.0 mL) was added LiOH.Math.H.sub.2O (1.36 g, 32.5 mmol, 3.0 eq). The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The organic phase was discarded. The aqueous layer was acidified to pH 6 by using HCl (1 M aqueous) and then extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a crude product(S)-5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (3.10 g) as a white solid. M100+H.sup.+=210.2 (LCMS).

Step 3: (S)-tert-Butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (312A-3)

[1760] To a solution of 1-(3-bromonaphthalen-1-yl)cyclopropanamine (150 mg, 572 mol, 1.0 eq) in DMF (2.0 mL) was added(S)-5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (212 mg, 686 mol, 1.2 eq), followed by HBTU (434 mg, 1.14 mmol, 2.0 eq) and DIEA (221 mg, 1.72 mmol, 299 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 13/100. (S)-tert-Butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (420 mg, 759 mol, 79% yield) was obtained as a yellow oil. M56+H.sup.+=497.1 (LCMS).

Step 4: (S)-5-(2-Aminopropoxy)-N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 541)

[1761] To a solution of HCl/EtOAc (4 M, 4.0 mL) was added(S)-tert-butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (360 mg, 650 mol, 1.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-5-(2-Aminopropoxy)-N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (161 mg, 328 mol, HCl salt) was obtained as a white solid. M+H.sup.+=453.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21 (s, 1H), 8.68-8.59 (m, 1H), 8.15 (s, 1H), 8.09 (br s, 2H), 7.94 (d, J=7.89 Hz, 1H), 7.88 (d, J=1.97 Hz, 1H), 7.66-7.54 (m, 2H), 7.08 (d, J=8.33 Hz, 1H), 6.89 (dd, J=8.33, 2.63 Hz, 1H), 6.68 (d, J=2.63 Hz, 1H), 4.03 (dd, J=10.41, 3.84 Hz, 1H), 3.88 (dd, J=10.19, 6.91 Hz, 1H), 3.58-3.45 (m, 1H), 1.96 (s, 3H), 1.35 (br s, 2H), 1.23 (d, J=6.58 Hz, 5H).

Example 313: N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 443)

##STR01159##

Step 1: N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (Compound 443)

[1762] To a solution of 4-(1-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (65.0 mg, 121 mol, 1.0 eq) in DMF (3.0 mL) were added Zn(CN).sub.2 (28.5 mg, 242 mol, 15.4 L, 2.0 eq), BrettPhos (11.0 mg, 12.1 mol, 0.10 eq) and BrettPhos Pd G3 (13.0 mg, 24.2 mol, 0.20 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamide (8.50 mg, 20.6 mol, 17% yield) was obtained as a white solid. M+H.sup.+=414.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 8.72 (d, J=8.5 Hz, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.85-7.76 (m, 1H), 7.73-7.65 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.8 Hz, 2H), 2.17 (s, 6H), 1.93 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H).

Example 314: N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 484)

##STR01160##

Step 1: N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 484)

[1763] To a solution of 4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 mol, 1.0 eq) in DMF (4.0 mL) were added ZnCN.sub.2 (64.2 mg, 547 mol, 34.7 L, 3.0 eq), BrettPhos (19.6 mg, 36.5 mol, 0.2 eq) and BrettPhos Pd G3 (16.5 mg, 18.2 mol, 0.1 eq) under a N.sub.2 atmosphere. The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B:

[1764] acetonitrile). N-(1-(3-Cyanonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (20.5 mg, 42.9 mol, 24% yield, FA salt) was obtained as a white solid. M+H.sup.+=426.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6)) 9.19 (s, 1H), 8.73 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.88-7.75 (m, 1H), 7.74-7.60 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.87 (dd, J=2.6, 8.3 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 3.99 (br d, J=5.3 Hz, 2H), 3.68 (br s, 2H), 3.10 (br s, 1H), 2.42 (s, 3H), 2.01 (s, 2H), 1.94 (s, 3H), 1.38 (br s, 2H), 1.28 (br s, 2H).

Example 315: tert-Butyl(4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (Compound 482)

##STR01161##

Step 1: tert-Butyl(4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (Compound 482)

[1765] To a solution of N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (100 mg, 209 mol, 1.0 eq) and tert-butyl carbamate (29.3 mg, 250 mol, 1.2 eq) in t-AmylOH (1.0 mL) were added Xphos Pd G3 (35.3 mg, 41.7 mol, 0.2 eq) and Cs.sub.2CO.sub.3 (272 mg, 834 mol, 4.0 eq). The mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). tert-Butyl(4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (13.0 mg, 20.7 mol, 10% yield, TFA salt) was obtained as a white solid. M+H.sup.+=516.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.20 (s, 1H), 8.51-8.42 (m, 1H), 7.99 (br s, 1H), 7.83-7.74 (m, 2H), 7.48-7.38 (m, 2H), 7.10 (d, J=8.50 Hz, 1H), 6.93 (dd, J=8.38, 2.75 Hz, 1H), 6.71 (d, J=2.75 Hz, 1H), 4.70-4.60 (m, 1H), 4.29-4.21 (m, 1H), 4.20-4.10 (m, 2H), 3.94 (q, J=9.55 Hz, 1H), 2.92 (s, 3H), 2.60-2.47 (m, 2H), 2.04 (s, 3H), 1.56 (s, 9H), 1.46-1.40 (m, 2H), 1.36-1.28 (m, 2H).

Example 316: N-(1-(3-Aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 496)

##STR01162##

Step 1: N-(1-(3-Aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzamide (Compound 496)

[1766] To a solution of tert-butyl(4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (170 mg, 330 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give N-(1-(3-aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (36.8 mg, 68.9 mol, 21% yield, TFA salt) as a pale yellow solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.38-9.28 (m, 1H), 8.61-8.54 (m, 1H), 7.95-7.90 (m, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.73-7.66 (m, 1H), 7.65-7.56 (m, 2H), 7.10 (d, J=8.5 Hz, 1H), 6.98-6.92 (m, 1H), 6.76 (d, J=2.6 Hz, 1H), 4.73-4.62 (m, 1H), 4.30-4.14 (m, 3H), 4.02-3.89 (m, 1H), 3.00-2.90 (m, 3H), 2.60-2.50 (m, 2H), 1.99-1.96 (m, 3H), 1.51-1.46 (m, 2H), 1.37-1.32 (m, 2H).

Example 317: N-(1-(3-(Dimethylamino) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 495)

##STR01163##

Step 1: N-(1-(3-(Dimethylamino) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 495)

[1767] To a solution of N-(1-(3-aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (60.0 mg, 144 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (20 L), followed by formaldehyde (25.8 mg, 318 mol, 23.6 L, 37% purity in water, 2.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (22.7 mg, 361 mol, 2.5 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N-(1-(3-(Dimethylamino) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (23.1 mg, 41.1 mol, 28% yield, TFA salt) was obtained as a yellow gum. M+H.sup.+=444.2 (LCMS); .sup.1H NMR (400 MHz, CD.sub.3OD) 9.33-9.23 (m, 1H), 8.50 (br d, J=7.8 Hz, 1H), 7.93-7.82 (m, 2H), 7.61-7.41 (m, 3H), 7.11 (d, J=8.4 Hz, 1H), 7.01-6.90 (m, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.75-4.60 (m, 1H), 4.30-4.24 (m, 1H), 4.24-4.11 (m, 2H), 4.00-3.91 (m, 1H), 3.26-3.24 (m, 6H), 3.03-2.88 (m, 3H), 2.59-2.50 (m, 2H), 2.02-1.98 (m, 3H), 1.51-1.44 (m, 2H), 1.39-1.32 (m, 2H).

Example 318:4-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthamide (Compound 520)

##STR01164##

Step 1:4-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthamide (Compound 520)

[1768] To a solution of N-(1-(3-cyanonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (30.0 mg, 70.5 mol, 1.0 eq) in a mixture of DMSO (0.3 mL) and EtOH (0.9 mL) were added H.sub.2O.sub.2 (35.9 mg, 212 mol, 30.5 L, 20% purity in H.sub.2O, 3.0 eq) and NaOH (8.46 mg, 212 mol, 3.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (1.0 mL) and extracted with EtOAc (0.5 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 4-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthamide (6.30 mg, 13.8 mol, 20% yield, FA salt) was obtained as a white solid. M+H.sup.+=444.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6)) 9.13 (s, 1H), 8.68 (d, J=8.1 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 8.19-8.08 (m, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.78-7.62 (m, 1H), 7.59 (br d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.95-6.82 (m, 1H), 6.68 (d, J=1.7 Hz, 1H), 4.25-4.05 (m, 2H), 3.92-3.70 (m, 1H), 2.72-2.62 (m, 2H), 2.49-2.40 (m, 3H), 2.31-2.08 (m, 2H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H).

Example 319: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 481)

##STR01165##

Step 1: tert-Butyl(1-(4-methyl-3-((1-(3-methylnaphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (319A-1)

[1769] To a solution of tert-butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (80.0 mg, 145 mol, 1.0 eq) in DMF (2.0 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (272 mg, 1.08 mmol, 303 L, 50% purity, 7.5 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (11.8 mg, 14.5 mol, 0.1 eq) and Cs.sub.2CO.sub.3 (155 mg, 477 mol, 3.3 eq). The mixture was stirred at 110 C. for 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Butyl(1-(4-methyl-3-((1-(3-methylnaphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (90.0 mg, 120 mol, 82% yield) was obtained as a yellow solid. M+H.sup.+=289.4 (LCMS).

Step 2: 5-(2-Aminopropoxy)-2-methyl-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 481)

[1770] To a solution of tert-butyl(1-(4-methyl-3-((1-(3-methylnaphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (90.0 mg, 184 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(2-aminopropoxy)-2-methyl-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (20.4 mg, 40.6 mol, 22% yield, TFA salt) as a yellow solid. M+H.sup.+=389.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.09 (s, 1H), 8.62-8.55 (m, 1H), 7.92 (br s, 2H), 7.79-7.86 (m, 1H), 7.66 (d, J=1.63 Hz, 1H), 7.60 (s, 1H), 7.51-7.43 (m, 2H), 7.08 (d, J=8.50 Hz, 1H), 6.88 (dd, J=8.32, 2.69 Hz, 1H), 6.66 (d, J=2.75 Hz, 1H), 4.02 (dd, J=10.26, 3.75 Hz, 1H), 3.84 (dd, J=10.32, 7.19 Hz, 1H), 3.59-3.45 (m, 1H), 2.47 (s, 3H), 1.99 (s, 3H), 1.33 (br s, 2H), 1.21 (d, J=6.63 Hz, 3H), 1.17 (br s, 2H).

Example 320: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 501)

##STR01166##

Step 1: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 501)

[1771] To a solution of N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 167 mol, 1.0 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (83.8 mg, 334 mol, 93.3 L, 50% purity, 2.0 eq) and Cs.sub.2CO.sub.3 (179 mg, 551 mol, 3.3 eq) in DMF (1.0 mL) was added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (13.6 mg, 16.7 mol, 0.1 eq). The mixture was stirred at 110 C. for 1 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-methylnaphthalen-1-yl)cyclopropyl)benzamide (35.0 mg, 66.1 mol, 39% yield, TFA salt) was obtained as a pale yellow solid. M+H.sup.+=415.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.90 (br s, 1H), 9.09 (s, 1H), 8.62-8.54 (m, 1H), 7.87-7.78 (m, 1H), 7.66 (d, J=1.50 Hz, 1H), 7.61 (s, 1H), 7.53-7.42 (m, 2H), 7.09 (d, J=8.50 Hz, 1H), 6.90 (dd, J=8.38, 2.75 Hz, 1H), 6.69 (d, J=2.63 Hz, 1H), 4.60 (br d, J=4.38 Hz, 1H), 4.28-4.15 (m, 2H), 4.08-3.95 (m, 1H), 3.91-3.82 (m, 1H), 2.83 (d, J=4.63 Hz, 3H), 2.47 (s, 3H), 2.42-2.25 (m, 2H), 1.99 (s, 3H), 1.33 (br s, 2H), 1.17 (br s, 2H).

Example 321: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(prop-1-en-2-yl)

[1772] naphthalen-1-yl)cyclopropyl)benzamide (Compound 508)

##STR01167##

Step 1: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(prop-1-en-2-yl) naphthalen-1-yl)cyclopropyl)benzamide (Compound 508)

[1773] To a solution of 4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (200 mg, 365 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (129 mg, 766 mol, 2.1 eq) in a mixture of dioxane (12 mL) and H.sub.2O (2.0 mL) were added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (29.8 mg, 36.5 mol, 0.1 eq) and Na.sub.2CO.sub.3 (8.9 mg, 839 mol, 2.3 eq). The mixture was degassed and purged with N.sub.2 three times, and then the mixture was stirred at 80 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(prop-1-en-2-yl) naphthalen-1-yl)cyclopropyl)benzamide (18.4 mg, 40.9 mol, 11% yield, HCl salt) was obtained as a yellow oil. M+H.sup.+=441.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.24-10.11 (m, 1H), 9.11 (s, 1H), 8.62 (d, J=7.6 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.99-7.93 (m, 1H), 7.89 (s, 1H), 7.58-7.48 (m, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.5, 8.1 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 5.62 (s, 1H), 5.25 (s, 1H), 4.66-4.55 (m, 1H), 4.31-4.18 (m, 2H), 4.05-3.79 (m, 2H), 2.86-2.65 (m, 3H), 2.39-2.22 (m, 5H), 1.99 (s, 3H), 1.37 (br s, 2H), 1.23 (br s, 2H).

Example 322: N-(1-(3-Isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methyl

[1774] azetidin-2-yl)methoxy)benzamide (Compound 521)

##STR01168##

Step 1: N-(1-(3-Isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 521)

[1775] To a solution of 2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(prop-1-en-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (90.0 mg, 204 mol, 1.0 eq) in EtOAc (7.0 mL) was added 10% palladium on carbon (90.0 mg). The suspension was degassed and purged with H.sub.2 several times. The mixture was stirred at 20 C. for 2 h under a H.sub.2 (15 psi) atmosphere.

[1776] LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(3-Isopropylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (18.0 mg, 37.0 mol, 18% yield, HCl salt) was obtained as a red solid. M+H.sup.+=443.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.13-10.01 (m, 1H), 9.06 (s, 1H), 8.60 (br d, J=6.6 Hz, 1H), 7.87 (br d, J=8.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.52-7.44 (m, 2H), 7.09 (br d, J=8.8 Hz, 1H), 6.90 (br dd, J=1.4, 7.9 Hz, 1H), 6.69 (br s, 1H), 4.59 (br dd, J=3.0, 7.8 Hz, 1H), 4.29-4.17 (m, 2H), 4.06-3.94 (m, 1H), 3.90-3.77 (m, 1H), 3.08-3.01 (m, 1H), 2.81 (br s, 3H), 2.37-2.32 (m, 2H), 2.00 (s, 3H), 1.35 (br s, 2H), 1.31 (br d, J=6.8 Hz, 6H), 1.19 (br s, 2H).

Example 323: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfinyl)naphthalen-1-yl)

[1777] cyclopropyl)-2-methylbenzamide (Compound 423)

##STR01169##

Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfinyl)naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 423)

[1778] To a solution of 5-(2-(dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclo propyl)-2-methylbenzamide (60.0 mg, 134 mol, 1.0 eq) in MeOH (300 L) were added NaIO.sub.4 (28.6 mg, 134 mol, 1.0 eq) and H.sub.2O (1.5 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHSO.sub.3 (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 12%-42% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfinyl)naphthalen-1-yl)cyclopropyl)-2-methyl benzamide (20.2 mg, 39.3 mol, 29% yield, FA salt) was obtained as a white solid. M+H.sup.+=465.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.57-8.51 (m, 1H), 8.45-8.40 (m, 1H), 8.24-8.20 (m, 1H), 8.03-7.95 (m, 2H), 7.71-7.57 (m, 2H), 7.03-6.97 (m, 1H), 6.83-6.70 (m, 3H), 4.16-4.04 (m, 2H), 3.14-3.00 (m, 1H), 2.97-2.81 (m, 3H), 2.48 (s, 6H), 2.08 (s, 3H), 1.64-1.52 (m, 2H), 1.49-1.34 (m, 2H), 1.30-1.18 (m, 3H).

Example 324: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfonyl)naphthalen-1-yl)

[1779] cyclopropyl)-2-methylbenzamide (Compound 471)

##STR01170##

[1780] 1 (Step 1: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methylbenzamide hydrochloride (324A-1)

[1781] To a solution of 5-(2-(dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalene-1-yl)cyclopropyl)-2-methylbenzamide (75.0 mg, 167 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 C. for 30 min. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methylbenzamide hydrochloride (80.0 mg, HCl salt) as a white solid, which was used in the next step without any further purification.

Step 2: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfonyl)naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 471)

[1782] To a solution of 5-(2-(dimethylamino)ethoxy)-N-(1-(3-(ethylthio) naphthalen-1-yl)cyclopropyl)-2-methylbenzamide hydrochloride (80.0 mg, 165 mol, 1.0 eq, HCl salt) in DCM (2.0 mL) was added m-CPBA (83.7 mg, 412 mol, 85% purity, 2.5 eq) at 0 C. The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHSO.sub.3 (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-(ethylsulfonyl)naphthalen-1-yl)cyclo propyl)-2-methyl benzamide (4.30 mg, 8.55 mol, 5% yield, FA salt) was obtained as a white solid. M+H.sup.+=481.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.77-8.61 (m, 1H), 8.47-8.43 (m, 1H), 8.36-8.30 (m, 2H), 8.08-8.02 (m, 1H), 7.82-7.74 (m, 1H), 7.71-7.62 (m, 1H), 7.11-6.94 (m, 2H), 6.84-6.56 (m, 2H), 4.33-4.18 (m, 2H), 3.30-3.22 (m, 2H), 3.20-3.12 (m, 2H), 2.75-2.61 (m, 6H), 2.19-2.03 (m, 3H), 1.64-1.56 (m, 2H), 1.48-1.41 (m, 2H), 1.37-1.31 (m, 3H).

Example 325: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 486)

##STR01171##

Step 1: tert-Butyl(2-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (325A-1)

[1783] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (236 mg, 763 mol, 1.0 eq) in DMF (15 mL) were added 1-(3-bromonaphthalen-1-yl)cyclo propanamine (200 mg, 763 mol, 1.0 eq), EDCI (219 mg, 1.14 mmol, 1.5 eq), HOBt (155 mg, 1.14 mmol, 1.5 eq) and TEA (154 mg, 153 mmol, 212 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl(2-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl) carbamate (340 mg, 614 mol, 81% yield) was obtained as a white solid. M+H.sup.+=553.1 (LCMS).

Step 2: tert-Butyl methyl(2-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclo propyl)carbamoyl)phenoxy)ethyl)carbamate (325A-2)

[1784] To a solution of tert-butyl(2-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (200 mg, 361 mol, 1.0 eq) in DMSO (10 mL) were added thiophen-2-ylboronic acid (55.5 mg, 434 mol, 1.2 eq), Pd(OAc) 2 (8.11 mg, 36.1 mol, 0.1 eq), KOAc (106 mg, 1.08 mmol, 3.0 eq) and CataCXium A (25.9 mg, 72.3 mol, 0.2 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (6.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.4). tert-Butyl methyl(2-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (74.0 mg, 133 mol, 37% yield) was obtained as a white solid. M+H.sup.+=557.3 (LCMS).

Step 3: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 486)

[1785] To a solution of tert-butyl methyl(2-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclo propyl)carbamoyl)phenoxy)ethyl)carbamate (74.0 mg, 133 mol, 1.0 eq) in EtOAc (1.5 mL) was added HCl/EtOAc (4 M, 7.4 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (36.4 mg, 71.5 mol, 54% yield, HCl salt) was obtained as a white solid. M+H.sup.+=457.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 8.76-8.65 (m, 2H), 8.62 (br d, J=8.9 Hz, 1H), 8.11 (d, J=7.6 Hz, 2H), 8.03-7.96 (m, 1H), 7.66 (d, J=3.1 Hz, 1H), 7.65-7.60 (m, 1H), 7.59-7.52 (m, 2H), 7.24-7.19 (m, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.93-6.86 (m, 1H), 6.66 (d, J=2.6 Hz, 1H), 4.13 (t, J=4.8 Hz, 2H), 3.30-3.22 (m, 2H), 2.58 (br t, J=5.1 Hz, 3H), 1.99 (s, 3H), 1.38 (br s, 2H), 1.27 (br s, 2H).

Example 326: (S)-5-(2-Aminopropoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 539)

##STR01172##

Step 1: (S)-tert-Butyl(1-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (326A-1)

[1786] To a solution of(S)-tert-butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (350 mg, 632 mol, 1.0 eq) and thiophen-2-ylboronic acid (121 mg, 948 mol, 1.5 eq) in DMSO (3.0 mL) were added Pd(OAc).sub.2 (14.2 mg, 63.2 mol, 0.1 eq), bis(1-adamantyl)-butyl-phosphane (45.3 mg, 126 mol, 0.2 eq) and KOAc (186 mg, 1.90 mmol, 3.0 eq). The resulting mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (S)-tert-Butyl(1-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (290 mg, 500 mol, 79% yield) was obtained as a white solid. M56+H.sup.+=501.3 (LCMS).

Step 2: (S)-5-(2-Aminopropoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 539)

[1787] To a solution of(S)-tert-butyl(1-(4-methyl-3-((1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (290 mg, 521 mol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B:

[1788] acetonitrile). (S)-5-(2-Aminopropoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (161 mg, 327 mol, 63% yield, HCl salt) was obtained as a white solid. M+H.sup.+=457.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18 (s, 1H), 8.66-8.60 (m, 1H), 8.13-8.06 (m, 4H), 8.03-7.98 (m, 1H), 7.67-7.65 (m, 1H), 7.62 (dd, J=1.0, 5.1 Hz, 1H), 7.55 (s, 2H), 7.24-7.19 (m, 1H), 7.10-7.05 (m, 1H), 6.91-6.86 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 4.06-3.99 (m, 1H), 3.91-3.84 (m, 1H), 3.59-3.47 (m, 1H), 1.99 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H), 1.23 (d, J=6.8 Hz, 3H).

Example 327: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 468)

##STR01173##

Step 1: 1-(3-(Thiophen-2-yl)naphthalen-1-yl)cyclopropanamine (327A-1)

[1789] To a solution of 1-(3-bromonaphthalen-1-yl)cyclopropanamine (160 mg, 610 mol, 1.0 eq) and thiophen-2-ylboronic acid (93.7 mg, 732 mol, 1.2 eq) in DMSO (1.5 mL) were added Pd(OAc).sub.2 (13.7 mg, 61.0 mol, 0.1 eq), bis(1-adamantyl)-butyl-phosphane (43.7 mg, 122 mol, 0.2 eq) and KOAc (179 mg, 1.83 mmol, 3.0 eq). The mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4. filtered, and concentrated under vacuum to give a crude product 1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropanamine (402 mg) as a black oil. M+H.sup.+=266.1 (LCMS).

Step 2: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 468)

[1790] To a solution of 1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropanamine (28.0 mg, 105 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (27.3 mg, 116 mol, 1.1 eq) in DMF (1.0 mL) were added HBTU (80.0 mg, 211 mol, 2.0 eq) and DIEA (54.5 mg, 422 mol, 73.5 L, 4.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (6.40 mg, 10.6 mol, 10% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=483.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.26 (s, 1H), 8.55 (d, J=8.00 Hz, 1H), 8.25 (d, J=1.63 Hz, 1H), 8.05 (s, 1H), 7.97-7.88 (m, 1H), 7.62-7.58 (m, 1H), 7.55-7.51 (m, 1H), 7.43 (d, J=4.63 Hz, 1H), 7.19-7.06 (m, 2H), 6.93 (dd, J=8.44, 2.56 Hz, 1H), 6.74 (d, J=2.50 Hz, 1H), 4.71-4.59 (m, 1H), 4.32-4.22 (m, 1H), 4.21-4.08 (m, 2H), 3.99-3.87 (m, 1H), 2.92 (s, 3H), 2.59-2.47 (m, 2H), 2.05 (s, 3H), 1.53-1.45 (m, 2H), 1.41-1.33 (m, 2H).

Example 328: 5-(2-Aminopropoxy)-2-methyl-N-(1-(3-phenylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 470)

##STR01174##

Step 1: tert-Butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (328A-1)

[1791] To a solution of 1-(3-bromonaphthalen-1-yl)cyclopropanamine (350 mg, 1.34 mmol, 1.0 eq) in DMF (2.0 mL) was added 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (454 mg, 1.47 mmol, 1.1 eq), followed by HBTU (1.01 g, 2.67 mmol, 2.0 eq) and DIEA (518 mg, 4.01 mmol, 698 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (8.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product tert-butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (1.64 g) as a yellow oil. M56+H.sup.+=479.1 (LCMS).

Step 2: tert-Butyl(1-(4-methyl-3-((1-(3-phenylnaphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (328A-2)

[1792] To a solution of tert-butyl(1-(3-((1-(3-bromonaphthalen-1-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (55.0 mg, 99.4 mol, 1.0 eq) and phenylboronic acid (18.2 mg, 149 mol, 1.5 eq) in DMSO (1.0 mL) were added Pd(OAc) 2 (2.23 mg, 9.94 mol, 0.1 eq), bis(1-adamantyl)-butyl-phosphane (7.13 mg, 19.9 mol, 0.2 eq) and KOAc (29.3 mg, 298 mol, 3.0 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that 3% starting material remained and 44% desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product tert-butyl(1-(4-methyl-3-((1-(3-phenylnaphthalen-1-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (110 mg) as a black oil. M56+H.sup.+=495.2 (LCMS).

Step 3: 5-(2-Aminoethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methyl benzamide (Compound 470)

[1793] To a solution of tert-butyl(1-(4-methyl-3-((1-(3-phenylnaphthalen-1-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (110 mg, 200 mol, 1.0 eq) in EtOAc (200 L) was added HCl/EtOAc (4 M, 500 L). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methyl benzamide (20.0 mg, 35.0 mol, 16% yield, TFA salt) as a white solid. M+H.sup.+=451.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.17 (s, 1H), 8.70-8.61 (m, 1H), 8.14 (s, 2H), 8.06-8.00 (m, 1H), 7.92-7.88 (m, 2H), 7.85-7.80 (m, 2H), 7.60-7.50 (m, 4H), 7.45-7.38 (m, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.91-6.85 (m, 1H), 6.66 (d, J=2.8 Hz, 1H), 4.01 (dd, J=3.8, 10.3 Hz, 1H), 3.83 (dd, J=7.3, 10.4 Hz, 1H), 3.53 (br d, J=4.1 Hz, 2H), 1.99 (s, 3H), 1.41-0.35 (m, 2H), 1.32-1.27 (m, 2H), 1.20 (d, J=6.8 Hz, 3H).

Example 329: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-phenylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 475)

##STR01175##

Step 1:4-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl trifluoromethanesulfonate (329A-1)

[1794] To a solution of N-(1-(3-hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (200 mg, 480 mol, 1.0 eq) in THF (10 mL) was added 1-BuOK (80.1 mg, 720 mol, 1.5 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. PhN(Tf).sub.2 (257 mg, 720 mol, 1.5 eq) was added in portions. The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (MeOH/DCM=1/4, R.sub.f=0.4). 4-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (120 mg, 219 mol, 46% yield) was obtained as a yellow solid. M+H.sup.+=549.2 (LCMS).

Step 2: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-phenylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 475)

[1795] To a solution of 4-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 mol, 1.0 eq) and phenylboronic acid (27.8 mg, 228 mol, 1.3 eq) in a mixture of toluene (5.0 mL) and EtOH (2.5 mL) were added Na.sub.2CO.sub.3 (2 M aqueous, 228 L, 2.5 eq) and Pd(dppf)Cl.sub.2 (6.67 mg, 9.11 mol, 0.05 eq) under a N.sub.2 atmosphere. The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (20040 mm, 10 m); flow rate: 75 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-phenoxynaphthalen-1-yl)cyclopropyl)benzamide (18.1 mg, 34.6 mol, 19% yield, FA salt) was obtained as a white solid. M+H.sup.+=477.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.15-9.09 (m, 1H), 8.71-8.64 (m, 1H), 8.20-8.16 (m, 1H), 8.15-8.11 (m, 2H), 8.05-7.99 (m, 1H), 7.87-7.80 (m, 2H), 7.62-7.51 (m, 4H), 7.45-7.37 (m, 1H), 7.06-7.00 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.59 (m, 1H), 3.90-3.83 (m, 2H), 3.28-3.24 (m, 2H), 2.80-2.72 (m, 1H), 2.25-2.21 (m, 3H), 2.03-1.82 (m, 5H), 1.42-1.36 (m, 2H), 1.32-1.26 (m, 2H).

Example 330: N-(1-(7-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 477)

##STR01176##

Step 1: 7-((tert-Butyldimethylsilyl)oxy)-1-naphthonitrile (330A-2)

[1796] To a solution of 7-hydroxy-1-naphthonitrile (1.40 g, 8.28 mmol, 1.0 eq) in DMF (15 mL) were added TBSCl (1.50 g, 9.93 mmol, 1.22 mL, 1.2 eq) and imidazole (1.13 g, 16.6 mmol, 2.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL4). The combined organic layers were washed with brine (20 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-((ter-Butyldimethylsilyl)oxy)-1-naphthonitrile (1.60 g, 5.64 mmol, 68% yield) was obtained as a yellow gum. M+H.sup.+=284.1 (LCMS).

Step 2: 1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (330A-3)

[1797] A solution of 7-((tert-butyldimethylsilyl)oxy)-1-naphthonitrile (800 mg, 2.82 mmol, 1.0 eq) in anhydrous Et.sub.2O (70 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (1.20 g, 4.23 mmol, 1.25 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 2.07 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (801 mg, 5.64 mmol, 697 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (390 mg, 1.24 mmol, 44% yield) was obtained as a yellow gum.

Step 3: N-(1-(7-((tert-Butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (330A-4)

[1798] To a solution of 1-(7-((tert-butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropanamine (150 mg, 478 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (146 mg, 622 mol, 1.3 eq) in DMF (6.0 mL) were added HBTU (181 mg, 478 mol, 1.0 eq) and DIEA (186 mg, 1.44 mmol, 250 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.5). N-(1-(7-((tert-Butyldimethyl silyl)oxy) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (150 mg, 283 mol, 59% yield) was obtained as a yellow gum. M+H.sup.+=531.6 (LCMS).

Step 4: N-(1-(7-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 477)

[1799] To a solution of N-(1-(7-((tert-butyldimethylsilyl)oxy) naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (150 mg, 283 mol, 1.0 eq) in THF (7.0 mL) was added TBAF (1 M in THF, 848 L, 3.0 eq) at 0 C. The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.2). N-(1-(7-Hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzamide (6.30 mg, 14.7 mol, 5% yield) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.60 (s, 1H), 9.02 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.77-7.64 (m, 3H), 7.20 (dd, J=7.2, 8.1 Hz, 1H), 7.12 (dd, J=2.3, 8.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 3.89 (br d, J=5.3 Hz, 2H), 3.31-3.12 (m, 2H), 2.87-2.68 (m, 1H), 2.25 (s, 3H), 2.07-1.81 (m, 5H), 1.32 (s, 2H), 1.15-1.07 (m, 2H).

Example 331:8-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthoic acid (Compound 465)

##STR01177##

Step 1:8-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl trifluoromethanesulfonate (331A-1)

[1800] To a solution of N-(1-(7-hydroxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (300 mg, 720 mol, 1.0 eq) in THF (10 mL) was added PhN (Tf) 2 (386 mg, 1.08 mmol, 1.5 eq) at 0 C., followed by 1-BuOK (121 mg, 1.08 mmol, 1.5 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 8-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (300 mg, 547 mol, 76% yield) was obtained as a yellow gum. M+H.sup.+=549.3 (LCMS).

Step 2: Methyl 8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclo propyl)-2-naphthoate (331A-2)

[1801] To a solution of 8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 mol, 1.0 eq) in MeOH (10 mL) were added Pd(dppf)Cl.sub.2 (13.3 mg, 18.2 mol, 0.1 eq) and TEA (148 mg, 1.46 mmol, 203 L, 8.0 eq). The suspension was degassed and purged with CO three times. The mixture was stirred at 80 C. for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.35). Methyl 8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthoate (70.0 mg, 153 mol, 84% yield) was obtained as a yellow gum. M+H.sup.+=459.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.09 (s, 1H), 8.06-7.93 (m, 2H), 7.86 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.79-6.61 (m, 3H), 3.98-3.80 (m, 5H), 3.65-3.38 (m, 2H), 2.47-2.34 (m, 2H), 2.19-2.05 (m, 1H), 2.02 (s, 3H), 1.98 (s, 3H), 1.51 (br s, 2H), 1.33 (br t, J=5.3 Hz, 2H).

Step 3:8-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-2-naphthoic acid (Compound 465)

[1802] To a solution of methyl 8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclo propyl)-2-naphthoate (60.0 mg, 131 mol, 1.0 eq) in a mixture of MeOH (1.0 mL) and THE (3.0 mL) was added NaOH (2 M aqueous, 262 L, 4.0 eq). The reaction mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and washed with MTBE (10 mL3). The aqueous was adjusted to pH 6 with HCl (1 M aqueous) and the mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 40 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B:

[1803] acetonitrile). 8-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclo propyl)-2-naphthoic acid (11.0 mg, 22.9 mol, 17% yield, HCl salt) was obtained as a white solid. M+H.sup.+=445.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 13.18-12.83 (m, 1H), 10.56-10.21 (m, 1H), 9.29 (s, 2H), 8.14-7.83 (m, 4H), 7.61 (dd, J=7.3, 8.0 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (br d, J=6.5 Hz, 1H), 6.70 (br s, 1H), 4.72-4.50 (m, 1H), 4.40-4.15 (m, 2H), 4.08-3.76 (m, 2H), 2.81 (br s, 3H), 2.44-2.19 (m, 2H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.21 (br s, 2H).

Example 332: N-(1-(7-Aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 483)

##STR01178##

Step 1: tert-Butyl(8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (332A-1)

[1804] To a solution of 8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) naphthalen-2-yltrifluoromethanesulfonate (100 mg, 183 mol, 182 L, 1.0 eq) in 2-methylbutan-2-ol (4.0 mL) were added tert-butyl carbamate (25.6 mg, 219 mol, 1.2 eq), Cs.sub.2CO.sub.3 (119 mg, 365 mol, 2.0 eq) and XPhos Pd G3 (15.4 mg, 18.2 mol, 0.1 eq) under a N.sub.2 atmosphere. The mixture was stirred at 90 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.3). tert-Butyl(8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (60.0 mg, 116 mol, 64% yield) was obtained as a yellow gum. M+H.sup.+=516.3 (LCMS).

Step 2: N-(1-(7-Aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 483)

[1805] To a solution of tert-butyl(8-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (100 mg, 194 mol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was treated with NH.sub.4OH (25% aqueous) to adjust pH to 7. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(7-Aminonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (2.60 mg, 6.00 mol, 3% yield) was obtained as a yellow solid. M+H.sup.+=416.2 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 8.80 (s, 1H), 7.66-7.48 (m, 4H), 7.10-7.00 (m, 2H), 6.98-6.73 (m, 2H), 6.61 (d, J=2.8 Hz, 1H), 5.09 (s, 2H), 3.86 (d, J=5.5 Hz, 2H), 3.25-3.17 (m, 2H), 2.73-2.65 (m, 1H), 2.21 (s, 3H), 2.08-1.76 (m, 5H), 1.29 (br s, 2H), 1.17-1.04 (m, 2H).

Example 333: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 434)

##STR01179##

Step 1: 7-Methoxyquinoline-5-carbonitrile (333A-2)

[1806] To a solution of 5-bromo-7-methoxyquinoline (10.0 g, 42.0 mmol, 1.0 eq) in DMF (250 mL) were added Zn(CN).sub.2 (9.86 g, 84.0 mmol, 2.0 eq) and Pd(PPh.sub.3).sub.4 (4.85 g, 4.20 mmol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured into H.sub.2O (1.0 L) and extracted with EtOAc (500 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to the volume to 50 mL, and a precipitate was formed. The mixture was filtered, and the filter cake was washed with EtOAc (200 mL) to give a white solid. The solid was dissolved with DCM (300 mL) and stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give 7-methoxyquinoline-5-carbonitrile (6.25 g, 34.0 mmol, 81% yield) as a white solid.

Step 2: 1-(7-Methoxyquinolin-5-yl)cyclopropanamine (333A-3)

[1807] A mixture of 7-methoxyquinoline-5-carbonitrile (2.00 g, 10.9 mmol, 1.0 eq) in anhydrous Et.sub.2O (160 mL) was degassed and purged with N.sub.2 three times. Then the white suspension was cooled to 78 C. To this mixture was added Ti(i-PrO).sub.4 (4.63 g, 16.3 mmol, 4.81 mL, 1.5 eq) slowly during a period of 5 min and stirred at 78 C. for 10 min. It still was a white suspension. EtMgBr (3 M, in Et.sub.2O, 7.96 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. The color of the mixture turned to brown after the addition was complete. The resulting mixture was stirred at the same temperature for 10 min and then warmed to room temperature (between 15-20 C.) slowly over 1.5 h. The mixture turned to black. To the mixture was added BF.sub.3.Math.Et.sub.2O (3.08 g, 21.7 mmol, 2.68 mL, 2.0 eq) in portions at the same temperature with no obvious temperature change. The resulting mixture was stirred at room temperature for another 1 h. LCMS showed some SM remained and 33% desired product was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous) (100 mL) and MTBE (100 mL) and extracted with MTBE (80 mL2). The MTBE organic layers were discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. 1-(7-Methoxyquinolin-5-yl)cyclopropanamine (1.00 g, 4.67 mmol, 43% yield) was obtained as a brown solid. M+H.sup.+=215.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.79 (dd, J=1.6, 4.3 Hz, 1H), 8.61 (dd, J=0.9, 8.4 Hz, 1H), 7.31-7.27 (m, 1H), 7.21 (s, 1H), 7.18 (d, J=2.5 Hz, 1H), 3.89 (s, 3H), 1.15-1.08 (m, 2H), 0.97-0.92 (m, 2H).

Step 3: 5-(2-(Dimethylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 434)

[1808] To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (400 mg, 1.79 mmol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropanamine (500 mg, 2.34 mmol, 1.3 eq) in DMF (20 mL) were added HATU (1.70 g, 4.48 mmol, 2.5 eq), and DIEA (694 mg, 5.38 mmol, 936 L, 3.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=5/1, R.sub.f=0.35) to give the free base product. The free base product was dealt with acetonitrile (1.0 mL), followed by HCl (0.40% aqueous, 2.0 mL) and lyophilized to give 5-(2-(dimethylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (122 mg, 254 mol, 14% yield, HCl salt) as a white solid. M+H.sup.+=420.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.95 (d, J=8.4 Hz, 1H), 8.82 (dd, J=1.6, 4.2 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.42 (dd, J=4.2, 8.4 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.86 (dd, J=2.7, 8.4 Hz, 1H), 6.64 (d, J=2.6 Hz, 1H), 4.05 (br t, J=5.4 Hz, 2H), 3.92 (s, 3H), 2.88 (br d, J=8.9 Hz, 2H), 2.39 (br s, 6H), 1.95 (s, 3H), 1.37-1.31 (m, 2H), 1.22-1.16 (m, 2H).

Example 334: (S)-5-(2-Aminopropoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 530)

##STR01180##

Step 1: tert-Butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (334A-1)

[1809] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropanamine (20.0 mg, 93.3 mol, 1.0 eq) and(S)-5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (28.9 mg, 93.4 mol, 1.0 eq) in DMF (1.0 mL) were added HBTU (8.5 mg, 233 mol, 2.5 eq) and DIEA (48.3 mg, 373 mol, 65.0 L, 4.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a curde product tert-butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (120 mg) as a colorless oil. M+H.sup.+=506.3 (LCMS).

Step 2: (S)-5-(2-Aminopropoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 530)

[1810] To a solution of tert-butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (120 mg, 237 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.62 g, 14.3 mmol, 1.05 mL, 60 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(2-Aminopropoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (4.04 mg, 7.54 mol, 3% yield, TFA salt) was obtained as a pale yellow gum. M+H.sup.+=406.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.16 (s, 1H), 9.10 (br d, J=8.0 Hz, 1H), 8.92 (d, J=3.5 Hz, 1H), 7.91 (br s, 2H), 7.60-7.53 (m, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.7, 8.4 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.03 (dd, J=3.9, 10.3 Hz, 1H), 3.95 (s, 3H), 3.85 (dd, J=7.2, 10.3 Hz, 1H), 3.60-3.51 (m, 1H), 1.96 (s, 3H), 1.38-1.32 (m, 2H), 1.22 (d, J=6.6 Hz, 5H).

Example 335: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)

[1811] ethoxy)benzamide (Compound 526)

##STR01181##

Step 1: tert-Butyl(2-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (335A-1)

[1812] To a solution of 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (150 mg, 485 mol, 1.0 eq) in DMF (6.0 mL) were added 1-(7-methoxyquinolin-5-yl)cyclopropanamine (260 mg, 1.21 mmol, 2.5 eq), DIEA (188 mg, 1.45 mmol, 254 L, 3.0 eq) and HATU (461 mg, 1.21 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(2-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (200 mg, 396 mol, 82% yield) was obtained as a brown oil. M+H.sup.+=506.2 (LCMS).

Step 2: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (Compound 526)

[1813] To a solution of tert-butyl(2-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (200 mg, 396 mol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)ethoxy)benzamide (110 mg, 243 mol, 61% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=406.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.64 (br d, J=8.4 Hz, 1H), 9.36 (s, 1H), 9.22-9.05 (m, 3H), 7.94 (dd, J=5.3, 8.4 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.19 (t, J=5.1 Hz, 2H), 4.01 (s, 3H), 3.24 (quin, J=5.4 Hz, 2H), 2.57 (t, J=5.4 Hz, 3H), 1.97 (s, 3H), 1.44-1.38 (m, 2H), 1.33-1.28 (m, 2H).

Example 336: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)propoxy)benzamide (Compound 560)

##STR01182##

Step 1: (S)-tert-Butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)(methyl)carbamate (336A-1)

[1814] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropanamine (30.0 mg, 140 mol, 1.0 eq) and(S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoic acid (45.3 mg, 140 mol, 1.0 eq) in DMF (1.0 mL) were added DIEA (72.4 mg, 560 mol, 97.5 L, 4.0 eq) and HATU (133 mg, 350 mol, 2.5 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product(S)-tert-butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)(methyl)carbamate (80.0 mg) as a brown liquid. M+H.sup.+=520.3 (LCMS).

Step 2: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)propoxy)benzamide (Compound 560)

[1815] To a solution of(S)-tert-butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)(methyl)carbamate (80.0 mg, 154 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)propoxy)benzamide (15.8 mg, 33.5 mol, 21% yield, HCl salt) was obtained as a pale yellow gum. M+H.sup.+=420.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.73 (d, J=8.50 Hz, 1H), 9.43-9.36 (m, 1H), 9.34-9.25 (m, 1H), 9.20 (d, J=4.50 Hz, 1H), 9.17-9.06 (m, 1H), 8.00 (dd, J=8.38, 5.50 Hz, 1H), 7.77-7.71 (m, 2H), 7.09 (d, J=8.38 Hz, 1H), 6.92 (dd, J=8.38, 2.63 Hz, 1H), 6.76 (d, J=2.63 Hz, 1H), 4.18-4.13 (m, 1H), 4.11-4.07 (m, 1H), 4.02 (s, 3H), 3.56-3.45 (m, 1H), 2.56-2.52 (m, 3H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.33-1.27 (m, 5H).

Example 337: (S)-5-(2-(Dimethylamino)propoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 575)

##STR01183##

Step 1: (S)-5-(2-(Dimethylamino)propoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 575)

[1816] To a solution of(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)propoxy)benzamide (176 mg, 421 mol, 1.0 eq) in MeOH (2.0 mL) was added formaldehyde (68.4 mg, 842 mol, 62.7 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The resulting mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (79.4 mg, 1.26 mmol, 3.0 eq) was added. The reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 60 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-5-(2-(Dimethylamino)propoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (39.1 mg, 82.0 mol, 19% yield) was obtained as a pale yellow solid. M+H.sup.+=434.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.62 (br d, J=1.3 Hz, 1H), 9.73 (d, J=8.1 Hz, 1H), 9.39 (s, 1H), 9.19 (dd, J=1.1, 5.4 Hz, 1H), 8.05-7.93 (m, 1H), 7.79-7.65 (m, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.93 (dd, J=2.8, 8.4 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 4.21-4.18 (m, 2H), 4.02 (s, 3H), 3.74-3.68 (m, 1H), 2.73 (dd, J=5.0, 8.9 Hz, 6H), 1.96 (s, 3H), 1.47-1.40 (m, 2H), 1.31 (d, J=6.8 Hz, 5H).

Example 338: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 511)

##STR01184##

Step 1: (S)-tert-Butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (338A-1)

[1817] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (300 mg, 934 mol, 1.0 eq) in DMF (10 mL) were added 1-(7-methoxyquinolin-5-yl)cyclopropanamine (300 mg, 1.40 mmol, 1.5 eq), DIEA (362 mg, 2.80 mmol, 488 L, 3.0 eq) and HATU (87 mg, 2.33 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/5. (S)-tert-Butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (400 mg, 773 mol, 83% yield) was obtained as a yellow solid. M+H.sup.+=518.2 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 511)

[1818] To a solution of(S)-tert-butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (400 mg, 773 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (48.9 mg, 116 mol, 15% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.35 (br d, J=8.4 Hz, 1H), 9.28-9.13 (m, 2H), 9.03 (br d, J=3.8 Hz, 2H), 7.73 (dd, J=4.9, 8.4 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 4.65 (br d, J=6.4 Hz, 1H), 4.28 (dd, J=7.4, 11.1 Hz, 1H), 4.14 (dd, J=3.3, 11.1 Hz, 1H), 3.98 (s, 3H), 3.95-3.76 (m, 2H), 2.48-2.27 (m, 2H), 1.97 (s, 3H), 1.43-1.34 (m, 2H), 1.30-1.22 (m, 2H).

Example 339: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 527)

##STR01185##

Step 1: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 527)

[1819] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (250 mg, 599 mol, 1.0 eq) in MeOH (10 mL) was added TEA (50.0 L), followed by formaldehyde (36.0 mg, 1.20 mmol, 32.9 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (75.0 mg, 1.20 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (87.2 mg, 183 mol, 31% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.83-10.68 (m, 1H), 9.59-9.48 (m, 1H), 9.31 (s, 1H), 9.12 (br d, J=4.9 Hz, 1H), 7.87 (br s, 1H), 7.69 (s, 1H), 7.58 (br s, 1H), 7.15-7.06 (m, 1H), 7.00-6.89 (m, 1H), 6.83-6.71 (m, 1H), 4.68-4.58 (m, 1H), 4.38 (br dd, J=8.4, 10.8 Hz, 1H), 4.22 (dd, J=3.2, 11.2 Hz, 1H), 4.01 (s, 3H), 3.85 (br dd, J=6.7, 9.3 Hz, 2H), 2.81 (d, J=5.0 Hz, 3H), 2.45-2.22 (m, 2H), 1.96 (s, 3H), 1.41 (br s, 2H), 1.30 (br s, 2H).

Example 340: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 462)

##STR01186##

Step 1: (S)-tert-Butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (340A-1)

[1820] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropanamine (192 mg, 895 mol, 1.5 eq) and(S)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 596 mol, 1.0 eq) in DMF (10 mL) were added DIEA (231 mg, 1.79 mmol, 312 L, 3.0 eq) and HATU (567 mg, 1.49 mmol, 2.5 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5. (S)-tert-Butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (254 mg, 478 mol, 40% yield) was obtained as a yellow oil. M+H.sup.+=532.3 (LCMS).

Step 2: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 462)

[1821] To a solution of(S)-tert-butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-1-carboxylate (254 mg, 478 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (123 mg, 264 mol, 55% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.70 (d, J=8.4 Hz, 2H), 9.36 (s, 1H), 9.14 (d, J=5.3 Hz, 2H), 7.97 (dd, J=5.5, 8.5 Hz, 1H), 7.74 (d, J=2.4 Hz, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.6, 8.4 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.22-4.13 (m, 2H), 4.10-3.97 (m, 3H), 3.86-3.79 (m, 1H), 3.25-3.11 (m, 2H), 2.15-2.03 (m, 1H), 2.02-1.81 (m, 5H), 1.68 (qd, J=8.2, 12.7 Hz, 1H), 1.42 (br s, 2H), 1.30 (br s, 2H).

Example 341: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylpyrrolidin-2-yl)methoxy)benzamide (Compound 528)

##STR01187##

Step 1: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylpyrrolidin-2-yl)methoxy)benzamide (Compound 528)

[1822] To a solution of(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (70.0 mg, 150 mol, 1.0 eq, HCl salt) in MeOH (2.5 mL) was added TEA (0.30 mL), followed by formaldehyde (8.98 mg, 299 mol, 8.24 l, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min and NaBH.sub.3CN (18.8 mg, 299 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-15% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrrolidin-2-ylmethoxy)benzamide (22.1 mg, 45.9 mol, 31% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=446.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.94 (br s, 1H), 9.72 (d, J=8.5 Hz, 1H), 9.38 (s, 1H), 9.19 (d, J=4.8 Hz, 1H), 7.99 (dd, J=5.4, 8.4 Hz, 1H), 7.72 (dd, J=2.3, 16.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.77 (d, J=2.6 Hz, 1H), 4.38-4.30 (m, 1H), 4.28-4.22 (m, 1H), 4.02 (s, 3H), 3.74 (dt, J=3.3, 8.0 Hz, 1H), 3.61-3.45 (m, 1H), 3.15-3.01 (m, 1H), 2.88 (d, J=4.8 Hz, 3H), 2.28-2.14 (m, 1H), 2.03-1.87 (m, 5H), 1.83-1.69 (m, 1H), 1.42 (br s, 2H), 1.32 (br s, 2H).

Example 342: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl

[1823] piperidin-2-yl)methoxy)benzamide (Compound 550)

##STR01188##

Step 1: (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)piperidine-1-carboxylate (342A-1)

[1824] To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and(S)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (583 mg, 2.70 mmol, 1.5 eq) in toluene (15 mL) were added TMAD (930 mg, 5.42 mmol, 3.0 eq), PPh.sub.3 (1.40 g, 5.42 mmol, 3.0 eq). The resulting mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4. filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. (S)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)piperidine-1-carboxylate (470 mg, 1.16 mmol, 72% yield) was obtained as a yellow solid. M100+H.sup.+=264.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.34 (d, J=2.8 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.09 (dd, J=2.8, 8.4 Hz, 1H), 4.48-4.38 (m, 1H), 4.17-4.05 (m, 2H), 3.92-3.83 (m, 1H), 3.81 (s, 3H), 2.84 (br t, J=12.4 Hz, 1H), 2.42 (s, 3H), 1.78 (br d, J=7.4 Hz, 1H), 1.64-1.48 (m, 4H), 1.35 (s, 9H), 1.32-1.25 (m, 1H).

Step 2: (S)-5-((1-(tert-Butoxycarbonyl) piperidin-2-yl)methoxy)-2-methylbenzoic acid (342A-2)

[1825] To a solution of(S)-tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)piperidine-1-carboxylate (470 mg, 1.16 mmol, 1.0 eq) in a mixture of THF (3.0 mL) and MeOH (1.0 mL) was added NaOH (2 M aqueous, 2.33 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and washed with EtOAc (10 mL3). The aqueous layer was acidified to pH 3 with HCl (1 M aqueous). The product was extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give the crude product(S)-5-((1-(tert-Butoxycarbonyl) piperidin-2-yl)methoxy)-2-methylbenzoic acid (260 mg) was obtained as a white solid, which was used in the next step without any further purification. M100+H.sup.+=250.1 (LCMS).

Step 3: (S)-tert-Butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)piperidine-1-carboxylate (342A-3)

[1826] To a solution of(S)-5-((1-(tert-butoxycarbonyl) piperidin-2-yl)methoxy)-2-methylbenzoic acid (230 mg, 658 mol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropanamine (141 mg, 658 mol, 1.0 eq) in DCM (1.0 mL) were added EDCI (189 mg, 987 mol, 1.5 eq), HOBt (133 mg, 987 mol, 1.5 eq) and TEA (200 mg, 1.97 mmol, 275 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/0, R.sub.f=0.5). (S)-tert-Butyl2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)methyl)piperidine-1-carboxylate (200 mg, 367 mol, 56% yield) was obtained as a yellow oil. M+H.sup.+=546.3 (LCMS).

Step 4: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(piperidin-2-yl methoxy)benzamide (Compound 550)

[1827] To a solution of(S)-tert-butyl 2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)piperidine-1-carboxylate (200 mg, 330 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL) slowly. The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was filtered, and the cake was washed with EtOAc (5.0 mL3). The cake was dried under vacuum to give(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(piperidin-2-yl methoxy)benzamide (120 mg, 269 mol, 82% yield, HCl salt) as a yellow solid. M+H.sup.+=446.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.65 (br d, J=8.1 Hz, 1H), 9.36 (s, 1H), 9.17 (br d, J=4.8 Hz, 1H), 9.12 (br s, 1H), 7.95 (dd, J=5.3, 8.3 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.3 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 4.15-4.10 (m, 1H), 4.08-4.04 (m, 1H), 4.02 (s, 3H), 3.45-3.33 (m, 1H), 3.22 (br d, J=12.3 Hz, 1H), 2.88 (br d, J=6.8 Hz, 1H), 1.96 (s, 3H), 1.86-1.76 (m, 2H), 1.75-1.60 (m, 2H), 1.59-1.45 (m, 2H), 1.41 (br s, 2H), 1.31 (br s, 2H).

Example 343: 5-((4-Methoxypyridin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 561)

##STR01189##

Step 1: 5-Hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (343A-1)

[1828] To a solution of 5-hydroxy-2-methylbenzoic acid (700 mg, 4.60 mmol, 0.98 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropanamine (1.00 g, 4.67 mmol, 1.0 eq) in DMF (15 mL) were added TEA (472 mg, 4.67 mmol, 650 L, 1.0 eq), EDCI (939 mg, 4.90 mmol, 1.05 eq) and HOBt (126 mg, 933 mol, 0.2 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (40 mL) and extracted with EtOAc (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-Hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (1.10 g, 3.16 mmol, 68% yield) was obtained as a yellow solid. M+H.sup.+=349.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.27 (s, 1H), 9.07 (s, 1H), 8.97-8.92 (m, 1H), 8.82 (dd, J=1.5, 4.3 Hz, 1H), 7.49-7.39 (m, 2H), 7.31 (d, J=2.5 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.64 (dd, J=2.6, 8.3 Hz, 1H), 6.44 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 1.92 (s, 3H), 1.34-1.28 (m, 2H), 1.23-1.16 (m, 2H).

Step 2: 5-((4-Methoxypyridin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 561)

[1829] A mixture of 5-hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (70.0 mg, 201 mol, 1.0 eq), (4-methoxypyridin-2-yl)methanol (55.9 mg, 402 mol, 2.0 eq), and CMBP (72.7 mg, 302 mol, 1.5 eq) in toluene (3.5 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-((4-Methoxypyridin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (81.9 mg, 153 mol, 76% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=470.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.74-9.65 (m, 1H), 9.67 (br d, J=8.5 Hz, 1H), 9.40 (s, 1H), 9.19-9.12 (m, 1H), 8.70 (d, J=6.8 Hz, 1H), 7.95 (dd, J=5.3, 8.4 Hz, 1H), 7.77-7.64 (m, 2H), 7.56 (d, J=2.5 Hz, 1H), 7.46 (dd, J=2.6, 6.6 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 6.87 (d, J=2.8 Hz, 1H), 5.36 (s, 2H), 4.03 (d, J=13.5 Hz, 6H), 1.98 (s, 3H), 1.45-1.37 (m, 2H), 1.35-1.27 (m, 2H).

Example 344: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyridin-4-yloxy)benzamide (Compound 584)

##STR01190##

Step 1: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyridin-4-yloxy)benzamide (Compound 584)

[1830] To a solution of 5-hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (60.0 mg, 172 mol, 1.0 eq) and 4-bromopyridine (81.6 mg, 517 mol, 3.0 eq) in dioxane (4.0 mL) were added Cs.sub.2CO.sub.3 (112 mg, 344 mol, 2.0 eq), Pd.sub.2 (dba) 3 (15.8 mg, 17.2 mol, 0.1 eq) and Xantphos (20.9 mg, 36.2 mol, 0.2 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (4.0 mL) and extracted with DCM (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyridin-4-yloxy)benz amide (11.2 mg, 26.1 mol, 15% yield) was obtained as a brown solid. M+H.sup.+=426.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18 (s, 1H), 8.91 (d, J=8.3 Hz, 1H), 8.79 (dd, J=1.3, 4.1 Hz, 1H), 8.43 (d, J=6.1 Hz, 2H), 7.46 (d, J=2.5 Hz, 1H), 7.38 (dd, J=4.3, 8.4 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.09 (dd, J=2.5, 8.3 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 6.86 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.04 (s, 3H), 1.40-1.27 (m, 2H), 1.23-1.13 (m, 2H).

Example 345: (S)-4-Amino-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 597)

##STR01191##

Step 1: Methyl 5-fluoro-2-methyl-4-nitrobenzoate (345A-2)

[1831] To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (500 mg, 2.14 mmol, 1.0 eq) in MeOH (10 mL) were added TEA (1.73 g, 17.1 mmol, 2.38 mL, 8.0 eq) and Pd(dppf)Cl.sub.2 (156 mg, 214 mol, 0.1 eq). The mixture was degassed and purged with CO three times, then stirred at 80 C. for 16 h under a CO (50 psi) atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/5, Ry-0.5). Methyl 5-fluoro-2-methyl-4-nitrobenzoate (200 mg, 938 mol, 44% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.93 (d, J=7.1 Hz, 1H), 7.83 (d, J=11.2 Hz, 1H), 3.96 (s, 3H), 2.64 (s, 3H).

Step 2: (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (345A-3)

[1832] To a solution of methyl 5-fluoro-2-methyl-4-nitrobenzoate (180 mg, 844 mol, 1.0 eq) and(S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (237 mg, 1.27 mmol, 1.5 eq) in DMSO (15 mL) were added CsF (257 mg, 1.69 mmol, 62.3 L, 2.0 eq) and DIEA (327 mg, 2.53 mmol, 441 L, 3.0 eq). The mixture was stirred at 120 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with MTBE (6.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The mixture was extracted with EtOAc (6.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (200 mg, 546 mol, 65% yield) was obtained as a yellow solid. M56+H.sup.+=311.0 (LCMS).

Step 3: (S)-tert-Butyl 2-((5-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (345A-4)

[1833] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (198 mg, 539 mol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropanamine (57.8 mg, 270 mol, 0.5 eq) in DMF (12 mL) were added TEA (54.6 mg, 539 mol, 75.0 L, 1.0 eq), EDCI (109 mg, 566 mol, 1.05 eq) and HOBt (14.6 mg, 108 mol, 0.2 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. (S)-tert-Butyl 2-((5-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl-2-nitro phenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 160 mol, 30% yield) was obtained as a yellow solid. M+H.sup.+=563.3 (LCMS).

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-nitrobenzamide (345A-5)

[1834] To a solution of(S)-tert-butyl 2-((5-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 160 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.31 g, 20.3 mmol, 1.5 mL, 127 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to the crude (S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-nitrobenzamide (80.0 mg, 139 mol, 87% yield, TFA salt) as a yellow oil. M+H.sup.+=463.1 (LCMS).

Step 5: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitrobenzamide (345A-6)

[1835] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-nitrobenzamide (80.0 mg, 139 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (30.0 L), followed by formaldehyde (22.5 mg, 278 mol, 7.65 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (17.4 mg, 278 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitrobenzamide (65.0 mg) as a yellow oil. M+H.sup.+=477.2 (LCMS).

Step 6: (S)-4-Amino-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 597)

[1836] To a solution of(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitrobenzamide (60.0 mg, 126 mol, 1.0 eq) in MeOH (6.0 mL) and H.sub.2O (1.2 mL) were added NH.sub.4Cl (33.7 mg, 630 mol, 5.0 eq) and iron powder (35.2 mg, 630 mol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (7.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (15040 mm, 10 m); flow rate: 50 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (S)-4-Amino-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (6.50 mg, 14.6 mol, 12% yield) was obtained as a brown solid. M+H.sup.+=447.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (d, J=8.3 Hz, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.70 (s, 1H), 7.53-7.36 (m, 2H), 7.29 (d, J=2.3 Hz, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 4.98-4.83 (m, 2H), 3.91 (s, 3H), 3.87-3.74 (m, 2H), 3.25 (br d, J=8.5 Hz, 2H), 2.78-2.69 (m, 1H), 2.22 (s, 3H), 2.03-1.84 (m, 5H), 1.31 (br s, 2H), 1.20-1.11 (m, 2H).

Example 346: (S)N-(1-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 587)

##STR01192##

Step 1: (S)N-(1-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 587)

[1837] To a solution of(S)N-(1-(7-hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (18.0 mg, 43.1 mol, 1.0 eq) and propan-2-ol (7.77 mg, 129 mol, 9.90 L, 3.0 eq) in toluene (2.0 mL) were added TMAD (22.2 mg, 129 mol, 3.0 eq) and PPh.sub.3 (33.9 mg, 129 mol, 3.0 eq) at 25 C. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and then concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 60 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (3.60 mg, 6.99 mol, 16% yield) was obtained as a pale yellow gum. M+H.sup.+=460.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.51-10.34 (m, 1H), 9.49-9.34 (m, 1H), 9.24 (s, 1H), 9.06 (br d, J=2.8 Hz, 1H), 7.85-7.71 (m, 1H), 7.61 (br s, 1H), 7.52-7.46 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.93 (br d, J=2.5 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 4.86 (s, 1H), 4.67-4.58 (m, 1H), 4.35-4.29 (m, 1H), 4.24 (br d, J=2.9 Hz, 1H), 4.04-3.98 (m, 1H), 3.89-3.82 (m, 1H), 2.84-2.81 (m, 3H), 2.33 (br d, J=1.8 Hz, 2H), 1.96 (s, 3H), 1.41 (d, J=6.0 Hz, 8H), 1.28 (br s, 2H).

Example 347: (S)N-(1-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl

[1838] azetidin-2-yl)methoxy)benzamide (Compound 598)

##STR01193##

Step 1: 5-Bromoquinolin-7-ol (347A-1)

[1839] To a solution of 5-bromo-7-methoxy-quinoline (2.00 g, 8.40 mmol, 1.0 eq) in HBr (30.0 g, 110 mmol, 20 mL, 30% purity in H.sub.2O, 13 eq). The mixture was stirred at 130 C. for 24 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to 0 C. and slowly adjusted to pH 6 with saturated aqueous NaHCO.sub.3. The mixture was extracted with DCM (50 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product, which was used in the next step without any further purification. 5-Bromoquinolin-7-ol (3.50 g) was obtained as a yellow solid. M+H.sup.+=223.9 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.78 (dd, J=1.4, 4.2 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.41 (dd, J=4.2, 8.4 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H).

Step 2: 7-(Benzyloxy)-5-bromoquinoline (347A-2)

[1840] To a solution of 5-bromoquinolin-7-ol (1.00 g, 2.68 mmol, 1.0 eq) in DMF (20 mL) was added (bromomethyl)benzene (504 mg, 295 mmol, 350 L 1.1 eq), followed by K.sub.2CO.sub.3 (1.11 g, 8.03 mmol, 3.0 eq). The resulting mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (50 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-(Benzyloxy)-5-bromoquinoline (800 mg, 2.54 mmol, 95% yield) was obtained as yellow oil M+H.sup.+=313.9 (LCMS).

Step 3: 7-(Benzyloxy)quinoline-5-carbonitrile (347A-3)

[1841] To a solution of 7-(benzyloxy)-5-bromoquinoline (500 mg, 1.59 mmol, 1.0 eq) in DMF (10 mL) were added Zn(CN).sub.2 (374 mg, 3.18 mmol, 2.0 eq), and Pd(PPh.sub.3).sub.4 (184 mg, 159 mol, 0.1 eq). The resulting mixture was degassed and purged with N.sub.2 three times, and then the mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 7-(Benzyloxy)quinoline-5-carbonitrile (400 mg, 1.54 mmol, 97% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.99 (dd, J=1.5, 4.3 Hz, 1H), 8.41 (d, J=8.1 Hz, 1H), 8.10 (d, J=2.5 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.63 (dd, J=4.3, 8.4 Hz, 1H), 7.53 (d, J=7.3 Hz, 2H), 7.47-7.34 (m, 3H), 5.37 (s, 2H).

Step 4: 1-(7-(Benzyloxy)quinolin-5-yl)cyclopropanamine (347A-4)

[1842] A mixture of 7-(benzyloxy)quinoline-5-carbonitrile (200 mg, 771 mol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (329 mg, 1.16 mmol, 341 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 566 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (219 mg, 1.54 mmol, 190 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (10 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL3).

[1843] The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (MeOH/DCM=1/10, R.sub.f=0.2). 1-(7-(Benzyloxy)quinolin-5-yl)cyclopropanamine (30.0 mg, 103 mol, 13% yield) was obtained as a yellow oil. M+H.sup.+=291.1 (LCMS).

Step 5: (S)N-(1-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (Compound 598)

[1844] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (30.0 mg, 128 mol, 1.0 eq) and 1-(7-(benzyloxy)quinolin-5-yl)cyclopropanamine (39.0 mg, 134 mol, 1.1 eq) in DMF (2.0 mL) were added HATU (145 mg, 383 mol, 3.0 eq) and DIEA (33.0 mg, 255 mol, 44.0 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (12.7 mg, 22.6 mol, 18% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=508.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.86-10.61 (m, 1H), 9.62-9.45 (m, 1H), 9.31 (s, 1H), 9.11 (br d, J=4.8 Hz, 1H), 7.96-7.82 (m, 1H), 7.75 (s, 1H), 7.67 (br s, 1H), 7.57 (br d, J=7.3 Hz, 2H), 7.49-7.35 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 5.36 (s, 2H), 4.70-4.54 (m, 1H), 4.41-4.35 (m, 1H), 4.22 (br dd, J=2.6, 11.2 Hz, 1H), 3.99 (br dd, J=4.8, 9.0 Hz, 1H), 3.89-3.82 (m, 1H), 2.82-2.66 (m, 3H), 2.33 (br s, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.30 (br s, 2H).

Example 348: (S)N-(1-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 563)

##STR01194##

Step 1: 5,7-Dibromoquinoline (348A-2)

[1845] To a solution of 3,5-dibromoaniline (10.0 g, 39.8 mmol, 1.0 eq) and sodium 3-nitrobenzenesulfonate (26.9 g, 119 mmol, 3.0 eq) in a mixture of H.sub.2SO.sub.4 (56 mL) and H.sub.2O (72 mL) was added propane-1,2,3-triol (14.7 g, 159 mmol, 11.9 mL, 4.0 eq) at 100 C. The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 130 C. for 4 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice water (200 mL). The aqueous layer was basified to pH 9-10 by using saturated aqueous NH.sub.3H.sub.2O and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 5,7-Dibromoquinoline (25.0 g, 87.1 mmol, 73% yield) was obtained as a white solid. M+H.sup.+=285.8 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.05-8.98 (m, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J=1.7 Hz, 1H), 7.75 (dd, J=4.2, 8.5 Hz, 1H).

Step 2: 7-Bromoquinoline-5-carbonitrile (348A-3)

[1846] To a solution of 5,7-dibromoquinoline (1.00 g, 3.48 mmol, 1.0 eq) in DMF (5.0 mL) were added Py (6.34 g, 80.2 mmol, 6.47 mL, 23 eq) and CuCN (312 mg, 3.48 mmol, 761 L, 1.0 eq) at 20 C. The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 150 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Bromoquinoline-5-carbonitrile (1.00 g, crude) was obtained as a white solid. M+H.sup.+=233.1 (LCMS).

Step 3: 1-(7-Bromoquinolin-5-yl)cyclopropanamine (348A-4)

[1847] A mixture of 7-bromoquinoline-5-carbonitrile (500 mg, 2.15 mmol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (915 mg, 3.22 mmol, 950 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.57 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 5 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (609 mg, 4.29 mmol, 529 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (50 mL) and MTBE (25 mL) and extracted with MTBE (25 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 40 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 1-(7-Bromoquinolin-5-yl)cyclopropanamine (20.0 mg, 76.0 mol, 4% yield, HCl salt) was obtained as a white solid. M+H.sup.+=263.0 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.55 (d, J=8.6 Hz, 1H), 9.31 (d, J=5.0 Hz, 1H), 8.55 (s, 1H), 8.37 (d, J=1.3 Hz, 1H), 8.20 (dd, J=5.2, 8.7 Hz, 1H), 1.93-1.66 (m, 2H), 1.60-1.35 (m, 2H).

Step 4: (S)N-(1-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 563)

[1848] To a solution of 1-(7-bromoquinolin-5-yl)cyclopropanamine (20.0 mg, 76.1 mol, 1.0 eq) and (S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (17.9 mg, 76.1 mol, 1.0 eq) in DMF (3.0 mL) were added DIEA (49.1 mg, 380 mol, 66.2 L, 5.0 eq) and HATU (57.8 mg, 152 mol, 2.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (18.0 mg, 34.1 mol, 45% yield, HCl salt) was obtained as a white solid. M+H.sup.+=480.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.31-10.08 (m, 1H), 9.22 (s, 1H), 9.09 (d, J=8.3 Hz, 1H), 9.00-8.92 (m, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.73-7.62 (m, 1H), 7.15-7.04 (m, 1H), 6.92 (dd, J=2.7, 8.2 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 4.71-4.49 (m, 1H), 4.36-4.17 (m, 2H), 4.00 (br dd, J=4.9, 9.9 Hz, 1H), 3.85 (br d, J=3.4 Hz, 1H), 2.82 (d, J=5.0 Hz, 3H), 2.37-2.30 (m, 2H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.28 (br s, 2H).

Example 349: 5-(2-Aminopropoxy)-2-methyl-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 497)

##STR01195##

Step 1: tert-Butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (349A-1)

[1849] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropanamine (300 mg, 1.40 mmol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (390 mg, 1.26 mmol, 0.9 eq) in DMF (5.0 mL) were added HBTU (1.33 g, 3.50 mmol, 2.5 eq) and DIEA (724 mg, 5.60 mmol, 976 L, 4.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (485 mg, 959 mol, 68% yield) was obtained as a yellow oil. M+H.sup.+=506.3 (LCMS).

Step 2: tert-Butyl(1-(3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (349A-2)

[1850] To a solution of tert-butyl(1-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (485 mg, 959 mol, 1.0 eq) in DCM (10 mL) was added BBr.sub.3 (3.60 g, 14.4 mmol, 1.39 mL, 15 eq) at 78 C. The mixture was stirred at 78 C. under a N.sub.2 atmosphere for 1 h. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into saturated aqueous NaHCO.sub.3 (30 mL), then the mixture was concentrated under vacuum to give the crude product tert-butyl(1-(3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (108 mg) as a yellow oil. M+H.sup.+=492.2 (LCMS).

Step 3: 5-(1-(5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (349A-3)

[1851] To a solution of tert-butyl(1-(3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbamate (108 mg, 220 mol, 1.0 eq) in THF (2.0 mL) was added 1-BuOK (36.9 mg, 330 mol, 1.5 eq) at 0 C. The mixture was stirred at 0 C. for 15 min. Then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (117 mg, 330 mol, 1.5 eq) was added at 0 C. The mixture was stirred at 0 C. for 30 min. LCMS indicated that the starting material was completely consumed. The mixture was quenched by saturated aqueous NaHCO.sub.3 (5.0 mL), and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.46). 5-(1-(5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (75.0 mg, 120 mol, 54% yield) was obtained as a colourless oil. M+H.sup.+=624.2 (LCMS).

Step 4: tert-Butyl(1-(4-methyl-3-((1-(7-methylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (349A-4)

[1852] To a solution of 5-(1-(5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (75.0 mg, 120 mol, 1.0 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (60.4 mg, 241 mol, 67.3 L, 50% purity, 2.0 eq) in DMF (1.5 mL) were added Cs.sub.2CO.sub.3 (129 mg, 397 mol, 3.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (9.82 mg, 12.0 mol, 0.1 eq). The mixture was stirred at 110 C. under a N.sub.2 atmosphere for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product tert-butyl(1-(4-methyl-3-((1-(7-methylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (80.0 mg) as a brown liquid. M+H.sup.+=490.3 (LCMS).

Step 5: 5-(2-Aminopropoxy)-2-methyl-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 497)

[1853] To a solution of tert-butyl(1-(4-methyl-3-((1-(7-methylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (80.0 mg, 163 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-Aminopropoxy)-2-methyl-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (36.2 mg, 71.9 mol, 44% yield, TFA salt) as a white solid. M+H.sup.+=390.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.31 (br d, J=7.88 Hz, 1H), 9.18 (s, 1H), 9.03 (br d, J=3.50 Hz, 1H), 7.98 (br s, 3H), 7.84 (br d, J=6.13 Hz, 2H), 7.76 (br dd, J=8.25, 4.13 Hz, 1H), 7.09 (d, J=8.50 Hz, 1H), 6.90 (dd, J=8.32, 2.56 Hz, 1H), 6.68 (d, J=2.50 Hz, 1H), 4.03 (dd, J=10.26, 3.75 Hz, 1H), 3.86 (dd, J=10.19, 7.07 Hz, 1H), 3.62-3.47 (m, 1H), 2.58 (s, 3H), 1.96 (s, 3H), 1.37 (br s, 2H), 1.30-1.16 (m, 5H).

Example 350: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 581)

##STR01196##

Step 1: 5-Bromo-7-methylquinoline (350A-1)

[1854] To a solution of 5,7-dibromoquinoline (1.50 g, 5.23 mmol, 1.0 eq) and methylboronic acid (313 mg, 5.23 mmol, 1.0 eq) in a mixture of 1,4-dioxane (45 mL) and H.sub.2O (11 mL) were added Pd(dppf)Cl.sub.2 (382 mg, 523 mol, 0.1 eq) and K.sub.2CO.sub.3 (1.44 g, 10.5 mmol, 2.0 eq). The mixture was degassed and purged with N.sub.2 three times, and then stirred at 70 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (20 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 5-Bromo-7-methylquinoline (1.00 g, 4.50 mmol, 43% yield) was obtained as a white solid. M+H.sup.+=222.1 (LCMS).

Step 2: 7-Methylquinoline-5-carbonitrile (350A-2)

[1855] To a solution of 5-bromo-7-methylquinoline (1.00 g, 4.50 mmol, 1.0 eq) in DMF (30 mL) were added Zn(CN).sub.2 (1.59 g, 13.5 mmol, 857 L, 3.0 eq) BrettPhos Pd G3 (816 mg, 900 mol, 0.2 eq), and BrettPhos (483 mg, 900 mol, 0.2 eq). The mixture was stirred at 80 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (40 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7-Methylquinoline-5-carbonitrile (600 mg, 3.57 mmol, 79% yield) was obtained as a white solid. M+H.sup.+=169.2 (LCMS).

Step 3: 1-(7-Methylquinolin-5-yl)cyclopropanamine (350A-3)

[1856] A mixture of 7-methylquinoline-5-carbonitrile (180 mg, 1.07 mmol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (456 mg, 1.61 mmol, 473 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 784 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (304 mg, 2.14 mmol, 264 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(7-Methylquinolin-5-yl)cyclopropanamine (220 mg, crude) was obtained as a white solid. M+H.sup.+=199.0 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 581)

[1857] A mixture of 1-(7-methylquinolin-5-yl)cyclopropanamine (20.0 mg, 101 mol, 1.0 eq), (S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (23.7 mg, 101 mol, 1.0 eq), HATU (76.7 mg, 202 mol, 2.0 eq), and DIEA (39.1 mg, 303 mol, 52.7 L, 3.0 eq) in DMF (2.0 mL) was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (2.0 mL2), dried over Na.sub.2SO.sub.4 filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-methylquinolin-5-yl)cyclopropyl)benzamide (10.0 mg, 21.7 mol, 22% yield) was obtained as a white solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.08 (s, 1H), 9.01 (d, J=8.4 Hz, 1H), 8.85 (d, J=4.1 Hz, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.50 (dd, J=4.3, 8.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.6, 8.4 Hz, 1H), 6.59 (d, J=2.6 Hz, 1H), 3.86 (d, J=5.5 Hz, 2H), 3.30 (s, 3H), 3.26-3.17 (m, 2H), 2.75-2.67 (m, 1H), 2.20 (s, 3H), 1.98-1.91 (m, 4H), 1.89-1.78 (m, 1H), 1.40-1.30 (m, 2H), 1.19 (br s, 2H).

Example 351: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(trifluoromethyl)quinolin-5-yl)cyclopropyl)benzamide (Compound 600)

##STR01197##

Step 1: 5-Bromo-7-(trifluoromethyl)quinoline (351A-2)

[1858] To a solution of 7-(trifluoromethyl)quinoline (900 mg, 4.56 mmol, 1.0 eq) in H.sub.2SO.sub.4 (9.0 mL, 98% purity) was added NBS (1.62 g, 9.13 mmol, 2.0 eq) at 70 C. The mixture was stirred at 70 C. for 3.5 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and then quenched by saturated aqueous NaHCO.sub.3 (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 5-Bromo-7-(trifluoromethyl)quinoline (735 mg, 2.50 mmol, 93% yield) was obtained as a white solid. M+H.sup.+=276.0 (LCMS).

Step 2: 7-(Trifluoromethyl)quinoline-5-carbonitrile (351A-3)

[1859] To a solution of 5-bromo-7-(trifluoromethyl)quinoline (735 mg, 2.66 mmol, 1.0 eq) in DMF (10 mL) were added Pd(PPh.sub.3).sub.4 (307 mg, 266 mol, 0.1 eq) and Zn(CN).sub.2 (712 mg, 6.07 mmol, 2.3 eq) at 20 C. The resulting mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature. The mixture was treated with H.sub.2O (50 mL) and extracted with EtOAc (25 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 0/1. 7-(Trifluoromethyl)quinoline-5-carbonitrile (528 mg, 2.31 mmol, 86% yield) was obtained as a white solid. M+H.sup.+=223.1 (LCMS).

Step 3: 1-(7-(Trifluoromethyl)quinolin-5-yl)cyclopropanamine (351A-4)

[1860] A mixture of 7-(trifluoromethyl)quinoline-5-carbonitrile (50.0 mg, 225 mol, 1.0 eq) in anhydrous Et.sub.2O (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (95.9 mg, 337 mol, 99.6 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 165 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (63.8 mg, 450 mol, 55.5 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.55). 1-(7-(Trifluoromethyl)quinolin-5-yl)cyclopropanamine (10.0 mg, 37.0 mol, 16% yield) was obtained as a yellow oil. M+H.sup.+=253.1 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(trifluoromethyl)quinolin-5-yl)cyclopropyl)benzamide (Compound 600)

[1861] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (11.3 mg, 41.0 mol, 1.2 eq, HCl salt) and 1-(7-(trifluoromethyl)quinolin-5-yl)cyclopropanamine (10.0 mg, 34.6 mol, 1.0 eq, HCl salt) in DMF (1.0 mL) were added HBTU (32.8 mg, 86.6 mol, 2.5 eq) and DIEA (13.4 mg, 103 mol, 18.1 L, 3.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenomenex Gemini C18 column (15040 mm, 10 m); flow rate: 60 mL/min; gradient: 5%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(trifluoromethyl)quinolin-5-yl)cyclopropyl)benzamide (6.90 mg, 99.7 mol, 39% yield) was obtained as a yellow solid. M+H.sup.+=470.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.55-10.38 (m, 1H), 9.29 (s, 1H), 9.24 (br d, J=8.6 Hz, 1H), 9.11 (dd, J=1.4, 4.1 Hz, 1H), 8.34 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.83 (dd, J=4.3, 8.6 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.66-4.56 (m, 1H), 4.35-4.28 (m, 1H), 4.25-4.18 (m, 1H), 3.85-3.80 (m, 2H), 2.90-2.85 (m, 1H), 2.81 (d, J=4.9 Hz, 3H), 2.44 (br d, J=5.5 Hz, 1H), 1.94 (s, 3H), 1.42 (br s, 2H), 1.31 (br s, 2H).

Example 352: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(prop-1-en-2-yl) quinolin-5-yl)cyclopropyl)benzamide (Compound 568)

##STR01198##

Step 1: (S)-5-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (352A-1)

[1862] To a solution of(S)N-(1-(7-hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (450 mg, 1.08 mmol, 1.0 eq) in THF (27 mL) was added 1-BuOK (242 mg, 2.16 mmol, 2.0 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (770 mg, 2.16 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (S)-5-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (370 mg, 673 mol, 31% yield) was obtained as a yellow solid. M+H.sup.+=550.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.21 (s, 1H), 9.14 (d, J=8.5 Hz, 1H), 9.05 (dd, J=1.5, 4.3 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.74 (dd, J=4.2, 8.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.85 (dd, J=2.7, 8.3 Hz, 1H), 6.64 (d, J=2.8 Hz, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.29-3.25 (m, 1H), 2.84-2.73 (m, 1H), 2.24 (s, 3H), 1.99 (s, 1H), 1.98-1.94 (m, 1H), 1.92 (s, 3H), 1.90-1.81 (m, 1H), 1.44-1.38 (m, 2H), 1.30-1.25 (m, 2H).

Step 2: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(prop-1-en-2-yl) quinolin-5-yl)cyclopropyl)benzamide (Compound 568)

[1863] To a solution of(S)-5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (70.0 mg, 127 mol, 1.0 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.5 mg, 140 mol, 1.1 eq) in a mixture of dioxane (5.0 mL) and H.sub.2O (1.0 mL) were added Na.sub.2CO.sub.3 (31.0 mg, 293 mol, 2.3 eq) and Pd(dppf)Cl.sub.2 (10.4 mg, 12.7 mol, 0.1 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-15% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (28.0 mg, 54.0 mol, 43% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=442.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.65 (br d, J=8.5 Hz, 1H), 9.33 (s, 1H), 9.21 (br d, J=4.8 Hz, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.03 (dd, J=5.1, 8.4 Hz, 1H), 7.09 (br d, J=8.4 Hz, 1H), 6.91 (br dd, J=2.4, 8.4 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 5.87 (s, 1H), 5.51 (s, 1H), 4.70-4.56 (m, 1H), 4.38-4.27 (m, 1H), 4.26-4.15 (m, 1H), 4.08-3.95 (m, 1H), 3.91-3.77 (m, 1H), 2.81 (s, 3H), 2.69 (s, 1H), 2.34-2.31 (m, 1H), 2.27 (s, 3H), 1.96 (s, 3H), 1.44 (br s, 2H), 1.34 (br s, 2H).

Example 353: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 551)

##STR01199##

Step 1: 5-Bromo-7-(thiophen-2-yl)quinoline (353A-1)

[1864] To a mixture of 5,7-dibromoquinoline (2.00 g, 6.97 mmol, 1.0 eq) and thiophen-2-ylboronic acid (713 mg, 5.58 mmol, 0.8 eq) in DMSO (100 mL) were added KOAc (2.74 g, 27.9 mmol, 4.0 eq), cataCXium A (1.25 g, 3.48 mmol, 0.5 eq) and Pd(OAc) 2 (313 mg, 1.39 mmol, 0.2 eq). The mixture was degassed and purged with N.sub.2 for 3 times, then stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (100 mL) and extracted with EtOAc (50 mL4). The combined organic layers were washed with brine (50 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 5-Bromo-7-(thiophen-2-yl)quinoline (220 mg, 758 mol, 11% yield) was obtained as a yellow solid. M+H.sup.+=289.9 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.98 (dd, J=1.5, 4.3 Hz, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.35 (d, J=1.6 Hz, 1H), 8.25 (s, 1H), 7.89 (dd, J=0.9, 3.6 Hz, 1H), 7.77-7.63 (m, 2H), 7.23 (dd, J=3.8, 5.0 Hz, 1H).

Step 2: 7-(Thiophen-2-yl)quinoline-5-carbonitrile (353A-2)

[1865] To a mixture of 5-bromo-7-(thiophen-2-yl)quinoline (160 mg, 551 mol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN).sub.2 (130 mg, 1.10 mmol, 70.0 L, 2.0 eq), BrettPhos Pd G3 (100 mg, 110 mol, 0.2 eq), BrettPhos (59.1 mg, 110 mol, 0.2 eq). The mixture was stirred at 80 C. for 1 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 7-(Thiophen-2-yl)quinoline-5-carbonitrile (100 mg, 422 mol 89% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (dd, J=1.6, 4.2 Hz, 1H), 8.71 (d, J=1.9 Hz, 1H), 8.54-8.42 (m, 2H), 7.95 (dd, J=0.9, 3.6 Hz, 1H), 7.82-7.70 (m, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H).

Step 3: 1-(7-(Thiophen-2-yl)quinolin-5-yl)cyclopropanamine (353A-3)

[1866] A mixture of 7-(thiophen-2-yl)quinoline-5-carbonitrile (100 mg, 423 mol, 1.0 eq) in anhydrous Et.sub.2O (20 mL) was degassed and purged with N.sub.2 three times. The mixture was cooled to 78 C. To this mixture was added Ti(i-PrO).sub.4 (180 mg, 635 mol, 187 L, 1.5 eq) slowly, and then EtMgBr (3 M, 310 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 2 h. BF.sub.3.Math.Et.sub.2O (120 mg, 846 mol, 104 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (8.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.24). 1-(7-(Thiophen-2-yl)quinolin-5-yl)cyclopropanamine (25.0 mg, 93.9 mol, 22% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.97 (br d, J=2.7 Hz, 1H), 8.79 (br d, J=8.2 Hz, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.56 (d, J=4.0 Hz, 1H), 7.49 (br dd, J=4.1, 8.6 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.19 (dd, J=3.7, 5.0 Hz, 1H), 1.31-1.18 (m, 4H).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 551)

[1867] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (20.0 mg, 85.0 mol, 1.0 eq) and 1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropanamine (22.6 mg, 85.0 mol, 1.0 eq) in DMF (2.0 mL) were added HATU (80.8 mg, 213 mol, 2.5 eq) and DIEA (33.0 mg, 255 mol, 44.4 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (8.70 mg, 17.4 mol, 21% yield) was obtained as a yellow solid. M+H.sup.+=484.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.02 (d, J=8.6 Hz, 1H), 8.94 (dd, J=1.4, 4.1 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.47 (dd, J=4.1, 8.5 Hz, 1H), 7.38 (d, J=5.0 Hz, 1H), 7.16 (dd, J=3.8, 4.9 Hz, 1H), 7.04-6.97 (m, 1H), 6.82-6.76 (m, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.51-6.37 (m, 1H), 3.94-3.83 (m, 2H), 3.44 (br d, J=4.1 Hz, 1H), 3.37-3.26 (m, 1H), 2.84 (q, J=7.6 Hz, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 2.08-1.98 (m, 2H), 1.67-1.64 (m, 2H), 1.46-1.41 (m, 2H).

Example 354: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(oxazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 588)

##STR01200##

Step 1: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(oxazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 588)

[1868] To a solution of(S)-5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yltrifluoromethanesulfonate (65.0 mg, 118 mol, 1.0 eq) and 2-(tributylstannyl)oxazole (84.7 mg, 237 mol, 2.0 eq) in DMF (5.0 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 (8.30 mg, 11.8 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times, and then the mixture was stirred at 60 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex luna C18 column (80 40 mm, 3 m); flow rate: 40 mL/min; gradient: 5%-35% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(oxazol-2-yl)quinolin-5-yl)cyclo propyl)benzamide (12.1 mg, 24.8 mol, 21% yield, HCl salt) was obtained as a white solid. M+H.sup.+=469.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.34 (d, J=8.5 Hz, 1H), 9.28 (s, 1H), 9.12 (dd, J=1.4, 4.5 Hz, 1H), 8.62-8.52 (m, 2H), 8.37 (s, 1H), 7.85 (dd, J=4.6, 8.6 Hz, 1H), 7.53 (s, 1H), 7.14-7.06 (m, 1H), 6.99-6.88 (m, 1H), 6.80-6.69 (m, 1H), 4.73-4.52 (m, 1H), 4.32-4.17 (m, 2H), 4.01 (dt, J=4.8, 9.6 Hz, 1H), 3.85 (q, J=9.4 Hz, 1H), 2.82 (s, 3H), 2.40-2.26 (m, 2H), 1.94 (s, 3H), 1.45 (br s, 2H), 1.31 (br s, 2H).

Example 355: N-(1-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 436)

##STR01201##

Step 1: tert-Butyl(1-(quinolin-5-yl)cyclopropyl)carbamate (355A-1)

[1869] To a solution of 1-(quinolin-5-yl)cyclopropanamine (590 mg, 2.71 mmol, 1.0 eq) in DCM (40 mL) were added TEA (549 mg, 5.43 mmol, 755 L, 2.0 eq) and Boc.sub.2O (711 mg, 3.26 mmol, 748 L, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (30 mL) and extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl(1-(quinolin-5-yl)cyclopropyl)carbamate (590 mg, 2.07 mmol, 76% yield) was obtained as a white solid. M+H.sup.+=285.1 (LCMS).

Step 2: 5-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (355A-2)

[1870] To a solution of tert-butyl(1-(quinolin-5-yl)cyclopropyl)carbamate (290 mg, 1.02 mmol, 1.0 eq) in DCM (20 mL) was added m-CPBA (311 mg, 1.53 mmol, 85% purity, 1.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHCO.sub.3 (20 mL) and extracted with DCM (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 0/1 to 1/5. 5-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (240 mg, 799 mol, 78% yield) was obtained as a white solid. M+H.sup.+=301.1 (LCMS).

Step 3: 1-(2-Chloroquinolin-5-yl)cyclopropanamine (355A-3)

[1871] A solution of 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (410 mg, 1.37 mmol, 1.0 eq) in POCl.sub.3 (6.60 g, 43.1 mmol, 4.00 mL, 31 eq) was stirred at 80 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to remove POCl.sub.3, the residue was diluted with H.sub.2O (5.0 mL), basified to pH 7 by using NH.sub.3.Math.H.sub.2O (25% purity), and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5. 1-(2-Chloroquinolin-5-yl)cyclopropanamine (150 mg, 686 mol, 50% yield) was obtained as a white solid. M+H.sup.+=219.0 (LCMS).

Step 4: N-(1-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 436)

[1872] To a solution of 1-(2-chloroquinolin-5-yl)cyclopropanamine (50.0 mg, 229 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (53.8 mg, 229 mol, 1.0 eq) in DMF (5.0 mL) were added DIEA (8.6 mg, 686 mol, 119 L, 3.0 eq) and HBTU (173 mg, 457 mol, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N-(1-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (12.1 mg, 21.7 mol, 9% yield, TFA salt) was obtained as a white solid. M+H.sup.+=436.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6)) 9.87 (br dd, J=1.8, 8.0 Hz, 1H), 9.24-9.05 (m, 2H), 7.91 (dd, J=7.7, 14.4 Hz, 2H), 7.82-7.74 (m, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.61 (br d, J=4.0 Hz, 1H), 4.33-4.16 (m, 2H), 4.07-3.98 (m, 1H), 3.91-3.85 (m, 1H), 2.84 (d, J=4.8 Hz, 3H), 2.42-2.20 (m, 2H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.29-1.19 (m, 2H).

Example 356: N-(1-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 529)

##STR01202##

Step 1: 1-(2-Fluoroquinolin-5-yl)cyclopropanamine (356A-1)

[1873] To a solution of tert-butyl(1-(2-chloroquinolin-5-yl)cyclopropyl)carbamate (130 mg, 408 mol, 1.0 eq) in DMSO (5.0 mL) was added CsF (92.9 mg, 612 mol, 22.5 L, 1.5 eq). The mixture was stirred at 140 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.1). 1-(2-Fluoroquinolin-5-yl)cyclopropanamine (35.0 mg, 173 mol, 42% yield) was obtained as a white solid. M+H.sup.+=203.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14-9.03 (m, 1H), 7.78-7.73 (m, 1H), 7.71 (d, J=7.1 Hz, 1H), 7.58-7.53 (m, 1H), 7.40 (dd, J=2.9, 9.0 Hz, 1H), 1.04 (d, J=2.3 Hz, 2H), 0.95-0.79 (m, 2H).

Step 2: N-(1-(2-Fluoroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 529)

[1874] To a solution of 1-(2-fluoroquinolin-5-yl)cyclopropanamine (20.0 mg, 98.9 mol, 1.0 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (23.3 mg, 98.9 mol, 1.0 eq) in DMF (2.0 mL) were added DIEA (38.4 mg, 297 mol, 51.7 L, 3.0 eq) and HATU (75.2 mg, 198 mol, 2.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (2.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3 with NH.sub.3.Math.H.sub.2O (0.05%), mobile phase B: acetonitrile). N-(1-(2-Fluoroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (6.00 mg, 14.5 mol, 15% yield) was obtained as a yellow solid. M+H.sup.+=420.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.29 (t, J=8.8 Hz, 1H), 9.13 (s, 1H), 7.96-7.86 (m, 1H), 7.85-7.72 (m, 2H), 7.45 (dd, J=2.6, 9.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 3.87 (d, J=5.4 Hz, 2H), 3.24 (br dd, J=2.3, 6.2 Hz, 2H), 2.80-2.62 (m, 1H), 2.21 (s, 3H), 1.95 (s, 5H), 1.49-1.30 (m, 2H), 1.29-1.16 (m, 2H).

Example 357: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(2-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 547)

##STR01203##

Step 1: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(2-methylquinolin-5-yl)cyclopropyl)benzamide (Compound 547)

[1875] To a solution of(S)N-(1-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 184 mol, 1.0 eq) in DMF (4.0 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (185 mg, 734 mol, 205 L, 50% purity in THF, 4.0 eq), Cs.sub.2CO.sub.3 (197 mg, 606 mol, 3.3 eq) and Pd(dppf)Cl.sub.2 (44.9 mg, 55.1 mol, 0.3 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(2-methylquinolin-5-yl)cyclopropyl)benzamide (27.2 mg, 58.9 mol, 32% yield, FA salt) was obtained as a white solid. M+H.sup.+=416.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.18 (s, 1H), 7.94-7.74 (m, 2H), 7.69-7.59 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.85 (dd, J=2.6, 8.4 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 3.95-3.86 (m, 2H), 3.43-3.31 (m, 2H), 2.87 (br d, J=7.9 Hz, 1H), 2.67 (s, 3H), 2.29 (s, 3H), 2.08-1.97 (m, 1H), 1.97-1.93 (m, 3H), 1.91 (s, 1H), 1.36 (s, 2H), 1.19 (br d, J=1.3 Hz, 2H).

Example 358: (S)N-(1-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 545)

##STR01204##

Step 1: (S)N-(1-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 545)

[1876] To a solution of(S)N-(1-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (70.0 mg, 161 mol, 1.0 eq) in a mixture of dioxane (7.0 mL) and H.sub.2O (7.0 mL) were added KOH (180 mg, 3.21 mmol, 20 eq), Pd.sub.2 (dba) 3 (2.94 mg, 3.21 mol, 0.02 eq) and t-Bu Xphos (5.45 mg, 12.8 mol, 0.08 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-15% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)N-(1-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (15.0 mg, 35.4 mol, 22% yield, FA salt) was obtained as a white solid. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.74 (br s, 1H), 9.02 (s, 1H), 8.65 (d, J=9.9 Hz, 1H), 7.53-7.35 (m, 2H), 7.32-7.14 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.85 (dd, J=2.6, 8.3 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 6.54 (d, J=9.9 Hz, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.28-3.25 (m, 2H), 2.75 (br d, J=8.1 Hz, 1H), 2.24 (s, 3H), 2.01 (s, 3H), 1.98-1.74 (m, 2H), 1.28 (br s, 2H), 1.13 (br s, 2H).

Example 359: (S)N-(1-(2-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 544)

##STR01205##

Step 1: (S)N-(1-(2-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 544)

[1877] To a solution of(S)N-(1-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (70.0 mg, 161 mol, 1.0 eq) in MeOH (4.0 mL) was added NaOMe (49.5 mg, 916 mol, 4.0 eq). The mixture was stirred at 70 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)N-(1-(2-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (14.8 mg, 34.1 mol, 21% yield, FA salt) was obtained as a white solid. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07 (s, 1H), 8.97 (d, J=9.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.64-7.51 (m, 1H), 7.05 (dd, J=8.8, 16.3 Hz, 2H), 6.83 (dd, J=2.6, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.98 (s, 3H), 3.87 (d, J=5.3 Hz, 1H), 3.28-3.11 (m, 3H), 2.73 (br d, J=8.3 Hz, 1H), 2.22 (s, 3H), 1.95 (s, 4H), 1.90-1.77 (m, 1H), 1.48-1.26 (m, 2H), 1.24-1.03 (m, 2H).

Example 360: (S)N-(1-(2-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 548)

##STR01206##

Step 1: (S)N-(1-(2-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 548)

[1878] To a solution of(S)N-(1-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (70.0 mg, 161 mol, 1.0 eq) and dimethylamine (2 M in THF, 161 mol, 2.0 eq) in DMSO (4.0 mL) were added DIEA (41.5 mg, 321 mol, 55.9 L, 2.0 eq) and CsF (48.8 mg, 321 mol, 11.8 L, 2.0 eq). The mixture was stirred at 120 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)N-(1-(2-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (22.0 mg, 49.3 mol, 31% yield, FA salt) was obtained as a white solid. M+H.sup.+=445.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.02 (s, 1H), 8.77 (d, J=9.4 Hz, 1H), 8.16 (s, 2H), 7.59-7.34 (m, 3H), 7.16-6.99 (m, 2H), 6.84 (dd, J=2.6, 8.3 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H), 3.95 (br d, J=4.4 Hz, 2H), 3.56-3.34 (m, 2H), 3.16 (s, 6H), 3.02-2.86 (m, 1H), 2.34 (s, 3H), 2.03 (br s, 1H), 1.98 (s, 3H), 1.96-1.78 (m, 1H), 1.31 (s, 2H), 1.12 (br s, 2H).

Example 361: (S)N-(1-(2-Methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 555)

##STR01207##

Step 1:4-Chloro-2-methoxyquinoline (361A-2)

[1879] To a solution of 2,4-dichloroquinoline (3.00 g, 15.2 mmol, 1.0 eq) in toluene (200 mL) was added NaOMe (3.11 g, 57.6 mmol, 3.8 eq). The mixture was stirred at 120 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (150 mL) and extracted with EtOAc (80 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. 4-Chloro-2-methoxyquinoline (2.27 g, 11.7 mmol, 77% yield) was obtained as a white solid. M+H.sup.+=194.0 (LCMS).

Step 2: 2-Methoxyquinoline-4-carbonitrile (361A-3)

[1880] To a solution of 4-chloro-2-methoxyquinoline (1.00 g, 5.16 mmol, 1.0 eq) in DMA (50 mL) were added Zn(CN).sub.2 (1.09 g, 9.30 mmol, 590 L, 1.8 eq), Pd.sub.2 (dba) 3 (709 mg, 775 mol, 0.2 eq), Zn (101 mg, 1.55 mmol, 0.3 eq) and XPhos (492 mg, 1.03 mmol, 0.2 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 120 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (50 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. The crude product 2-methoxyquinoline-4-carbonitrile (940 mg) was obtained as a yellow solid. M+H.sup.+=185.1 (LCMS).

Step 3: 1-(2-Methoxyquinolin-4-yl)cyclopropanamine (361A-4)

[1881] A mixture of 2-methoxyquinoline-4-carbonitrile (600 mg, 3.26 mmol, 1.0 eq) in Et.sub.2O (60 mL) was degassed and purged with N.sub.2 three times. To this mixture was added Ti(i-PrO).sub.4 (1.34 g, 4.88 mmol, 1.44 mL, 1.5 eq) slowly at 78 C. and then EtMgBr (3 M, 2.38 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. Then BF.sub.3.Math.Et.sub.2O (924 mg, 6.52 mmol, 804 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (120 mL) and MTBE (30 mL), and was extracted with MTBE (30 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. 1-(2-Methoxyquinolin-4-yl)cyclopropanamine (190 mg, 87 mol, 27% yield) was obtained as a yellow oil. M+H.sup.+=215.1 (LCMS).

Step 4: (S)N-(1-(2-Methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 555)

[1882] To a solution of 1-(2-methoxyquinolin-4-yl)cyclopropanamine (65.0 mg, 303 mol, 1.0 eq) and(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (71.4 mg, 303 mol, 1.0 eq) in DMF (7.0 mL) were added DIEA (118 mg, 910 mol, 159 L, 3.0 eq) and HBTU (127 mg, 334 mol, 1.1 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (S)N-(1-(2-Methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (4.40 mg, 10.1 mol, 3% yield) was obtained as a white solid. M+H.sup.+=332.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.16 (s, 1H), 8.52 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.65 (t, J=6.9 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.6, 8.4 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 3.98 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 3.24-3.11 (m, 2H), 2.73 (br d, J=2.1 Hz, 1H), 2.22 (s, 3H), 1.95 (s, 5H), 1.33 (s, 2H), 1.26-1.18 (m, 2H).

Example 362: N-(1-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 467)

##STR01208##

Step 1:2,4-Dichloro-7-fluoroquinoline (362A-2)

[1883] To a solution of malonic acid (7.59 g, 72.9 mmol, 7.59 mL, 1.0 eq) in POCl.sub.3 (30 mL) was added 3-fluoroaniline (8.10 g, 72.9 mmol, 6.98 mL, 1.0 eq) at 20 C. The mixture was stirred at 100 C. for 7 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue. The residue was diluted with EtOAc (20 mL), and then saturated aqueous NaHCO.sub.3 solution was added to the solution slowly at 0 C. to adjust the pH 8. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/100. 2,4-Dichloro-7-fluoroquinoline (5.17 g, 24.0 mmol, 33% yield) was obtained as a white solid. M+H.sup.+=216.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.26-8.16 (m, 1H), 7.68 (ddd, J=9.38, 4.44, 2.31 Hz, 1H), 7.52-7.39 (m, 2H).

Step 2:4-Chloro-7-fluoro-2-methoxyquinoline (362A-3)

[1884] To a solution of 2,4-dichloro-7-fluoroquinoline (4.77 g, 22.1 mmol, 1.0 eq) in MeOH (50 mL) was added NaOMe (19.9 g, 110 mmol, 30% purity in MeOH, 5.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was treated with water (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/100. 4-Chloro-7-fluoro-2-methoxyquinoline (3.60 g, 15.7 mmol, 71% yield) was obtained as a white solid. M+H.sup.+=212.1 (LCMS).

Step 3: 7-Fluoro-2-methoxyquinoline-4-carbonitrile (362A-4)

[1885] To a solution of 4-chloro-7-fluoro-2-methoxyquinoline (1.40 g, 6.62 mmol, 1.0 eq) in DMF (30 mL) were added Zn(CN).sub.2 (1.55 g, 13.2 mmol, 2.0 eq) and Pd(PPh.sub.3).sub.4 (764 mg, 662 mol, 0.1 eq). The mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (90 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Fluoro-2-methoxyquinoline-4-carbonitrile (1.14 g, 4.86 mmol, 73% yield) was obtained as a white solid. M+H.sup.+=203.1 (LCMS).

Step 4: 1-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (362A-5)

[1886] To a solution of 7-fluoro-2-methoxyquinoline-4-carbonitrile (100 mg, 495 mol, 1.0 eq) in anhydrous Et.sub.2O (40 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (211 mg, 742 mol, 219 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 363 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (140 mg, 989 mol, 122 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous) (40 mL) and MTBE (40 mL) and extracted with MTBE (40 mL2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 1-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (150 mg, 520 mol, 35% yield) was obtained as a yellow oil. M+H.sup.+=233.3 (LCMS).

Step 5: N-(1-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 467)

[1887] To a solution of 1-(7-fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (120 mg, 517 mol, 1.5 eq) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (93.6 mg, 344 mol, 1.0 eq, HCl salt) in DMF (2.0 mL) were added HBTU (327 mg, 861 mol, 2.5 eq) and DIEA (223 mg, 1.72 mmol, 300 L, 5.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with H.sub.2O (3.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were washed with brine (9.0 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 40%-75% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3 with NH.sub.3.Math.H.sub.2O (0.05%), mobile phase B: acetonitrile). N-(1-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (14.7 mg, 32.7 mol, 10% yield) was obtained as a pale yellow solid. M+H.sup.+=450.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.51-8.45 (m, 1H), 7.54-7.46 (m, 1H), 7.29-7.23 (m, 1H), 7.23-7.20 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.87-6.83 (m, 1H), 6.65 (d, J=2.6 Hz, 1H), 4.06-4.02 (m, 3H), 3.91 (d, J=5.4 Hz, 2H), 3.51-3.43 (m, 1H), 3.42-3.36 (m, 1H), 2.98-2.89 (m, 1H), 2.39-2.35 (m, 3H), 2.10-2.01 (m, 2H), 2.01-1.98 (m, 3H), 1.46-1.40 (m, 2H), 1.34-1.29 (m, 2H).

Example 363: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(3-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 565)

##STR01209##

Step 1:4-(1-Aminocyclopropyl)quinolin-2-ol (363A-1)

[1888] A solution of 1-(2-methoxyquinolin-4-yl)cyclopropanamine (180 mg, 840 mol, 1.0 eq) in HBr (30 mL, 30% purity in water) was stirred at 130 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into NaHCO.sub.3 aqueous (30 mL) at 25 C. and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue was used in the next step without any further purification. 4-(1-Aminocyclopropyl)quinolin-2-ol (120 mg, 600 mol, 72% yield) was obtained as a yellow solid. M+H.sup.+=201.1 (LCMS).

Step 2: (S)N-(1-(2-Hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 565)

[1889] To a solution of 4-(1-aminocyclopropyl)quinolin-2-ol (110 mg, 549 mol, 1.0 eq) and(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (129 mg, 549 mol, 1.0 eq) in DMF (6.0 mL) were added DIEA (213 mg, 1.65 mmol, 287 L, 3.0 eq) and HBTU (229 mg, 604 mol, 1.1 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (7.8 mg, 16.8 mol, 3% yield, HCl salt) was obtained as a white solid. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.27 (br d, J=8.4 Hz, 1H), 7.50 (br t, J=7.6 Hz, 1H), 7.34 (br d, J=8.3 Hz, 1H), 7.21 (br t, J=7.4 Hz, 1H), 7.11 (br d, J=8.5 Hz, 1H), 6.93 (br dd, J=2.5, 8.5 Hz, 1H), 6.74 (br d, J=1.9 Hz, 1H), 6.68 (s, 1H), 4.69-4.57 (m, 1H), 4.36-4.19 (m, 2H), 4.11-3.97 (m, 1H), 3.93-3.79 (m, 1H), 2.90-2.79 (m, 3H), 2.39-2.26 (m, 2H), 1.99 (s, 3H), 1.27 (br s, 2H), 1.18 (br s, 2H).

Example 364: (S)N-(1-(7-Fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 542)

##STR01210##

Step 1:4-(1-Aminocyclopropyl)-7-fluoroquinolin-2-ol (364A-1)

[1890] To a solution of HBr (30 mL, 30% purity in water) was added 1-(7-fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (320 mg, 1.38 mmol, 1.0 eq). The mixture was stirred at 120 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 4-(1-Aminocyclopropyl)-7-fluoroquinolin-2-ol (150 mg, 513 mol, 37% yield, TFA salt) was obtained as a yellow oil. M+H.sup.+=219.2 (LCMS).

Step 2: (S)N-(1-(7-Fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 542)

[1891] To a solution of 4-(1-aminocyclopropyl)-7-fluoroquinolin-2-ol (120 mg, 550 mol, 1.0 eq, TFA salt) in DMF (1.0 mL) was added(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (129 mg, 550 mol, 1.2 eq), followed by HBTU (521 mg, 1.37 mmol, 2.5 eq) and DIEA (210 mg, 1.65 mmol, 2.87 mL, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give(S)N-(1-(7-fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (32.0 mg, 69.8 mol, 13% yield, HCl salt) as a white solid. M+H.sup.+=436.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ppm 11.79 (br s, 1H), 9.07 (s, 1H), 8.37-8.26 (m, 1H), 7.13-7.03 (m, 3H), 6.85 (dd, J=8.44, 2.52 Hz, 1H), 6.65-6.57 (m, 2H), 3.87 (d, J=5.48 Hz, 2H), 3.26-3.19 (m, 2H), 2.75-2.67 (m, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.98-1.79 (m, 2H), 1.29-1.23 (m, 2H), 1.19-1.13 (m, 2H).

Example 365: (S)N-(1-(2-Chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 586)

##STR01211##

Step 1: (S)N-(1-(2-Chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 586)

[1892] To a solution of(S)N-(1-(7-fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (43.0 mg, 98.7 mol, 1.0 eq) in SOCl.sub.2 (1.7 mL) was added DMF (100 L). The mixture was stirred at 20 C. for 3.5 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by saturated aqueous NaHCO.sub.3 (30 mL) at 0 C. and extracted with EtOAc (15 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (800 30 mm, 3 m); flow rate: 60 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(2-Chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (2.30 mg, 4.69 mol, 5% yield) was obtained as a yellow gum. M+H.sup.+=454.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.35 (s, 1H), 8.74 (dd, J=6.2, 9.3 Hz, 1H), 7.79 (dd, J=2.6, 10.1 Hz, 1H), 7.72-7.63 (m, 2H), 7.15-7.06 (m, 1H), 6.93 (dd, J=2.6, 8.3 Hz, 1H), 6.81-6.68 (m, 1H), 4.70-4.58 (m, 1H), 4.37-4.28 (m, 1H), 4.27-4.18 (m, 1H), 4.05-3.97 (m, 1H), 3.91-3.85 (m, 1H), 2.86-2.80 (m, 3H), 2.40-2.27 (m, 2H), 2.00-1.90 (m, 3H), 1.41-1.31 (m, 4H).

Example 366: (S)N-(1-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 538)

##STR01212##

Step 1: (Z)N-(3-Bromo-5-methoxybenzylidene)-2,2-dimethoxyethanamine (366A-2)

[1893] To a solution of 3-bromo-5-methoxybenzaldehyde (21.0 g, 97.7 mmol, 1.0 eq) in toluene (220 mL) was added 2,2-dimethoxyethanamine (10.3 g, 97.7 mmol, 10.6 mL, 1.0 eq) at 20 C. The mixture was stirred at 110 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a crude product (Z)N-(3-bromo-5-methoxybenzylidene)-2,2-dimethoxyethanamine (30.0 g) as a yellow oil. M+H.sup.+=302.0 (LCMS).

Step 2: 5-Bromo-7-methoxyisoquinoline (366A-3)

[1894] To a solution of (Z)N-(3-bromo-5-methoxybenzylidene)-2,2-dimethoxyethanamine (10.0 g, 33.0 mmol, 1.0 eq) in toluene (30 mL) were added TFAA (13.9 g, 66.2 mmol, 9.21 mL, 2.0 eq) and BF.sub.3.Math.Et.sub.2O (9.39 g, 66.2 mmol, 8.17 mL, 2.0 eq) at 0 C. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was treated with water (50 mL), the aqueous layer was adjusted to pH 8 by using saturated aqueous NaHCO.sub.3. The aqueous layer was then extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 5-Bromo-7-methoxyisoquinoline (8.30 g, 34.8 mmol, 35% yield) was obtained as a yellow solid. M+H.sup.+=238.1 (LCMS).

Step 3: 7-Methoxyisoquinoline-5-carbonitrile (366A-4)

[1895] To a solution of 5-bromo-7-methoxyisoquinoline (300 mg, 1.26 mmol, 1.0 eq) in DMF (4.0 mL) were added Zn(CN).sub.2 (370 mg, 3.15 mmol, 2.5 eq) and Pd(PPh.sub.3).sub.4 (146 mg, 126 mol, 0.1 eq). The mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (30 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7-Methoxyisoquinoline-5-carbonitrile (210 mg, 842 mol, 67% yield) was obtained as a yellow solid. M+H.sup.+=185.3 (LCMS).

Step 4: 1-(7-Methoxyisoquinolin-5-yl)cyclopropanamine (366A-5)

[1896] A mixture of 7-methoxyisoquinoline-5-carbonitrile (50.0 mg, 271 mol, 1.0 eq) in anhydrous Et.sub.2O (10 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (116 mg, 407 mol, 120 L, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 199 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (77.1 mg, 543 mol, 67.0 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that 29% starting material remained and 50% desired compound was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (60 mL) and MTBE (60 mL) and extracted with MTBE (60 mL2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (60 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. 1-(7-Methoxyisoquinolin-5-yl)cyclopropanamine (12.5 mg, 30.5 mol, 11% yield) was obtained as a yellow oil. M+H.sup.+=215.3 (LCMS).

Step 5: (S)N-(1-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 538)

[1897] To a solution of 1-(7-methoxyisoquinolin-5-yl)cyclopropanamine (50.0 mg, 233 mol, 1.0 eq) and(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (54.9 mg, 233 mol, 1.0 eq) in DMF (1.0 mL) were added HATU (177 mg, 467 mol, 2.0 eq) and DIEA (90.5 mg, 700 mol, 122 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3 with NH.sub.3.Math.H.sub.2O (0.05%), mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (11.3 mg, 25.3 mol, 11% yield) was obtained as a white solid. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.25-9.17 (m, 1H), 9.17-9.09 (m, 1H), 8.48-8.39 (m, 1H), 8.39-8.33 (m, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.89-6.81 (m, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.95-3.89 (m, 3H), 3.86 (d, J=5.4 Hz, 2H), 3.28-3.20 (m, 2H), 2.75-2.67 (m, 1H), 2.27-2.19 (m, 3H), 2.04-1.90 (m, 4H), 1.90-1.79 (m, 1H), 1.39-1.24 (m, 2H), 1.23-1.15 (m, 2H).

Example 367: N-(1-(3-Hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 509)

##STR01213##

Step 1:3-Methoxyisoquinoline-5-carbonitrile (367A-2)

[1898] To a solution of 5-bromo-3-methoxyisoquinoline (4.00 g, 16.8 mmol, 1.0 eq) in DMF (40 mL) were added Zn(CN).sub.2 (4.10 g, 35.0 mmol, 2.22 mL, 2.1 eq) and Pd(PPh.sub.3).sub.4 (1.94 g, 1.68 mmol, 0.1 eq). The mixture was stirred at 120 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (40 mL) and extracted with EtOAc (40 mL3). The combined organic layers were washed with brine (120 mL3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/10. 3-Methoxyisoquinoline-5-carbonitrile (3.00 g, 16.2 mmol, 96% yield) was obtained as a white solid. M+H.sup.+=185.1 (LCMS).

Step 2: 1-(3-Methoxyisoquinolin-5-yl)cyclopropanamine (367A-3)

[1899] A mixture of 3-methoxyisoquinoline-5-carbonitrile (500 mg, 2.71 mmol, 1.0 eq) in anhydrous Et.sub.2O (100 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 78 C. To this mixture was added Ti(i-PrO).sub.4 (1.16 g, 4.07 mmol, 1.20 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 1.99 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. under a N.sub.2 atmosphere. After the addition was completed, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (771 mg, 5.43 mmol, 670 L, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that 12% starting material remained and 40% desired compound was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (100 mL) and MTBE (100 mL) and extracted with MTBE (100 mL2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of (DCM/MeOH=10:1)/petroleum ether from 0/1 to 2/10. 1-(3-Methoxyisoquinolin-5-yl)cyclopropanamine (300 mg, 1.29 mmol, 24% yield) was obtained as a yellow oil. M+H.sup.+=215.2 (LCMS).

Step 3: 5-(1-Aminocyclopropyl)isoquinolin-3-ol (367A-4)

[1900] To a solution of 1-(3-methoxyisoquinolin-5-yl)cyclopropanamine (200 mg, 933 mol, 1.0 eq) in DCM (2.0 mL) was added BBr.sub.3 (3.51 g, 14.0 mmol, 1.35 mL, 15 eq) dropwise at 78 C. The mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS and HPLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NaHCO.sub.3 solution (10 mL) slowly at 0 C., extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(1-aminocyclopropyl)isoquinolin-3-ol (40.0 mg, 127 mol, 14% yield, TFA salt) as a red solid. M+H.sup.+=201.3 (LCMS).

Step 4: N-(1-(3-Hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 509)

[1901] To a solution of 5-(1-aminocyclopropyl)isoquinolin-3-ol (35.0 mg, 111 mol, 1.0 eq, TFA salt) and 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (26.2 mg, 96.4 mol, 0.9 eq, HCl salt) in DMF (1.0 mL) were added HBTU (84.5 mg, 223 mol, 2.0 eq) and DIEA (43.2 mg, 334 mol, 58.2 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give N-(1-(3-hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (10.7 mg, 18.8 mol, 17% yield, TFA salt) as a yellow solid. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.83-8.65 (m, 1H), 8.02-7.92 (m, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.57-7.50 (m, 1H), 7.31-7.19 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.98-6.93 (m, 1H), 6.79 (d, J=2.8 Hz, 1H), 4.74-4.63 (m, 1H), 4.33-4.26 (m, 1H), 4.26-4.09 (m, 2H), 4.02-3.90 (m, 1H), 3.02-2.90 (m, 3H), 2.61-2.50 (m, 2H), 2.12-2.05 (m, 3H), 1.45-1.38 (m, 2H), 1.30-1.24 (m, 2H).

Example 368: N-(3-Fluorobenzyl)-1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 549)

##STR01214##

Step 1: 1-(Quinolin-5-yl)ethanol (368A-2)

[1902] To a solution of 1-(quinolin-5-yl)ethanone (200 mg, 1.17 mmol, 1.0 eq) in MeOH (12 mL) was added NaBH.sub.4 (66.3 mg, 1.75 mmol, 1.5 eq) at 0 C. The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into ice water (15 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.6). 1-(Quinolin-5-yl)ethanol (120 mg, 693 mol, 60% yield) was obtained as a colorless oil. M+H.sup.+=174.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.94 (dd, J=1.5, 4.1 Hz, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.11-8.03 (m, 1H), 7.77-7.69 (m, 2H), 7.45 (dd, J=4.1, 8.6 Hz, 1H), 5.72-5.53 (m, 1H), 2.06-1.99 (m, 1H), 1.70 (d, J=6.5 Hz, 3H).

Step 2: Ethyl 1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxylate (368A-3)

[1903] To a solution of 1-(quinolin-5-yl)ethanol (70.0 mg, 404 mol, 1.0 eq) and DIEA (209 mg, 1.62 mmol, 282 L, 4.0 eq) in DCM (5.0 mL) was added a mixture of Ms.sub.2O (70.4 mg, 404 mol, 1.0 eq) in DCM (500 L) dropwise at 0 C. The mixture was stirred at 0 C. for 30 min. Then ethyl piperidine-4-carboxylate (63.5 mg, 404 mol, 62.3 L, 1.0 eq) was added. The mixture was stirred at 20 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.5). Ethyl 1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxylate (100 mg) was obtained as a colorless oil.

Step 3: 1-(1-(Quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (368A-4)

[1904] To a solution of ethyl 1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxylate (100 mg, 320 mol, 1.0 eq) in a mixture of MeOH (3.0 mL) and H.sub.2O (0.6 mL) was added NaOH (1 M aqueous, 640 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. H.sub.2O (5.0 mL) was added and the mixture was washed with MTBE (3.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (100 mg), which was used in the next step without any further purification. M+H.sup.+=285.0 (LCMS).

Step 4: N-(3-Fluorobenzyl)-1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 549)

[1905] To a solution of 1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (100 mg, 352 mol, 1.0 eq) and (3-fluorophenyl)methanamine (48.4 mg, 387 mol, 44.0 L 1.1 eq) in DMF (5.0 mL) were added DIEA (45.5 mg, 352 mol, 61.3 L, 1.0 eq), EDCI (67.4 mg, 352 mol, 1.0 eq) and HOBt (57.0 mg, 422 mol, 1.2 eq). The mixture was stirred at 20 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-1-(1-(quinolin-5-yl)ethyl)piperidine-4-carboxamide (19.3 mg, 45.1 mol, 13% yield, HCl salt) was obtained as a white solid. M+H.sup.+=392.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.76-10.57 (m, 1H), 9.23-9.10 (m, 2H), 8.57-8.46 (m, 1H), 8.38 (br d, J=7.1 Hz, 1H), 8.26 (br d, J=8.4 Hz, 1H), 8.04 (br t, J=7.9 Hz, 1H), 7.85 (br dd, J=4.2, 8.4 Hz, 1H), 7.45-7.26 (m, 1H), 7.16-6.93 (m, 3H), 5.55-5.34 (m, 1H), 4.26 (br d, J=5.9 Hz, 2H), 3.95 (br d, J=12.1 Hz, 1H), 3.20-2.77 (m, 3H), 2.41 (br d, J=4.0 Hz, 1H), 2.20-1.97 (m, 2H), 1.91-1.75 (m, 5H).

Example 369: N-(3-Fluorobenzyl)-1-(1-(isoquinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 522)

##STR01215##

Step 1: 1-(Isoquinolin-5-yl)ethanol (369A-2)

[1906] A solution of isoquinoline-5-carbaldehyde (500 mg, 3.18 mmol, 1.0 eq) in THF (10 mL) was degassed and purged with N.sub.2 three times. To this mixture was added MeMgBr (3 M in Et.sub.2O, 1.06 mL, 1.0 eq) dropwise at 78 C. The mixture was stirred at the same temperature for 30 min under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 1-(Isoquinolin-5-yl)ethanol (238 mg, 1.37 mmol, 43% yield) was obtained as a yellow solid. M+H.sup.+=174.1 (LCMS).

Step 2: N-(3-Fluorobenzyl)-1-(1-(isoquinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 522)

[1907] To a solution of 1-(isoquinolin-5-yl)ethanol (127 mg, 733 mol, 1.0 eq) in DCM (5.0 mL) were added DIEA (379 mg, 2.93 mmol, 511 L, 4.0 eq) and methylsulfonyl methanesulfonate (128 mg, 733 mol, 1.0 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. N-(3-Fluorobenzyl) piperidine-4-carboxamide (200 mg, 733 mol, 1.0 eq, HCl salt) was added in portions. The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 40 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-1-(1-(isoquinolin-5-yl)ethyl)piperidine-4-carboxamide (5.60 mg, 14.3 mol, 2% yield) was obtained as a white solid. M+H.sup.+=392.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.29 (s, 1H), 8.50 (d, J=6.1 Hz, 1H), 8.27 (br d, J=6.0 Hz, 2H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (d, J=7.1 Hz, 1H), 7.64 (s, 1H), 7.40-7.24 (m, 1H), 7.09-6.93 (m, 3H), 4.24 (d, J=6.0 Hz, 2H), 4.19-4.13 (m, 1H), 3.06-2.96 (m, 1H), 2.82-2.73 (m, 1H), 2.19-2.09 (m, 1H), 2.07-1.96 (m, 2H), 1.76-1.67 (m, 1H), 1.59 (br s, 3H), 1.40 (d, J=6.6 Hz, 3H).

Example 370: N-(3-Fluorobenzyl)-1-(1-(3-methoxynaphthalen-1-yl)ethyl)piperidine-4-carboxamide (Compound 524)

##STR01216##

Step 1: 1-(1-Ethoxyvinyl)-3-methoxynaphthalene (370A-1)

[1908] To a solution of 1-bromo-3-methoxynaphthalene (100 mg, 422 mol, 1.0 eq) in toluene (2.0 mL) were added tributyl(1-ethoxyvinyl) stannane (305 mg, 844 mol, 2.0 eq) and Pd (dppf) C12 (30.9 mg, 42.2 mol, 0.1 eq). The mixture was stirred at 110 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into water (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/10, R.sub.f=0.6). 1-(1-Ethoxyvinyl)-3-methoxynaphthalene (82.2 mg, 360 mol, 85% yield) was obtained as a white solid. M+H.sup.+=229.2 (LCMS).

Step 2: 1-(3-Methoxynaphthalen-1-yl)ethanone (370A-2)

[1909] To a solution of HCl/EtOAc (4 M, 1.0 mL) was added 1-(1-ethoxyvinyl)-3-methoxynaphthalene (82.2 mg, 360 mol, 1.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/10, R.sub.f=0.59). 1-(3-Methoxynaphthalen-1-yl)ethanone (40.1 mg, 178 mol, 50% yield) was obtained as a yellow oil. M+H.sup.+=201.1 (LCMS).

Step 3: 1-(3-Methoxynaphthalen-1-yl)ethanol (370A-3)

[1910] To a solution of 1-(3-methoxynaphthalen-1-yl)ethanone (100 mg, 499 mol, 1.0 eq) in EtOH (2.0 mL) was added NaBH.sub.4 (20.0 mg, 529 mol, 1.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a crude product 1-(3-methoxynaphthalen-1-yl)ethanol (110 mg) as a yellow oil. M+H.sup.+18=185.2 (LCMS).

Step 4: N-(3-Fluorobenzyl)-1-(1-(3-methoxynaphthalen-1-yl)ethyl)piperidine-4-carboxamide (Compound 524)

[1911] To a solution of 1-(3-methoxynaphthalen-1-yl)ethanol (40.0 mg, 198 mol, 1.0 eq) in DCM (2.0 mL) were added DIEA (102 mg, 791 mol, 4.0 eq) and methylsulfonyl methanesulfonate (34.5 mg, 198 mol, 1.0 eq) dropwise at 0 C. The mixture was stirred at 0 C. for 30 min, then N-(3-fluorobenzyl) piperidine-4-carboxamide (46.7 mg, 198 mol, 1.0 eq) was added and the mixture was stirred at 40 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 50%-75% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-1-(1-(3-methoxynaphthalen-1-yl)ethyl)piperidine-4-carboxamide (2.97 mg, 6.50 mol, 3% yield) was obtained as a pale yellow gum. M+H.sup.+=421.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.39-8.24 (m, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.43 (t, J=7.4 Hz, 1H), 7.38-7.27 (m, 2H), 7.23-7.15 (m, 2H), 7.08-6.90 (m, 3H), 4.24 (d, J=6.0 Hz, 2H), 4.09 (br d, J=6.6 Hz, 1H), 3.86 (s, 3H), 3.07 (br d, J=10.4 Hz, 1H), 2.78 (br d, J=11.9 Hz, 1H), 2.20-2.09 (m, 1H), 2.00 (br d, J=11.4 Hz, 2H), 1.77-1.67 (m, 1H), 1.65-1.56 (m, 2H), 1.55 (br d, J=3.3 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H).

Example 371: (R)-4-Methyl-3-(((1-(naphthalen-1-yl)ethyl)amino)methyl) aniline (Compound 106)

##STR01217##

Step 1: (R)-4-Methyl-3-(((1-(naphthalen-1-yl)ethyl)amino)methyl) aniline (Compound 106)

[1912] To a solution of (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (50.0 mg, 164 mol, 1.0 eq) in THF (2.0 mL) was added BH.sub.3-Me.sub.2S (10 M, 164 L, 10 eq) at 0 C. The mixture was stirred at 60 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (1.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 50%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-4-Methyl-3-(((1-(naphthalen-1-yl)ethyl)amino)methyl) aniline (18.2 mg, 60.2 mol, 37% yield) was obtained as a yellow oil. M+H.sup.+=291.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.19 (br d, J=7.8 Hz, 1H), 7.95-7.86 (m, 1H), 7.78 (br dd, J=5.4, 6.8 Hz, 2H), 7.59-7.45 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 6.53 (dd, J=2.0, 7.9 Hz, 1H), 4.73 (q, J=6.5 Hz, 1H), 3.73-3.58 (m, 2H), 2.16 (s, 3H), 1.55 (d, J=6.5 Hz, 3H).

Example 372: N-((1H-indazol-5-yl)methyl)-1-(naphthalen-1-yl)cyclopropan-1-amine (Compound 178)

##STR01218##

Step 1: N-((1H-Indazol-5-yl)methyl)-1-(naphthalen-1-yl)cyclopropan-1-amine (Compound 178)

[1913] To a stirred solution of 1H-indazole-5-carbaldehyde (100 mg, 684 mol, 1.0 eq) and 1-(naphthalen-1-yl)cyclopropan-1-amine (125 mg, 684 mol, 1.0 eq) in MeOH (5.0 mL) was added NaBH.sub.3CN (86.0 mg, 1.37 mmol, 2.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 50%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-((1H-Indazol-5-yl)methyl)-1-(naphthalen-1-yl)cyclopropan-1-amine (200 mg, 619 mol, 90% yield) was obtained as white solid. M+H.sup.+=314.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.34-9.65 (m, 1H), 8.55-8.39 (m, 1H), 7.98-7.90 (m, 2H), 7.85-7.78 (m, 1H), 7.61-7.43 (m, 5H), 7.38-7.31 (m, 1H), 7.23-7.17 (m, 1H), 3.77-3.61 (m, 2H), 1.35-1.16 (m, 2H), 1.12-0.94 (m, 2H).

Example 373: N-((1H-Indazol-5-yl)methyl)-N-methyl-1-(naphthalen-1-yl)cyclopropane amine (Compound 184)

##STR01219##

Step 1: N-((1H-Indazol-5-yl)methyl)-N-methyl-1-(naphthalen-1-yl)cyclopropanamine (Compound 184)

[1914] To a stirred solution of N-(1H-indazol-5-ylmethyl)-1-(1-naphthyl)cyclopropanamine (140 mg, 447 mol, 1.0 eq) in MeOH (5.0 mL) was added formaldehyde (72.5 mg, 893 mol, 66.5 L, 37% purity in water, 2.0 eq), followed by NaBH.sub.3CN (56.1 mg, 893 mol, 2.0 eq). The mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N-((1H-Indazol-5-yl)methyl)-N-methyl-1-(naphthalen-1-yl)cyclopropanamine (42.2 mg, 127 mol, 28% yield) was obtained as white solid. M+H.sup.+=328.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.69-8.58 (m, 1H), 8.06-7.94 (m, 3H), 7.89-7.82 (m, 1H), 7.71-7.48 (m, 5H), 7.40-7.32 (m, 1H), 4.26-4.12 (m, 1H), 4.38-3.95 (m, 2H), 2.56-2.39 (m, 3H), 1.85-1.64 (m, 2H), 1.51-1.28 (m, 2H).

Example 374: N, 1,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 208)

##STR01220##

Step 1: N,1,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (Compound 208)

[1915] To a solution of 5-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (50.0 mg, 147 mol, 1.0 eq) in THF (2.0 mL) was added sodium hydride (11.8 mg, 294 mol, 60% purity, 2.0 eq) at 0 C., followed by Mel (20.9 mg, 147 mol, 9.14 L, 1.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 40%-80% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N,1,5-Trimethyl-N-(1-(naphthalen-1-yl)cyclopropyl)-1H-indole-6-carboxamide (17.0 mg, 46.1 mol, 31% yield, HCl salt) was obtained as a white solid. M+H.sup.+=339.1 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 9.37-9.12 (m, 1H), 8.02-7.94 (m, 1H), 7.93-7.81 (m, 2H), 7.69-7.59 (m, 1H), 7.58-7.44 (m, 2H), 7.37-7.31 (m, 1H), 7.02-6.99 (m, 1H), 6.99-6.97 (m, 1H), 6.39-6.34 (m, 1H), 3.69 (s, 3H), 2.85 (s, 3H), 2.10 (s, 3H), 1.92-1.72 (m, 2H), 1.58-1.41 (m, 2H).

Example 375: N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxamide (Compound 179)

##STR01221##

Step 1: Dimethyl 2,2-bis((1,3-dioxolan-2-yl)methyl)malonate (375A-2)

[1916] A mixture of dimethyl malonate (5.01 g, 37.9 mmol, 4.35 mL, 1.0 eq) and t-BuOK (5.10 g, 45.5 mmol, 1.2 eq) in DMSO (100 mL) was stirred at 20 C. for 1 h. 2-(Bromomethyl)-1,3-dioxolane (7.60 g, 45.5 mmol, 4.66 mL, 1.2 eq) was added, and the mixture was stirred at 80 C. for 12 h. The solution was cooled to room temperature, 1-BuOK (5.10 g, 45.5 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 1 h. 2-(Bromomethyl)-1,3-dioxolane (7.60 g, 45.5 mmol, 4.66 mL, 1.2 eq) was added again, and the solution was stirred at 80 C. for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (100 mL) and extracted with EtOAc (40 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/10. Dimethyl 2,2-bis((1,3-dioxolan-2-yl)methyl)malonate (5.00 g, 16.4 mmol, 43% yield) was obtained as a colorless oil. M+H.sup.+=305.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 5.02 (t, J=4.8 Hz, 2H), 3.95-3.88 (m, 4H), 3.83-3.77 (m, 4H), 3.74-3.68 (m, 6H), 2.45 (d, J=4.9 Hz, 4H).

Step 2: Dimethyl 2,2-bis(2-oxoethyl)malonate (375A-3)

[1917] To a solution of dimethyl 2,2-bis((1,3-dioxolan-2-yl)methyl)malonate (2.00 g, 6.57 mmol, 1.0 eq) in THF (40 mL) was added HCl (10% purity in water, 40.0 mL). The mixture was stirred at 20 C. for 12 h. TLC indicated that the starting material was completely consumed. Dimethyl 2,2-bis(2-oxoethyl)malonate was obtained as a mixture (40 mL), which was used in the next step without any further purification.

Step 3: Dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl)pyridine-4,4(1H)-dicarboxylate (375A-4)

[1918] To a solution of dimethyl 2,2-bis(2-oxoethyl)malonate (590 mg, 2.73 mmol, 40 mL, 1.0 eq) was added NaHCO.sub.3 (458 mg, 5.46 mmol, 212 L, 2.0 eq) to adjust the pH to 7, followed by a solution of 1-(naphthalen-1-yl)cyclopropan-1-amine (500 mg, 2.73 mmol, 1.0 eq) in THF (5.0 mL). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was extracted with DCM (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl)pyridine-4,4(1H)-dicarboxylate (300 mg, 826 mol, 30% yield) was obtained as a white solid. M+H.sup.+=364.2 (LCMS).

Step 4: Dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4,4-dicarboxylate (375A-5)

[1919] To a solution of dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl)pyridine-4,4(1H)-dicarboxylate (150 mg, 413 mol, 1.0 eq) in MeOH (5.0 mL) was added 10% palladium on carbon (100 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred at 20 C. for 12 h under a H.sub.2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with MeOH (3.0 mL5). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative TLC (petroleum ether/EtOAc=5/1, R.sub.f=0.4). Dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4,4-dicarboxylate (100 mg, 272 mol, 66% yield) was obtained as a white solid. M+H.sup.+=368.2 (LCMS).

Step 5: Methyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylate (375A-6)

[1920] To a solution of dimethyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4,4-dicarboxylate (100 mg, 272 mol, 1.0 eq) in DMSO (2.0 mL) were added NaCl (79.5 mg, 1.36 mmol, 5.0 eq) and H.sub.2O (24.5 mg, 1.36 mmol, 5.0 eq). The mixture was stirred at 140 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (2.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude methyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylate (80.0 mg), which was used in the next step without any further purification. M+H.sup.+=310.3 (LCMS).

Step 6: 1-(1-(Naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylic acid (375A-7)

[1921] To a solution of methyl 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylate (40.0 mg, 129 mol, 1.0 eq) in a mixture of H.sub.2O (2.0 mL) and THF (5.0 mL) was added LiOH.Math.H.sub.2O (16.3 mg, 388 mol, 3.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (7.0 mL) and washed with MTBE (4.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylic acid (30.0 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=296.1 (LCMS).

Step 7: N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxamide (Compound 179)

[1922] To a solution of 1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxylic acid (30.0 mg, 102 mol, 1.0 eq) and (3-fluorophenyl)methanamine (14.0 mg, 112 mol, 12.7 L, 1.1 eq) in DCM (2.0 mL) were added TEA (30.8 mg, 305 mol, 42 L, 3.0 eq), EDCI (38.9 mg, 203 mol, 2.0 eq) and HOBt (27.5 mg, 203 mol, 2.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (2.0 mL) and extracted with DCM (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). N-(3-Fluorobenzyl)-1-(1-(naphthalen-1-yl)cyclopropyl) piperidine-4-carboxamide (6.31 mg, 12.2 mol, 12% yield, TFA salt) was obtained as a yellow gum. M+H.sup.+=403.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.50 (d, J=8.6 Hz, 1H), 8.42-8.32 (m, 1H), 8.14-8.07 (m, 1H), 8.04-7.98 (m, 1H), 7.94-7.86 (m, 1H), 7.75-7.68 (m, 1H), 7.66-7.58 (m, 2H), 7.35-7.24 (m, 1H), 7.09-7.01 (m, 1H), 7.00-6.87 (m, 2H), 4.41-4.25 (m, 2H), 4.23-3.80 (m, 2H), 3.14-2.94 (m, 1H), 2.80-2.60 (m, 1H), 2.31-2.16 (m, 1H), 2.14-1.85 (m, 5H), 1.80-1.25 (m, 4H).

Example 376: N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthalen-1-yl) propanamide (Compound 577)

##STR01222##

Step 1: N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthalen-1-yl)propanamide (Compound 577)

[1923] To a stirred solution of 2-(naphthalen-1-yl) propanoic acid (65.0 mg, 325 mol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylaniline (69.4 mg, 357 mol, 1.1 eq) in DMF (3.5 mL) was added DIEA (126 mg, 974 mol, 170 L, 3.0 eq), followed by HATU (370 mg, 974 mol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H.sub.2O (5 mL) and extracted with EtOAc (5.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthalen-1-yl) propanamide (36.2 mg, 85.4 mol, 26% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=377.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.91-9.73 (m, 1H), 9.52-9.43 (m, 1H), 8.37-8.28 (m, 1H), 8.00-7.93 (m, 1H), 7.89-7.82 (m, 1H), 7.63-7.48 (m, 4H), 7.15-7.08 (m, 2H), 6.77-6.68 (m, 1H), 4.83-4.69 (m, 1H), 4.24 (t, J=4.8 Hz, 2H), 3.46 (q, J=4.9 Hz, 2H), 2.82 (d, J=4.6 Hz, 6H), 2.04 (s, 3H), 1.60 (d, J=7.0 Hz, 3H).

Example 377: N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-1-(naphthalen-1-yl)cyclopropane-1-carboxamide (Compound 580)

##STR01223##

Step 1: N,N-Dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-1-amine (377A-2)

[1924] To a mixture of 4-methyl-3-nitrophenol (1.50 g, 9.80 mmol, 1.0 eq) and 2-(dimethylamino)ethanol (873 mg, 9.80 mmol, 98.9 L, 1.0 eq) in toluene (80 mL) were added TMAD (5.06 g, 29.4 mmol, 3.0 eq) and PPh.sub.3 (7.71 g, 29.4 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 100 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (80 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. N,N-Dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-1-amine (1.80 g, 8.03 mmol, 82% yield) was obtained as a brown solid. M+H.sup.+=225.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylaniline (377A-3)

[1925] To a mixture of N,N-dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-1-amine (1.00 g, 4.46 mmol, 1.0 eq) in a mixture of MeOH (15 mL) and H.sub.2O (3.0 mL) were added iron powder (1.25 g, 22.3 mmol, 5.0 eq) and NH.sub.4Cl (1.19 g, 22.3 mmol, 5.0 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 100 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was triturated with EtOAc (2.0 mL). 5-(2-(Dimethylamino)ethoxy)-2-methylaniline (500 mg, crude) was obtained as a brown solid, which was used in the next step without any further purification. M+H.sup.+=219.1 (LCMS).

Step 3: 1-(Naphthalen-1-yl)cyclopropane-1-carbonitrile (377A-5)

[1926] To a solution of 2-(1-naphthyl) acetonitrile (1.67 g, 9.99 mmol, 1.0 eq) in DMF (10 mL) was added NaH (1.20 g, 30.0 mmol, 60% purity, 3.0 eq) at 30 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at the same temperature for 1 h, then a solution of 1,2-dibromoethane (3.75 g, 20.0 mmol, 1.5 mL, 2.0 eq) in DMF (10 mL) was added dropwise. The resulting mixture was warmed slowly to 25 C. and stirred at the same temperature for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with saturated aqueous NH.sub.4Cl (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/8. 1-(Naphthalen-1-yl)cyclopropane-1-carbonitrile (1.00 g, 5.17 mmol, 52% yield) was obtained as a white solid. M+H.sup.+=194.1 (LCMS).

Step 4: 1-(Naphthalen-1-yl)cyclopropane-1-carboxylic acid (377A-6)

[1927] To a solution of (400 mg, 2.07 mmol, 1.0 eq) in ethane-1,2-diol (5.0 mL) was added KOH (1.16 g, 20.7 mmol, 10 eq). The resulting mixture was stirred at 190 C. for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (7.0 mL), and washed with MTBE (4.0 mL2). The aqueous layer was acidified to pH 5 with HCl (1 M aqueous). The product was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the crude 1-(naphthalen-1-yl)cyclopropane-1-carboxylic acid (300 mg, 1.41 mmol, 68% yield) as a brown solid, which was used in the next step without any further purification. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.09 (d, J=8.3 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.87-7.81 (m, 1H), 7.59-7.41 (m, 4H), 1.75-1.55 (m, 2H), 1.31-1.14 (m, 2H).

Step 5: 1-(Naphthalen-1-yl)cyclopropane-1-carbonyl chloride (377A-7)

[1928] To a solution of 1-(naphthalen-1-yl)cyclopropane-1-carboxylic acid (100 mg, 471 mol, 1.0 eq) in SOCl.sub.2 (224 mg, 1.88 mmol, 137 L, 4.0 eq) was added DMF (3.44 mg, 47.0 mol, 3.63 L, 0.1 eq). The resulting mixture was stirred at 90 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a crude 1-(naphthalen-1-yl)cyclopropane-1-carbonyl chloride (100 mg) as a brown oil, which was used in the next step without any further purification. M+H.sup.+=227.1 (LCMS, quenched by MeOH for testing).

Step 6: N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-1-(naphthalen-1-yl)cyclopropane-1-carboxamide (Compound 580)

[1929] To a mixture of 5-(2-(dimethylamino)ethoxy)-2-methylaniline (75.8 mg, 390 mol, 1.0 eq) in THF (2.0 mL) was added TEA (79.0 mg, 780 mol, 110 L, 2.0 eq), then a solution of 1-(naphthalen-1-yl)cyclopropanecarbonyl chloride (90.0 mg, 390 mol, 1.0 eq) in THF (1.0 mL) was added dropwise. The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-1-(naphthalen-1-yl)cyclopropane-1-carboxamide (11.3 mg, 28.7 mol, 7% yield, HCl salt) was obtained as a brown solid. M+H.sup.+=389.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.66 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.00 (br d, J=16.1 Hz, 2H), 7.73 (d, J=6.5 Hz, 1H), 7.54-7.65 (m, 4H), 7.29 (d, J=2.5 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.62 (dd, J=2.6, 8.3 Hz, 1H), 4.16-4.23 (m, 2H), 3.46 (br d, J=5.1 Hz, 2H), 2.83 (s, 6H), 1.74 (br d, J=2.3 Hz, 2H), 1.21-1.30 (m, 2H), 1.34-1.40 (m, 3H).

Example 378: (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindolin-2-yl)methanone (Compound 111)

##STR01224## ##STR01225##

Step 1: tert-Butyl 5-(5-formylthiophen-2-yl)isoindoline-2-carboxylate (378A-2)

[1930] To a stirred solution of tert-butyl 5-bromoisoindoline-2-carboxylate (200 mg, 671 mol, 1.0 eq) in DMSO (10 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (192 mg, 805 mol, 1.2 eq), Pd(OAc).sub.2 (15.1 mg, 67.1 mol, 0.1 eq), cataCxium A (48.1 mg, 134.15 mol, 0.2 eq), and KOAc (198 mg, 2.01 mmol, 3.0 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, treated with H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue. The residue was triturated from TBME (5 mL) and filtered. The cake was dried under vacuum to give tert-butyl 5-(5-formyl-2-thienyl)isoindoline-2-carboxylate (150 mg, 455 mol, 68% yield) as an off-white solid.

Step 2: tert-Butyl 5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carboxylate (378A-3)

[1931] To a stirred solution of tert-butyl 5-(5-formyl-2-thienyl)isoindoline-2-carboxylate (120 mg, 364 mol, 1.0 eq) and pyrrolidine (51.8 mg, 729 mol, 2.0 eq) in MeOH (15 mL) was added NaBH.sub.3CN (68.7 mg, 1.09 mmol, 3.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 20 C. for 12 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (20 mL) and extracted with DCM (15 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue. The residue was treated with TBME (5.0 mL) and a precipitate was formed. The mixture was filtered and the cake was dried under vacuum to give the crude tert-butyl 5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carboxylate (150 mg, crude) as a yellow solid.

Step 3: 5-(5-(Pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline (378A-4)

[1932] To a stirred solution of tert-butyl 5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carboxylate (170 mg, 442 mol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 11 mL). The mixture was stirred at 20 C. for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the crude 5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline (180 mg, HCl Salt) as a yellow gum, which was used in the next step without any further purification.

Step 4: tert-Butyl 3-((4-methyl-3-(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carbonyl)phenyl)amino)azetidine-1-carboxylate (378A-5)

[1933] To a stirred solution of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (172 mg, 561 mol, 1.0 eq) and 5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline (180 mg, 561 mol, 1.0 eq, HCl Salt) in DCM (10 mL) were added TEA (170 mg, 1.68 mmol, 234 L, 3.0 eq), EDCI (129 mg, 673 mol, 1.2 eq) and HOBt (91.0 mg, 673 mol, 1.2 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue, which was triturated with TMBE (5 mL) and filtered. The cake was dried under vacuum to give the crude tert-butyl 3-((4-methyl-3-(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carbonyl)phenyl)amino)azetidine-1-carboxylate (300 mg, 524 mol, 93% yield) as a yellow solid.

Step 5: (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindolin-2-yl)methanone (Compound 111)

[1934] To a stirred solution of tert-butyl 3-((4-methyl-3-(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindoline-2-carbonyl)phenyl)amino)azetidine-1-carboxylate (150 mg, 262 mol, 1.0 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated in vacuum at 25 C. to give a residue, which was purified by preparative HPLC (Phenomenex Luna column (80 40 mm, 3 m); flow rate: 40 mL/min; gradient: 10%-34% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)isoindolin-2-yl)methanone (72.8 mg, 135.85 mol, 52% yield, HCl salt) was obtained as yellow gum. M+H.sup.+=473.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.76-7.51 (m, 2H), 7.48-7.25 (m, 3H), 7.24-7.18 (m, 1H), 6.85-6.80 (m, 1H), 6.76-6.72 (m, 1H), 5.03-4.96 (m, 2H), 4.69-4.55 (m, 5H), 4.47-4.36 (m, 2H), 4.14-4.03 (m, 2H), 3.64-3.57 (m, 2H), 3.29-3.19 (m, 2H), 2.27-2.13 (m, 5H), 2.10-1.99 (m, 2H).

Example 379: 5-(Azetidin-3-ylamino)-2-methyl-N-(4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 116)

##STR01226## ##STR01227##

Step 1: tert-Butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (379A-2)

[1935] To a stirred solution of tert-butyl 4-bromobenzylcarbamate (200 mg, 699 mol, 1.0 eq) in DMSO (10 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (109 mg, 699 mol, 1.0 eq), cataCxium A (50.1 mg, 140 mol, 0.2 eq), Pd(OAc) 2 (15.7 mg, 69.9 mol, 0.1 eq), and KOAc (206 mg, 2.10 mmol, 3.0 eq) under a N.sub.2 atmosphere. The mixture was stirred at 80 C. for 6 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (200 mg, 630 mol, 90% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.90 (s, 1H), 7.75 (d, J=3.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.40 (d, J=3.9 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 4.91 (br s, 1H), 4.36 (br d, J=5.4 Hz, 2H), 1.48 (s, 9H).

Step 2: tert-Butyl 4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (379A-3)

[1936] To a stirred solution of tert-butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (200 mg, 630 mol, 1.0 eq) in MeOH (20 mL) was added pyrrolidine (89.6 mg, 1.26 mmol, 105 L, 2.0 eq), followed by NaBH.sub.3CN (119 mg, 1.89 mmol, 3.0 eq). The mixture was stirred at 20 C. for 16 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (20 mL) and extracted with DCM (15 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude tert-butyl 4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (250 mg, crude) as a yellow solid, which was used in the next step without any further purification.

Step 3: (4-(5-(Pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)methanamine (379A-4)

[1937] To a stirred solution of tert-butyl 4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzylcarbamate (250 mg, 671 mol, 1.0 eq) in EtOAc (15 mL) was added HCl/EtOAc (4 M, 17 mL). The mixture was stirred at 20 C. for 2 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated in vacuum at 25 C. to give the crude (4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)methanamine (250 mg, crude HCl salt) as a yellow gum, which was used in the next step without any further purification.

Step 4: tert-Butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (379A-5)

[1938] To a stirred solution of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (200 mg, 653 mol, 1.0 eq) and (4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)phenyl)methanamine (202 mg, 653 mol, 1.0 eq, HCl salt) in DCM (10 mL) were added HOBt (106 mg, 783 mol, 1.2 eq), EDCI (150 mg, 783 mol, 1.2 eq) and TEA (198 mg, 1.96 mmol, 273 L, 3.0 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (250 mg, 446 mol, 68% yield) was obtained as a yellow solid.

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-N-(4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 116)

[1939] To a stirred solution of tert-butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (200 mg, 357 mol, 1.0 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated in vacuum at 25 C. to give a residue, which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-N-(4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)benzyl)benzamide (44.6 mg, 76.1 mol, 21% yield, TFA salt) was obtained as a yellow gum. M+H.sup.+=461.1 (LCMS); 1HNMR (400 MHZ, CD.sub.3OD) 7.68-7.62 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.40 (d, J=3.8 Hz, 1H), 7.30 (d, J=3.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.61-6.57 (m, 2H), 4.62 (s, 2H), 4.57-4.45 (m, 3H), 4.41-4.33 (m, 2H), 3.95 (dd, J=6.8, 11.3 Hz, 2H), 3.59 (br s, 2H), 3.26 (br s, 2H), 2.25 (s, 5H), 2.10-1.95 (m, 2H).

Example 380: tert-Butyl (R)-3-((3-((1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (Compound 161)

##STR01228##

Step 1: tert-Butyl (R)-4-(1-(2-methyl-5-nitrobenzamido)ethyl)piperidine-1-carboxylate (380A-2)

[1940] To a solution of tert-butyl (R)-4-(1-aminoethyl)piperidine-1-carboxylate (500 mg, 2.19 mmol, 1.0 eq) and 2-methyl-5-nitrobenzoic acid (397 mg, 2.19 mmol, 0.53 mL, 1.0 eq) in DCM (10 mL) were added TEA (444 mg, 4.38 mmol, 610 L, 2.0 eq), EDCI (504 mg, 2.63 mmol, 1.2 eq) and HOBt (355 mg, 2.63 mmol, 1.2 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude tert-butyl (R)-4-(1-(2-methyl-5-nitrobenzamido)ethyl)piperidine-1-carboxylate (950 mg) as a colorless oil. M56+H.sup.+=336.3 (LCMS).

Step 2: (R)-2-Methyl-5-nitro-N-(1-(piperidin-4-yl)ethyl)benzamide (380A-3)

[1941] To a stirred solution of tert-butyl (R)-4-(1-(2-methyl-5-nitrobenzamido)ethyl)piperidine-1-carboxylate (800 mg, 2.04 mmol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude (R)-2-methyl-5-nitro-N-(1-(piperidin-4-yl)ethyl)benzamide (800 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=292.1 (LCMS).

Step 3: (R)N-(1-(1-(Ethylsulfonyl) piperidin-4-yl)ethyl)-2-methyl-5-nitrobenzamide (380A-4)

[1942] To a solution of (R)-2-methyl-5-nitro-N-(1-(piperidin-4-yl)ethyl)benzamide (500 mg, 1.72 mmol, 1.0 eq) in DCM (30 mL) were added TEA (521 mg, 5.15 mmol, 717 L, 3.0 eq) and ethanesulfonyl chloride (265 mg, 2.06 mmol, 1.2 eq). The mixture was stirred at 0 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. (R)N-(1-(1-(Ethylsulfonyl) piperidin-4-yl)ethyl)-2-methyl-5-nitrobenzamide (500 mg, 1.30 mmol, 76% yield) was obtained as a colorless oil. M+H.sup.+=384.1 (LCMS).

Step 4: (R)-5-Amino-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (380A-5)

[1943] To a solution of (R)N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methyl-5-nitrobenzamide (500 mg, 1.30 mmol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) were added iron powder (365 mg, 6.52 mmol, 5.0 eq) and NH.sub.4Cl (349 mg, 6.52 mmol, 5.0 eq). The mixture was stirred at 80 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude (R)-5-amino-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (26.8 mg, 83.0 mol, 29% yield) as a white solid. M+H.sup.+=354.2 (LCMS).

Step 5: tert-Butyl (R)-3-((3-((1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (Compound 161)

[1944] To a solution of (R)-5-amino-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (50.0 mg, 141 mol, 1.0 eq) and tert-butyl 3-oxoazetidine-1-carboxylate (24.3 mg, 141 mol, 1.0 eq) in MeOH (4.0 mL) was added NaBH.sub.3CN (10.7 mg, 170 mol, 1.2 eq). The resulting mixture was stirred at 25 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7030 mm, 3 m); flow rate: 25 mL/min; gradient: 30%-70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give tert-butyl (R)-3-((3-((1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (2.09 mg, 4.11 mol, 3% yield) as a white solid. M+Na.sup.+=531.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.04 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.48 (dd, J=2.4, 8.2 Hz, 1H), 5.49 (br d, J=8.9 Hz, 1H), 4.34-4.25 (m, 2H), 4.24-4.14 (m, 2H), 3.92-3.84 (m, 2H), 3.72 (dd, J=4.4, 8.9 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 2.85-2.73 (m, 2H), 2.31 (s, 3H), 1.89-1.76 (m, 2H), 1.51-1.40 (m, 13H), 1.37 (t, J=7.4 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H).

Example 381: (R)-5-(Azetidin-3-ylamino)-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (Compound 166)

##STR01229##

Step 1: (R)-5-(Azetidin-3-ylamino)-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (Compound 166)

[1945] To a stirred solution of tert-butyl (R)-3-((3-((1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl) carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (150 mg, 295 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 300 L). The mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 C. to give a residue which was treated with small amount of NH.sub.3.Math.H.sub.2O to pH 7 and purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (R)-5-(Azetidin-3-ylamino)-N-(1-(1-(ethylsulfonyl) piperidin-4-yl)ethyl)-2-methylbenzamide (30.0 mg, 71.6 mol, 24% yield) was obtained as a white solid. M+H.sup.+=409.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.00 (d, J=8.1 Hz, 1H), 6.60-6.49 (m, 2H), 4.38 (t, J=7.1 Hz, 1H), 4.05-3.92 (m, 2H), 4.12-3.90 (m, 1H), 3.80 (br d, J=12.5 Hz, 2H), 3.61 (br t, J=8.1 Hz, 2H), 3.03 (q, J=7.3 Hz, 2H), 2.89-2.74 (m, 2H), 2.24 (s, 3H), 1.95-1.80 (m, 2H), 1.59 (dt, J=3.2, 7.4 Hz, 1H), 1.47-1.27 (m, 5H), 1.21 (d, J=6.8 Hz, 3H).

Example 382: N-(2-Methoxy-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (Compound 108)

##STR01230##

Step 1: 2-Amino-2-(naphthalen-1-yl)ethanol (382A-2)

[1946] To a solution of 2-amino-2-(naphthalen-1-yl) acetic acid (400 mg, 1.99 mmol, 1.0 eq) in THF (32 mL) was added LiAlH.sub.4 (755 mg, 19.9 mmol, 10 eq) in portions at 0 C. The mixture was stirred at 65 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was cooled to 0 C., quenched by addition of 0.8 mL of H.sub.2O, followed by 0.8 mL of 10% aqueous NaOH. The suspension was stirred at room temperature for 5 min, then filtered through a pad of celite. The combined filtrates were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude 2-amino-2-(naphthalen-1-yl)ethanol (400 mg) as an orange solid, which was used in the next step without any further purification. M+H.sup.+=188.3 (LCMS).

Step 2: tert-Butyl(2-hydroxy-1-(naphthalen-1-yl)ethyl)carbamate (382A-3)

[1947] To a solution of 2-amino-2-(naphthalen-1-yl)ethanol (200 mg, 1.07 mmol, 1.0 eq) in THF (1.0 mL) was added Boc.sub.2O (233 mg, 1.07 mmol, 246 L, 1.0 eq). The resulting mixture was stirred at 20 C. for 13 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was triturated with EtOAc (2.0 mL) and filtered. The solid cake was dried in vacuum to give tert-butyl(2-hydroxy-1-(naphthalen-1-yl)ethyl)carbamate (300 mg, 1.04 mmol, 98% yield) as a white solid. M+H.sup.+=288.3 (LCMS).

Step 3: tert-Butyl(2-methoxy-1-(naphthalen-1-yl)ethyl)carbamate (382A-4)

[1948] To a solution of tert-butyl(2-hydroxy-1-(naphthalen-1-yl)ethyl)carbamate (100 mg, 348 mol, 1.0 eq) in THF (1.0 mL) was added sodium hydride (16.7 mg, 418 mol, 60% purity, 1.2 eq) and Mel (54.3 mg, 383 mol, 23.8 L, 1.1 eq) at 0 C. The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (petroleum ether/EtOAc=3/1, R.sub.f=0.6). tert-Butyl(2-methoxy-1-(naphthalen-1-yl)ethyl)carbamate (60.0 mg, 199 mol, 57% yield) was obtained as a white solid. M+H.sup.+=302.3 (LCMS).

Step 4: 2-Methoxy-1-(naphthalen-1-yl) ethan-1-amine (382A-5)

[1949] To a solution of tert-butyl(2-methoxy-1-(naphthalen-1-yl)ethyl)carbamate (50.0 mg, 166 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (333 L). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude 2-methoxy-1-(naphthalen-1-yl) ethan-1-amine (30.0 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=202.2 (LCMS).

Step 5: N-(2-Methoxy-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (Compound 108)

[1950] To a solution of 2-methyl-5-nitrobenzoic acid (29.7 mg, 164 mol, 1.1 eq) and 2-methoxy-1-(naphthalen-1-yl) ethan-1-amine (30.0 mg, 149 mol, 1.0 eq, TFA salt) in DCM (2.0 mL) was added TEA (30.2 mg, 298 mol, 41.5 L, 2.0 eq) and T.sub.3P (94.9 mg, 149 mol, 8.7 L, 50% purity in EtOAc, 1.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m);

[1951] flow rate: 25 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(2-Methoxy-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (10.0 mg, 27.1 mol, 18% yield) was obtained as an off-white solid. M+H.sup.+=365.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.28 (d, J=2.3 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.17 (dd, J=2.4, 8.4 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.65-7.58 (m, 2H), 7.57-7.46 (m, 2H), 7.40 (d, J=8.5 Hz, 1H), 6.52 (br d, J=7.6 Hz, 1H), 6.31-6.10 (m, 1H), 4.07-3.85 (m, 2H), 3.46 (s, 3H), 2.55 (s, 3H).

Example 383: 5-Amino-N-(2-methoxy-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 118)

##STR01231##

Step 1: 5-Amino-N-(2-methoxy-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 118)

[1952] To a solution of N-(2-methoxy-1-(naphthalen-1-yl)ethyl)-2-methyl-5-nitrobenzamide (50.0 mg, 137 mol, 1.0 eq) in EtOAc (5.0 mL) was added 10% palladium on carbon (50.0 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred at 20 C. for 3 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (2.0 mL3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-N-(2-methoxy-1-(naphthalen-1-yl)ethyl)-2-methylbenzamide (13.1 mg, 37.0 mol, 27% yield) was obtained as a white solid. M+H.sup.+=335.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.24-8.16 (m, 1H), 7.92-7.84 (m, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.59-7.37 (m, 4H), 6.94 (d, J=8.3 Hz, 1H), 6.85 (br d, J=1.6 Hz, 1H), 6.74 (br d, J=8.0 Hz, 1H), 6.70 (br s, 1H), 6.21-6.12 (m, 1H), 3.94-3.79 (m, 2H), 3.38 (s, 3H), 2.28 (s, 3H).

Example 384: 2-Methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)-5-nitrobenzamide (Compound 105)

##STR01232##

Step 1: Naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanone (384A-1)

[1953] To a solution of 1-bromonaphthalene (430 mg, 2.08 mmol, 289 L, 1.2 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 831 L, 1.2 eq) dropwise at 78 C. under a N.sub.2 atmosphere. The mixture was stirred at the same temperature for 50 min. A solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (300 mg, 1.73 mmol, 1.0 eq) in THF (10 mL) was added dropwise at the same temperature. The resulting mixture was stirred at 78 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (2.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanone (200 mg, 832 mol, 48% yield) was obtained as a colorless oil. M+H.sup.+=241.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.29 (d, J=8.2 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.94-7.86 (m, 1H), 7.75 (d, J=7.1 Hz, 1H), 7.63-7.47 (m, 3H), 4.05 (td, J=3.4, 11.6 Hz, 2H), 3.59-3.38 (m, 3H), 1.98-1.79 (m, 4H).

Step 2: Naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanamine (384A-2)

[1954] To a solution of naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanone (150 mg, 624 mol, 1.0 eq) in MeOH (2.0 mL) were added NH.sub.3/MeOH (20 M, 5.0 mL) and Ti(i-PrO).sub.4 (87 mg, 3.12 mmol, 921 L, 5.0 eq) at 0 C. The mixture was stirred at 20 C. for 12 h. After that, the mixture was cooled to 0 C. and NaBH.sub.4 (118 mg, 3.12 mmol, 5.0 eq) was added. The resulting mixture was stirred at 0 C. for 1 h, and then stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (1.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanamine (150 mg) as a brown oil, which was used in the next step without any further purification. M17+H.sup.+=225.3 (LCMS).

Step 3: 2-Methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)-5-nitrobenzamide (Compound 105)

[1955] To a solution of naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methanamine (100 mg, 414 mol, 1.0 eq) and 2-methyl-5-nitro-benzoic acid (75.1 mg, 414 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (126 mg, 1.24 mmol, 173 L, 3.0 eq) and T.sub.3P (527 mg, 829 mol, 493 L, 50% in EtOAc, 2.0 eq) at 0 C. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (6.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 40%-75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)-5-nitrobenzamide (13.7 mg, 32.9 mol, 8% yield) was obtained as an off-white solid. M+H.sup.+=405.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.31 (d, J=8.5 Hz, 1H), 8.19-8.09 (m, 2H), 7.92 (d, J=8.1 Hz, 1H), 7.85 (dd, J=3.1, 6.1 Hz, 1H), 7.66-7.59 (m, 1H), 7.59-7.53 (m, 1H), 7.52-7.46 (m, 2H), 7.36 (d, J=8.9 Hz, 1H), 6.23-6.09 (m, 1H), 5.95 (t, J=9.1 Hz, 1H), 4.17-3.86 (m, 2H), 3.50-3.28 (m, 2H), 2.45 (s, 3H), 2.35 (br s, 1H), 1.94-1.69 (m, 2H), 1.59-1.40 (m, 2H).

Example 385: 5-Amino-2-methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 109)

##STR01233##

Step 1: 5-Amino-2-methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 109)

[1956] To a solution of 2-methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)-5-nitrobenzamide (80.0 mg, 198 mol, 1.0 eq) in EtOAc (5.0 mL) and MeOH (5.0 mL) was added 10% palladium on carbon (80.0 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred at 20 C. for 5 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (5.0 mL3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (15030 mm, 5 m); flow rate: 25 mL/min; gradient: 25%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-(naphthalen-1-yl(tetrahydro-2H-pyran-4-yl)methyl)benzamide (25.8 mg, 68.5 mol, 35% yield) was obtained as a white solid. M+H.sup.+=375.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.31 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.63-7.41 (m, 4H), 6.96 (d, J=8.8 Hz, 1H), 6.68-6.59 (m, 2H), 6.14-5.87 (m, 2H), 4.07 (br dd, J=2.4, 11.7 Hz, 1H), 3.92 (br d, J=11.0 Hz, 1H), 3.58 (br s, 2H), 3.44-3.28 (m, 2H), 2.39-2.14 (m, 4H), 1.88-1.67 (m, 2H), 1.62-1.44 (m, 2H).

Example 386: 5-Amino-2-methyl-N-(naphthalen-1-ylsulfonyl)benzamide (Compound 242)

##STR01234##

Step 1: Naphthalene-1-sulfonamide (386A-2)

[1957] To a solution of naphthalene-1-sulfonyl chloride (500 mg, 2.21 mmol, 1.0 eq) in acetone (10 mL) was added NH.sub.3.Math.H.sub.2O (12 mL, 25% purity) at 0 C. The mixture was stirred at 0 C. for 15 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 ml) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude naphthalene-1-sulfonamide (400 mg, 1.93 mmol, 8% yield) as a white solid. M+H.sup.+=208.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.63 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.73-7.60 (m, 5H).

Step 2: 2-Methyl-N-(naphthalen-1-ylsulfonyl)-5-nitrobenzamide (386A-3)

[1958] To a solution of naphthalene-1-sulfonamide (100 mg, 483 mol, 1.0 eq) and 2-methyl-5-nitro-benzoic acid (87.4 mg, 483 mol, 1.0 eq) in DCM (4.0 mL) were added DMAP (8.4 mg, 724 mol, 1.5 eq) and EDCI (185 mg, 965 mol, 2.0 eq). The mixture was stirred at 25 C. for 20 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give the crude product 2-methyl-N-(naphthalen-1-ylsulfonyl)-5-nitrobenzamide (170 mg, 459 mol, 95% yield) as a white solid. M+H.sup.+=371.2 (LCMS).

Step 3: 5-Amino-2-methyl-N-(naphthalen-1-ylsulfonyl)benzamide (Compound 242)

[1959] To a solution of 2-methyl-N-(naphthalen-1-ylsulfonyl)-5-nitrobenzamide (100 mg, 270 mol, 1.0 eq) in a mixture of MeOH (10 mL) and H.sub.2O (2.5 mL) was added iron powder (75.4 mg, 1.35 mmol, 5.0 eq), followed by NH.sub.4Cl (72.2 mg, 1.35 mmol, 5.0 eq). The mixture was stirred at 80 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-(naphthalen-1-ylsulfonyl)benzamide (16.0 mg, 41.4 mol, 15% yield, HCl salt) was obtained as a white solid. M+H.sup.+=341.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.63 (d, J=8.4 Hz, 1H), 8.37 (dd, J=7.5, 14.9 Hz, 2H), 8.16 (d, J=7.9 Hz, 1H), 7.81-7.66 (m, 3H), 7.24-6.96 (m, 3H), 1.85 (s, 3H).

Example 387: (R)-5-Amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzenesulfonamide (Compound 138)

##STR01235##

Step 1: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzenesulfonamide (387A-2)

[1960] To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (300 mg, 1.27 mmol, 1.0 eq) and (R)-1-(naphthalen-1-yl) ethan-1-amine (218 mg, 1.27 mmol, 204 L, 1.0 eq) in DCM (5.0 mL) was added TEA (155 mg, 1.53 mmol, 213 L, 1.2 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzenesulfonamide (400 mg) as a pale yellow solid, which was used in the next step without any further purification. (M+18).sup.+=388.2 (LCMS).

Step 2: (R)-5-Amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzenesulfonamide (Compound 138)

[1961] To a solution of (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzenesulfonamide (200 mg, 540 mol, 1.0 eq) in MeOH (2.5 mL) and H.sub.2O (0.5 mL) were added iron powder (151 mg, 2.70 mmol, 5.0 eq) and NH.sub.4Cl (144 mg, 2.70 mmol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (6.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-5-Amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzenesulfonamide (93.8 mg, 200 mol, 37% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=341.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.97-7.89 (m, 1H), 7.79-7.73 (m, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.44-7.39 (m, 2H), 7.34-7.28 (m, 1H), 7.13-7.07 (m, 2H), 5.25 (q, J=6.9 Hz, 1H), 2.56-2.30 (m, 3H), 1.57 (d, J=6.9 Hz, 3H).

Example 388: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-(phenylethynyl)benzamide (Compound 217)

##STR01236##

Step 1: 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-(phenylethynyl)benzamide (Compound 217)

[1962] A mixture of 5-amino-4-iodo-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (100 mg, 226 mol, 1.0 eq), TEA (45.8 mg, 452 mol, 62.9 L, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (4.76 mg, 6.78 mol, 0.03 eq), CuI (431 g, 2.26 mol, 0.01 eq) and ethynylbenzene (34.6 mg, 339 mol, 37.2 L, 1.5 eq) in toluene (5.0 mL) and H.sub.2O (2.5 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 70 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 40 mm, 3 m); flow rate: 25 mL/min; gradient: 43%-83% B over 7 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-Amino-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)-4-(phenylethynyl)benzamide (50.0 mg, 110 mol, 48% yield, HCl salt) was obtained as a white solid. M+H.sup.+=417.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.47 (d, J=8.5 Hz, 1H), 7.98-7.88 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.62-7.47 (m, 5H), 7.37-7.31 (m, 3H), 7.11 (s, 1H), 6.51 (s, 1H), 6.47 (s, 1H), 2.08 (s, 3H), 1.57 (br d, J=1.8 Hz, 2H), 1.42-1.38 (m, 2H).

Example 389: (S)N-(1-(7-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 624)

##STR01237##

Step 1: 5-Bromo-7-chloroquinoline (389A-2)

[1963] To a solution of 3-bromo-5-chloroaniline (10.0 g, 48.4 mmol, 1.0 eq) and sodium 3-nitrobenzenesulfonate (21.8 g, 96.9 mmol, 2.0 eq) in H.sub.2SO.sub.4 (125 g, 1.25 mol, 68.1 mL, 98% purity, 26 eq) and H.sub.2O (29 mL) was added glycerol (17.8 g, 194 mmol, 14.5 mL, 4.0 eq) at 100 C. The mixture was stirred at 125 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/20 to 1/5. A mixture of 7-bromo-5-chloroquinoline and 5-bromo-7-chloroquinoline (8.00 g, 33.0 mmol, 64% yield) was obtained as a white solid, which was hard to be separated from each other. M+H.sup.+=241.9 (LCMS).

Step 2: 7-Chloroquinoline-5-carbonitrile (389A-3)

[1964] To a solution of 7-bromo-5-chloroquinoline and 5-bromo-7-chloroquinoline (1.00 g, 4.12 mmol, 1.0 eq) in DMF (10 mL) were added Zn(CN).sub.2 (242 mg, 2.06 mmol, 131 L, 0.5 eq) and Pd(PPh.sub.3).sub.4 (477 mg, 412 mol, 0.1 eq). The mixture was stirred at 120 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Chloroquinoline-5-carbonitrile (150 mg, 795 mol, 19% yield) was obtained as a white solid. M+H.sup.+=189.0 (LCMS).

Step 3: 1-(7-Chloroquinolin-5-yl)cyclopropan-1-amine (389A-4)

[1965] A mixture of 7-chloroquinoline-5-carbonitrile (1.30 g, 6.89 mmol, 1.0 eq) in anhydrous Et.sub.2O (100 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (2.94 g, 10.3 mmol, 3.05 mL, 1.5 eq) slowly, and then EtMgBr (2 M in Et.sub.2O, 7.58 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 73 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (1.96 g, 13.8 mmol, 1.70 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (100 mL) and extracted with MTBE (50 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 5%-25% B over 10 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 1-(7-chloroquinolin-5-yl)cyclopropan-1-amine (4.00 mg, 18.3 mol, HCl salt) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04 (dd, J=1.5, 4.1 Hz, 1H), 8.77 (br s, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.74 (dd, J=4.3, 8.6 Hz, 1H), 1.60 (s, 2H), 1.31 (s, 2H).

Step 4: (S)N-(1-(7-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 624)

[1966] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (5.38 mg, 22.9 mol, 1.0 eq) in DMF (15 mL) was added 1-(7-chloroquinolin-5-yl)cyclopropan-1-amine (5.00 mg, 22.9 mol, 1.0 eq), followed by HATU (17.4 mg, 45.7 mol, 2.0 eq) and DIEA (14.8 mg, 114 mol, 19.9 L, 5.0 eq). The resulting mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (1.0 mL) and extracted with EtOAc (1.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (2.00 mg, 4.36 mol, 19% yield, HCl salt) was obtained as a white solid. M+H.sup.+=436.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.77-10.14 (m, 1H), 9.28 (s, 1H), 9.21 (br d, J=8.6 Hz, 1H), 9.04 (d, J=4.0 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.75 (dd, J=4.4, 8.6 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.98-6.87 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.68-4.55 (m, 1H), 4.33 (br dd, J=7.8, 11.3 Hz, 1H), 4.26-4.18 (m, 1H), 3.99 (br dd, J=4.6, 10.0 Hz, 1H), 3.88-3.83 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 2.38-2.27 (m, 2H), 1.95 (s, 3H), 1.38 (br s, 2H), 1.30 (br s, 2H).

Example 390: (S)N-(1-(7-Aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 729)

##STR01238##

Step 1: tert-Butyl(S)-(5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl)carbamate (390A-1)

[1967] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (250 mg, 455 mol, 1.0 eq) and tert-butyl carbamate (63.9 mg, 546 mol, 1.2 eq) in t-AmylOH (13 mL) were added Cs.sub.2CO.sub.3 (296 mg, 910 mol, 2.0 eq) and Xphos Pd G3 (38.5 mg, 45.5 mol, 0.1 eq). The mixture was degassed, purged with N.sub.2 three times, and stirred at 80 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (12 mL), and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl(S)-(5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl)carbamate (170 mg, 329 mol, 72% yield) was obtained as a yellow oil. M+H.sup.+=517.3 (LCMS).

Step 2: (S)N-(1-(7-Aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl) methoxy)benzamide (Compound 729)

[1968] To a solution of tert-butyl(S)-(5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl)carbamate (170 mg, 329 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give(S)N-(1-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (5.10 mg, 8.10 mol, 3% yield) as a yellow solid. M+H.sup.+=417.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 1H), 8.74 (d, J=7.4 Hz, 1H), 8.58 (dd, J=1.6, 4.2 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.11 (dd, J=4.3, 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.86-6.81 (m, 2H), 6.61 (d, J=2.6 Hz, 1H), 5.75 (d, J=6.4 Hz, 2H), 3.87 (d, J=5.5 Hz, 2H), 3.27-3.21 (m, 2H), 2.77-2.67 (m, 1H), 2.22 (s, 3H), 1.99-1.97 (m, 3H), 1.96-1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.32-1.27 (m, 2H), 1.13-1.08 (m, 2H).

Example 391: (S)N-(1-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 627)

##STR01239##

Step 1: 5-(1-Aminocyclopropyl)quinolin-7-ol (391A-1)

[1969] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropan-1-amine (1.50 g, 5.98 mmol, 1.0 eq) in DCM (50 mL) was added a solution of BBr.sub.3 (22.5 g, 90.0 mmol, 8.7 mL, 15 eq) in DCM (20 mL) dropwise at 78 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at the same temperature for 2 h, then warmed to 20 C. and stirred for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with MeOH (20 mL) at 0 C. and treated with NH.sub.3.Math.H.sub.2O to adjust the pH 8. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1, followed by DCM/MeOH from 100/1 to 10/1. 5-(1-Aminocyclopropyl)quinolin-7-ol (1.73 g, 8.64 mmol, 72% yield) was obtained as a yellow solid. M+H.sup.+=201.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.51-10.23 (m, 1H), 8.90-8.78 (m, 1H), 8.62 (d, J=8.5 Hz, 1H), 7.43 (dd, J=4.3, 8.5 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 4.09 (q, J=5.1 Hz, 2H), 1.55-1.48 (m, 2H), 1.28-1.15 (m, 2H).

Step 2: 5-(1-Aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (391A-2)

[1970] To a solution of 5-(1-aminocyclopropyl)quinolin-7-ol (1.40 g, 6.99 mmol, 1.0 eq) in THF (50 mL) was added 1-BuOK (1.57 g, 14.0 mmol, 2.0 eq) at 0 C. under a N.sub.2 atmosphere. The mixture was stirred at 0 C. for 15 min. 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methane sulfonamide (5.00 g, 14.0 mmol, 2.0 eq) was added in portions. The resulting reaction mixture was stirred at 20 C. for 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-(1-Aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (1.25 g, 3.76 mmol, 54% yield) was obtained as a yellow oil. M+H.sup.+=333.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.05 (dd, J=1.6, 4.1 Hz, 1H), 8.96 (d, J=8.5 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.74 (dd, J=4.3, 8.6 Hz, 1H), 7.67 (d, J=2.6 Hz, 1H), 4.20-3.98 (m, 2H), 3.17 (s, 3H), 1.22-1.15 (m, 2H), 1.04-0.95 (m, 2H).

Step 3: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (391A-3)

[1971] To a solution of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (517 mg, 1.56 mmol, 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (500 mg, 1.56 mmol, 1.0 eq) in DMF (13 mL) were added DIEA (603 mg, 4.67 mmol, 813 L, 3.0 eq) and HATU (1.48 g, 3.89 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAC (30 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (840 mg, 1.32 mmol, 85% yield) was obtained as a yellow gum. M+H.sup.+=636.4 (LCMS).

Step 4: tert-Butyl(S)-2-((3-((1-(7-((tert-butoxycarbonyl)amino)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (391A-4)

[1972] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 315 mol, 1.0 eq) and tert-butyl carbamate (44.2 mg, 378 mol, 1.2 eq) in 1-AmylOH (10 mL) were added Cs.sub.2CO.sub.3 (205 mg, 629 mol, 2.0 eq) and XPhos Pd G3 (26.6 mg, 31.5 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times, and the mixture was stirred at 80 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl(S)-2-((3-((1-(7-((tert-butoxycarbonyl)amino)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (130 mg, 216 mol, 69% yield) was obtained as a colorless oil. M+H.sup.+=603.4 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.02 (d, J=8.4 Hz, 1H), 8.87 (dd, J=1.6, 4.2 Hz, 1H), 8.04 (br d, J=2.4 Hz, 2H), 7.39 (dd, J=4.3, 8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.87-6.80 (m, 2H), 6.75 (d, J=2.6 Hz, 1H), 6.65 (br s, 1H), 4.44 (br d, J=7.2 Hz, 1H), 4.23-4.16 (m, 1H), 4.02 (dd, J=2.6, 10.4 Hz, 1H), 3.86 (br t, J=7.5 Hz, 2H), 2.35-2.17 (m, 2H), 2.14 (s, 3H), 1.61 (br s, 9H), 1.41-1.38 (m, 2H), 1.34 (br s, 9H), 1.30-1.24 (m, 2H).

Step 5: (S)N-(1-(7-Aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (391A-5)

[1973] To a solution of tert-butyl(S)-2-((3-((1-(7-((tert-butoxycarbonyl)amino)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (130 mg, 132 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude product(S)N-(1-(7-aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (170 mg, TFA salt) as a yellow oil. M+H.sup.+==403.2 (LCMS).

Step 6: (S)N-(1-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 627)

[1974] To a solution of(S)N-(1-(7-aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (150 mg, 290 mol, 1.0 eq) in MeOH (5.0 mL) was added TEA (40.4 L) followed by formaldehyde (236 mg, 2.90 mmol, 216 L, 37% purity in water, 10 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (91.3 mg, 1.45 mmol, 5.0 eq) was added. The reaction mixture was stirred at 25 C. for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (52.9 mg, 117 mol, 40% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=445.2 (LCMS). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.86-10.77 (m, 1H), 9.43 (br d, J=8.0 Hz, 1H), 9.26 (s, 1H), 8.86 (dd, J=1.1, 5.5 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.59 (dd, J=5.6, 8.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.93 (dd, J=2.7, 8.5 Hz, 1H), 6.82-6.73 (m, 1H), 4.71-4.57 (m, 1H), 4.43-4.34 (m, 1H), 4.22 (dd, J=3.3, 11.4 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.79 (m, 1H), 3.21 (s, 6H), 2.81 (d, J=3.9 Hz, 3H), 2.36-2.26 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.33 (br s, 2H).

Example 392: (S)N-(1-(2-(Dimethylamino)-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 611)

##STR01240##

Step 1: (S)N-(1-(2-(Dimethylamino)-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 611)

[1975] To a solution of(S)N-(1-(2-chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 176 mol, 1.0 eq), dimethylamine (2 M in THF, 176 L, 2.0 eq) in DMSO (1.0 mL) were added DIEA (45.5 mg, 352 mol, 61.4 L, 2.0 eq) and CsF (53.5 mg, 352 mol, 2.0 eq) at 20 C. The mixture was stirred at 120 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(2-(Dimethylamino)-7-fluoroquinolin-4-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (5.50 mg, 10.5 mol, 6% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=463.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 13.12-12.61 (m, 1H), 11.03-10.89 (m, 1H), 9.38 (s, 1H), 8.60 (dd, J=6.0, 9.1 Hz, 1H), 8.26-8.10 (m, 1H), 7.52-7.43 (m, 1H), 7.37 (s, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.94 (dd, J=2.7, 8.4 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.63 (br s, 1H), 4.41 (dd, J=8.1, 11.1 Hz, 1H), 4.22 (dd, J=3.1, 11.1 Hz, 1H), 4.05-3.96 (m, 2H), 3.46 (s, 6H), 2.54 (s, 3H), 2.42-2.25 (m, 2H), 1.99 (s, 3H), 1.40 (s, 4H).

Example 393: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(propylamino)quinolin-5-yl)cyclopropyl)benzamide (Compound 743)

##STR01241##

Step 1: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(propylamino)quinolin-5-yl)cyclopropyl)benzamide (Compound 743)

[1976] To a solution of(S)N-(1-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (60.0 mg, 144 mol, 1.0 eq) in MeOH (3.0 mL) was added TEA (20.0 L), followed by propionaldehyde (8.37 mg, 144 mol, 10.5 L, 10 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. NaBH.sub.3CN (45.3 mg, 720 mol, 5.0 eq) was added. The resulting mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(propylamino)quinolin-5-yl)cyclopropyl)benzamide (1.9 mg, 3.84 mol, 3% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=459.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.23-10.14 (m, 1H), 9.31-9.22 (m, 1H), 9.17 (s, 1H), 8.77 (br d, J=6.1 Hz, 1H), 7.64-7.59 (m, 1H), 7.54-7.47 (m, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.93 (dd, J=2.7, 8.3 Hz, 1H), 6.76 (d, J=2.9 Hz, 1H), 6.72 (br s, 1H), 4.67-4.57 (m, 1H), 4.33-4.20 (m, 2H), 4.07-3.96 (m, 1H), 3.91-3.82 (m, 1H), 3.19-3.13 (m, 2H), 2.87-2.79 (m, 3H), 2.37-2.28 (m, 2H), 1.97 (s, 3H), 1.71-1.63 (m, 2H), 1.40-1.33 (m, 2H), 1.23-1.17 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).

Example 394: (S)N-(1-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 744)

##STR01242##

Step 1: (S)N-(1-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 744)

[1977] To a solution of(S)N-(1-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (50 mg, 120 mol, 1.0 eq) in DCM (5 mL) were added TEA (48.6 mg, 480 mol, 66.8 L, 4.0 eq) and Ac.sub.2O (24.5 mg, 240 mol, 22.5 L, 2.0 eq) at 0 C. The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (4.50 mg, 7.86 mol, 7% yield) was obtained as a white solid. M+H.sup.+=459.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.00 (s, 1H), 8.74 (d, J=7.4 Hz, 1H), 8.58 (dd, J=1.6, 4.2 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.11 (dd, J=4.3, 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.86-6.81 (m, 2H), 6.61 (d, J=2.6 Hz, 1H), 5.75 (d, J=6.4 Hz, 2H), 3.87 (d, J=5.5 Hz, 2H), 3.27-3.21 (m, 2H), 2.77-2.67 (m, 1H), 2.22 (s, 3H), 1.99-1.97 (m, 3H), 1.96-1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.32-1.27 (m, 2H), 1.13-1.08 (m, 2H)

Example 395: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (Compound 786)

##STR01243##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (395A-1)

[1978] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (250 mg, 393 mol, 1.0 eq) and methanesulfonamide (46.3 mg, 472 mol, 1.2 eq) in t-AmylOH (10 mL) were added Cs.sub.2CO.sub.3 (256 mg, 787 mol, 2.0 eq) and XPhos Pd G3 (33.3 mg, 39.3 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times, then the mixture was stirred at 80 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl 1 (S)-2-((4-methyl-3-((1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (210 mg, crude) was obtained as a yellow oil. M+H.sup.+=581.4 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.29-10.05 (m, 1H), 9.11 (d, J=19.6 Hz, 1H), 9.00-8.87 (m, 1H), 8.86-8.71 (m, 1H), 7.84-7.68 (m, 1H), 7.51-7.44 (m, 1H), 7.35-7.14 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.88 (dd, J=2.4, 8.4 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 4.38 (br dd, J=2.9, 7.6 Hz, 1H), 4.14 (dd, J=4.7, 10.3 Hz, 1H), 4.01-3.95 (m, 1H), 3.73 (br s, 2H), 3.30-3.28 (m, 6H), 2.30-2.22 (m, 1H), 2.20-2.15 (m, 9H), 2.11-2.03 (m, 1H), 1.23 (s, 2H), 1.16 (br d, J=7.0 Hz, 2H).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (395A-2)

[1979] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(methylsulfonamido)quinolin-5-yl)cyclo propyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 344 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude product(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (200 mg, TFA salt) as a yellow oil. M+H.sup.+=481.3 (LCMS).

Step 3: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (Compound 786)

[1980] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (200 mg, 336 mol, 1.0 eq) in MeOH (6.0 mL) was added TEA (47 L), followed by formaldehyde (20.2 mg, 673 mol, 19.0 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (63.4 mg, 1.01 mmol, 3.0 eq) was added. The reaction mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (100 40 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). The compound was further purified by SFC separation (DAICEL CHIRALCEL OJ (250 mm30 mm, 10 m); flow rate: 30 mL/min; gradient: 20% B over 17 min; mobile phase A: heptane, mobile phase B: i-PrOH (0.1% NH.sub.3.Math.H.sub.2O)). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (10.8 mg, 21.8 mol, 7% yield) was obtained as a yellow solid. M+H.sup.+=495.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.96 (br d, J=8.1 Hz, 1H), 8.87-8.79 (m, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.67 (s, 1H), 7.45 (dd, J=4.2, 8.4 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.5, 8.4 Hz, 1H), 6.61 (d, J=2.5 Hz, 1H), 3.86 (d, J=5.4 Hz, 2H), 3.25-3.21 (m, 2H), 3.10 (s, 3H), 2.76-2.67 (m, 1H), 2.21 (s, 3H), 1.98-1.81 (m, 5H), 1.36 (br s, 2H), 1.16 (br s, 2H).

Example 396: 2-Methyl-5-((S)-1-((S)-1-methylazetidin-2-yl) ethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 757)

##STR01244## ##STR01245##

Step 1: tert-Butyl(S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (396A-2)

[1981] To a solution of(S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (4.00 g, 11.8 mmol, 1.0 eq) and N,O-dimethylhydroxylamine hydrochloride (2.33 g, 23.8 mmol, 1.2 eq) in DMF (40 mL) were added EDCI (4.57 g, 11.8 mmol, 1.0 eq), HOBt (3.22 g, 23.8 mmol, 1.2 eq) and NMM (2.41 g, 23.8 mmol, 2.62 mL, 1.2 eq) at 20 C. The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was diluted with EtOAc (160 mL), then the solution was washed with HCl (1 M, 100 mL1), NaOH (2 M, 100 mL2) and brine (100 mL3). The organic layers was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl(S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (2.95 g, 12.1 mmol, 60% yield) as a yellow solid. M100+H.sup.+=145.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 5.03 (br dd, J=5.4, 8.5 Hz, 1H), 4.04 (dt, J=6.4, 8.4 Hz, 1H), 3.86 (dt, J=5.6, 8.4 Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 2.46 (dtd, J=6.3, 9.0, 11.2 Hz, 1H), 2.18-2.04 (m, 1H), 1.42 (s, 9H).

Step 2: tert-Butyl(S)-2-acetylazetidine-1-carboxylate (396A-3)

[1982] To a solution of tert-butyl(S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (2.95 g, 12.1 mmol, 1.0 eq) in THF (30 mL) were added MeMgBr (3 M in THF, 6.04 mL, 1.5 eq) at 78 C. The mixture was stirred at 20 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with NH.sub.4Cl (30 mL), the mixture was extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/7. tert-Butyl(S)-2-acetylazetidine-1-carboxylate (2.50 g) was obtained as a pale-yellow oil. M+Na.sup.+=222.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.60 (dd, J=6.1, 9.5 Hz, 1H), 3.96-3.84 (m, 2H), 2.52-2.40 (m, 1H), 2.27 (s, 3H), 2.13 (tdd, J=6.4, 8.7, 11.6 Hz, 1H), 1.44 (s, 9H).

Step 3: tert-Butyl(S)-2-((S)-1-hydroxyethyl)azetidine-1-carboxylate (396A-4) and tert-butyl(S)-2-((R)-1-hydroxyethyl)azetidine-1-carboxylate (396A-4A)

[1983] To a solution of tert-butyl(S)-2-acetylazetidine-1-carboxylate (2.51 g, 12.6 mmol, 1.0 eq) in MeOH (30 mL) was added NaBH.sub.4 (571 mg, 15.1 mmol, 1.2 eq) at 0 C. The mixture was stirred at 0 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with NH.sub.4Cl (30 mL), then extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4. filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl(S)-2-((S)-1-hydroxyethyl)azetidine-1-carboxylate (897 mg, 4.46 mmol, 35% yield) was obtained as a colourless oil. M+Na.sup.+=224.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.09-4.03 (m, 1H), 3.93-3.80 (m, 2H), 3.74 (dt, J=4.6, 8.9 Hz, 1H), 2.16 (dt, J=4.3, 7.8 Hz, 1H), 1.92-1.81 (m, 1H), 1.45 (s, 9H), 1.06 (d, J=6.3 Hz, 3H). tert-Butyl(S)-2-((R)-1-hydroxyethyl)azetidine-1-carboxylate (921 mg, 4.58 mmol, 36% yield) was obtained as a colourless oil. M+Na.sup.+=224.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 4.33 (br s, 1H), 3.96 (br dd, J=2.1, 6.4 Hz, 1H), 3.85 (q, J=8.1 Hz, 1H), 3.77-3.67 (m, 1H), 2.09 (q, J=7.7 Hz, 2H), 1.45 (s, 9H), 1.15 (d, J=6.5 Hz, 3H).

Step 4: tert-Butyl(S)-2-((S)-1-(3-(methoxycarbonyl)-4-methylphenoxy)ethyl)azetidine-1-carboxylate (396A-5)

[1984] To a solution of tert-butyl(S)-2-((S)-1-hydroxyethyl)azetidine-1-carboxylate (897 mg, 4.46 mmol, 1.0 eq) and methyl 5-hydroxy-2-methylbenzoate (740 mg, 4.45 mmol, 1.0 eq) in toluene (10 mL) were added TMAD (2.30 g, 13.3 mmol, 3.0 eq) and PPh.sub.3 (3.50 g, 13.3 mmol, 3.0 eq) at 20 C. The mixture was stirred at 100 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was allowed to cool to room temperature. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/50. tert-Butyl(S)-2-((S)-1-(3-(methoxycarbonyl)-4-methylphenoxy)ethyl)azetidine-1-carboxylate (1.04 g, 2.98 mmol, 66% yield) was obtained as a colourless oil. M+H.sup.+=350.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.51 (d, J=2.6 Hz, 1H), 7.16-7.08 (m, 1H), 7.03 (dd, J=2.3, 8.3 Hz, 1H), 4.84 (br d, J=1.5 Hz, 1H), 4.30-4.21 (m, 1H), 3.88 (s, 3H), 3.82 (br t, J=7.5 Hz, 2H), 2.51 (s, 3H), 2.45-2.32 (m, 1H), 2.29-2.15 (m, 1H), 1.36 (s, 9H), 1.20 (d, J=6.4 Hz, 3H).

Step 5: 5-((S)-1-((S)-1-(tert-Butoxycarbonyl)azetidin-2-yl) ethoxy)-2-methylbenzoic acid (396A-6)

[1985] To a solution of tert-butyl(S)-2-((S)-1-(3-(methoxycarbonyl)-4-methylphenoxy)ethyl)azetidine-1-carboxylate (1.04 g, 2.98 mmol, 1.0 eq) in MeOH (3.0 mL) and THF (12 mL) was added NaOH (2 M, 5.95 mL, 4.0 eq) at 20 C. The mixture was stirred at 70 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was allowed to cool to room temperature. The mixture was concentrated under vacuum. The residue was diluted with H.sub.2O (5.0 mL) and the mixture was extracted with EtOAc (5.0 mL1). The organic layer was discarded. The aqueous layer was acidified to pH 5 by using HCl (1 M aqueous), then extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 5-((S)-1-((S)-1-(tert-butoxycarbonyl)azetidin-2-yl) ethoxy)-2-methylbenzoic acid (994 mg, 2.87 mmol, 96% yield) as a yellow oil. M100+H.sup.+==280.1 (LCMS).

Step 6: tert-Butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)azetidine-1-carboxylate (396A-7)

[1986] To a solution of 5-((S)-1-((S)-1-(tert-butoxycarbonyl)azetidin-2-yl) ethoxy)-2-methylbenzoic acid (75.0 mg, 223 mol, 1.0 eq) and 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (74.3 mg, 223 mol, 1.0 eq) in DMF (1.0 mL) were added DIEA (86.7 mg, 670 mol, 116 L, 3.0 eq) and HBTU (169 mg, 447 mol, 2.0 eq) at 20 C. The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The residue was diluted with H.sub.2O (5.0 mL), the aqueous layer was extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.65). tert-Butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)ethyl)azetidine-1-carboxylate (104 mg, 160 mol, 71% yield) as a yellow oil.

Step 7: tert-Butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)ethyl)azetidine-1-carboxylate (396A-8)

[1987] To a solution of tert-butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl) azetidine-1-carboxylate (104 mg, 160 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (49.3 mg, 320 mol, 2.0 eq) in a mixture of dioxane (2.0 mL) and H.sub.2O (0.2 mL) were added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (13.1 mg, 16.0 mol, 0.1 eq) and Na.sub.2CO.sub.3 (39.0 mg, 368 mol, 2.3 eq) at 20 C. The mixture was stirred at 80 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and was diluted with H.sub.2O (5.0 mL). The aqueous layer was extracted with EtOAc (3.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.59). tert-Butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)azetidine-1-carboxylate (56.0 mg, 106 mol, 66% yield) was obtained as a pale yellow liquid.

Step 8: 5-((S)-1-((S)-Azetidin-2-yl) ethoxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (396A-9)

[1988] To a solution of tert-butyl(S)-2-((S)-1-(4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)azetidine-1-carboxylate (56.0 mg, 106 mol, 1.0 eq) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 63 eq) at 20 C. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 5-((S)-1-((S)-azetidin-2-yl) ethoxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (60.0 mg, crude, TFA salt) as a brown liquid, which was used in the next step without any further purification. M+H.sup.+=428.2 (LCMS).

Step 9: 2-Methyl-5-((S)-1-((S)-1-methylazetidin-2-yl) ethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 757)

[1989] To a solution of 5-((S)-1-((S)-azetidin-2-yl) ethoxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (60.0 mg, 111 mol, 1.0 eq, TFA salt) in MeOH (1.5 mL) was added TEA (15.0 L), followed by formaldehyde (18.0 mg, 221 mol, 6.34 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (20.9 mg, 332 mol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). LCMS indicated that the purity was 68%, then the residue was further purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-((S)-1-((S)-1-methylazetidin-2-yl) ethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (8.30 mg, 17.0 mol, 15% yield, HCl salt) was obtained as a colorless gum. M+H.sup.+=442.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.97-9.83 (m, 1H), 9.49 (br d, J=8.5 Hz, 1H), 9.30 (s, 1H), 9.12 (d, J=3.9 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.89 (dd, J=4.8, 8.3 Hz, 1H), 7.13-7.00 (m, 2H), 6.93 (dd, J=2.6, 8.4 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 6.19 (d, J=17.6 Hz, 1H), 5.62 (d, J=11.0 Hz, 1H), 4.85-4.77 (m, 1H), 4.50-4.39 (m, 1H), 4.04-3.97 (m, 1H), 3.81 (br dd, J=5.9, 9.4 Hz, 1H), 2.81 (d, J=4.9 Hz, 3H), 2.46-2.34 (m, 2H), 2.01-1.95 (m, 3H), 1.42 (br s, 2H), 1.33 (br d, J=5.0 Hz, 2H), 1.15-1.08 (m, 3H).

Example 397: (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 713)

##STR01246##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (397A-1)

[1990] To a solution of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (350 mg, 1.05 mmol, 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (353 mg, 1.05 mmol, 1.0 eq) in DMF (10 mL) were added DIEA (408 mg, 3.16 mmol, 3.0 eq) and HATU (1.00 g, 2.63 mmol, 2.5 eq). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL4).

[1991] The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoro methyl)sulfonyl)oxy)quinolin-5-yl)cyclopropy)carbamoyl)phenoxy)methyl)pyrolidine-1-carboxylate (520 mg, 800 mol, 75% yield) was obtained as a white solid. M+H.sup.+=650.3 (LCMS).

Step 2: tert-Butyl(S)-2-((4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (397A-2)

[1992] To a stirred solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (250 mg, 385 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (65.2 mg, 423 mol, 1.1 eq) in a mixture of dioxane (15 mL) and H.sub.2O (3.0 mL) were added Pd (dppf) C12 (31.4 mg, 38.5 mol, 0.1 eq), Na.sub.2CO.sub.3 (93.8 mg, 85 mol, 2.3 eq). The mixture was degassed, purged with N.sub.2 three times, and stirred at 80 C. for 4 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. tert-Butyl(S)-2-((4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) pyrrolidine-1-carboxylate (156 mg, 296 mol, 76% yield) was obtained as a white solid. M56+H.sup.+=472.3 (LCMS).

Step 3: (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 713)

[1993] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (46.0 mg, 87.1 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (770 mg, 6.75 mmol, 500 L). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (34.1 mg, 63.0 mol, 72% yield, TFA salt) was obtained as a white solid. M+H.sup.+=428.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18-9.09 (m, 3H), 8.96 (dd, J=1.5, 4.4 Hz, 1H), 8.73-8.51 (m, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.97 (s, 1H), 7.64 (dd, J=4.3, 8.5 Hz, 1H), 7.12-7.07 (m, 1H), 7.05-6.96 (m, 1H), 6.89 (dd, J=2.8, 8.4 Hz, 1H), 6.66 (d, J=2.8 Hz, 1H), 6.11 (d, J=17.6 Hz, 1H), 5.51 (d, J=11.0 Hz, 1H), 4.15 (dd, J=3.6, 10.6 Hz, 1H), 3.98 (dd, J=8.4, 10.5 Hz, 1H), 3.88-3.79 (m, 1H), 3.23-3.14 (m, 2H), 2.19-2.02 (m, 1H), 1.99-1.96 (m, 3H), 1.95-1.83 (m, 2H), 1.74-1.62 (m, 1H), 1.37 (br s, 2H), 1.29 (br s, 2H).

Example 398: 2-Methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 748)

##STR01247##

Step 1: Methyl 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoate (398A-1) and methyl 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoate (398A-2)

[1994] To a solution of methyl 5-hydroxy-2-methylbenzoate (2.00 g, 12.0 mmol, 1.0 eq) and (tetrahydro-1H-pyrrolizin-7a (5H)-yl)methanol (1.70 g, 12.0 mmol, 1.0 eq) in toluene (20 mL) was added TMAD (3.11 g, 18.0 mmol, 1.5 eq). The mixture was stirred at 100 C. under a N.sub.2 atmosphere for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (40 mL) and extracted with EtOAc (40 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoate and methyl 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoate (3.50 g, 7.38 mmol, 61% yield) were obtained as a mixture of a white solid. M+H.sup.+=290.2 (LCMS).

Step 2: 2-Methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoic acid (398A-3) and 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoic acid (398A-4)

[1995] To a mixture of methyl 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoate and methyl 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoate (2.68 g, 5.56 mmol, 1.0 eq) in a mixture of MeOH (4.0 mL) and THF (12 mL) was added NaOH (11.1 mL, 2 M aqueous, 4.0 eq). The mixture was stirred at 70 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoic acid and 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoic acid (300 mg, 1.09 mmol, 19% yield) as a mixture of a white solid. M+H.sup.+=276.2 (LCMS).

Step 3: 5-(1-(2-Methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (398A-5) and 5-(1-(5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (398A-6)

[1996] To a mixture of 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)benzoic acid and 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoic acid (130 mg, 472 mol, 1.0 eq) in DMF (2.0 mL) were added 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (156 mg, 472 mol, 1.0 eq), HATU (269 mg, 708 mol, 1.5 eq) and DIEA (183 mg, 1.42 mmol, 247 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 40%-70% B over 8 min; mobile phase A: 0.1% aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). 5-(1-(2-Methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (25.0 mg, 38.5 mol, 8% yield) was obtained as a white solid. M+H.sup.+=590.2 (LCMS). 5-(1-(5-((1-Azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (30.0 mg, 38.5 mol, 10% yield) was obtained as a white solid. M+H.sup.+=590.2 (LCMS).

Step 4: 2-Methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 748)

[1997] To a solution of 5-(1-(2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (25.0 mg, 42.4 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13.0 mg, 84.8 mol, 2.0 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (100 L) were added Na.sub.2CO.sub.3 (10.3 mg, 97.5 mol, 2.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (3.46 mg, 4.24 mol, 0.10 eq). The resulting mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 2-methyl-5-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (10.9 mg, 21.6 mol, 51% yield, HCl salt) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.32-10.11 (m, 1H), 9.32 (td, J=2.6, 4.9 Hz, 1H), 9.20 (s, 1H), 9.05 (br d, J=4.0 Hz, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.77 (br d, J=9.4 Hz, 1H), 7.12-6.99 (m, 2H), 6.90 (dd, J=2.7, 8.1 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.18 (s, 1H), 5.57 (d, J=10.7 Hz, 1H), 4.07 (s, 2H), 3.47-3.41 (m, 2H), 3.21-3.13 (m, 2H), 2.11-2.03 (m, 4H), 1.98-1.91 (m, 7H), 1.40 (br s, 2H), 1.32 (br s, 2H).

Example 399: 5-(1-Azabicyclo[3.3.1]nonan-5-yloxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 749)

##STR01248##

Step 1: 5-((1-Azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 749)

[1998] To a solution of 5-(1-(5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (19.5 mg, 33.1 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (10.2 mg, 66.2 mol, 2.0 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (100 L) were added Na.sub.2CO.sub.3 (8.00 mg, 76.2 mol, 2.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (2.71 mg, 3.31 mol, 0.10 eq). The resulting mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give 5-((1-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (5.80 mg, 11.4 mol, 34% yield, HCl salt) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.68 (br s, 1H), 9.36-9.17 (m, 2H), 9.10-8.98 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.77 (br dd, J=3.1, 4.7 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.03 (dd, J=10.9, 17.7 Hz, 1H), 6.92 (dd, J=2.6, 8.2 Hz, 1H), 6.67 (d, J=2.5 Hz, 1H), 6.15 (d, J=17.4 Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 3.23-3.11 (m, 6H), 2.24-2.11 (m, 2H), 2.02-1.99 (m, 3H), 1.99-1.93 (m, 2H), 1.87-1.77 (m, 4H), 1.40 (br s, 2H), 1.31 (br s, 2H).

Example 400: (S)-4-Fluoro-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 800)

##STR01249## ##STR01250##

Step 1: Methyl 2-bromo-4-fluoro-5-methoxybenzoate (400A-2)

[1999] To a solution of 2-bromo-4-fluoro-5-methoxybenzoic acid (1.20 g, 4.82 mmol, 1.0 eq) in acetonitrile (30 mL) were added CH.sub.3I (1.73 g, 9.64 mmol, 600 L, 2.0 eq) and DBU (1.25 g, 8.19 mmol, 1.23 mL 1.7 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 2-bromo-4-fluoro-5-methoxybenzoate (1.25 g, 4.75 mmol, 99% yield) was obtained as a white solid. M+H.sup.+=263.1 (LCMS).

Step 2: Methyl 4-fluoro-5-methoxy-2-methylbenzoate (400A-3)

[2000] A solution of methyl 2-bromo-4-fluoro-5-methoxybenzoate (1.25 g, 4.76 mmol, 1.0 eq) in a mixture of dioxane (60 mL) and H.sub.2O (12 mL) was degassed and purged with N.sub.2 three times. To this mixture were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.38 g, 9.50 mmol, 2.66 mL, 50% purity, 2.0 eq), K.sub.2CO.sub.3 (1.97 g, 14.3 mmol, 3.0 eq), and Pd (dppf) C12 (348 mg, 2.53 mmol, 475 L, 0.1 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (60 mL), and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 4-fluoro-5-methoxy-2-methylbenzoate (722 mg, 3.64 mmol, 77% yield) was obtained as a white solid.

Step 3: Methyl 4-fluoro-5-hydroxy-2-methylbenzoate (400A-4)

[2001] To a solution of methyl 4-fluoro-5-methoxy-2-methylbenzoate (722 mg, 3.64 mmol, 1.0 eq) in DCM (40 mL) was added BBr.sub.3 (13.7 g, 54.6 mmol, 6.92 mL, 15 eq). The mixture was stirred at 78 C. for 1 h under a N.sub.2 atmosphere, then at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue. The reaction mixture was poured into MeOH (2.0 ml) and basified to pH 8 with NH.sub.3.Math.H.sub.2O. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. Methyl 4-fluoro-5-hydroxy-2-methylbenzoate (500 mg, 2.71 mol, 75% yield) was obtained as a yellow solid. M+H.sup.+=185.2 (LCMS).

Step 4: tert-Butyl(S)-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (400A-5)

[2002] To a solution of methyl 4-fluoro-5-hydroxy-2-methylbenzoate (490 mg, 2.66 mmol, 1.0 eq) and tert-butyl(S)-2-(hydroxymethyl)azetidine-1-carboxylate (498 mg, 2.66 mmol, 1.0 eq) in toluene (30 mL) were added TMAD (1.37 g, 7.98 mmol, 3.0 eq) and PPh.sub.3 (2.09 g, 7.98 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl (S)-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (820 mg, 2.32 mmol, 87% yield) was obtained as a white oil. M56+H.sup.+==298.2 (LCMS).

Step 5: (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluoro-2-methylbenzoic acid (400A-6)

[2003] To a solution of tert-butyl(S)-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-1-carboxylate (820 mg, 2.32 mmol, 1.0 eq) in a mixture of MeOH (36 mL) and THF (18 mL) was added NaOH (2 M aqueous, 4.6 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL), and washed with MTBE (15 mL2). The aqueous layer was acidified to pH 6 with HCl (1 M aqueous) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluoro-2-methylbenzoic acid (787 mg, 2.32 mmol, 100% yield) as a brown oil. M56+H.sup.+=284.1 (LCMS).

Step 6: tert-Butyl(S)-2-((2-fluoro-4-methyl-5-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (400A-7)

[2004] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluoro-2-methylbenzoic acid (306 mg, 903 mol, 1.0 eq) and 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 903 mol, 1.0 eq) in DMF (30 mL) were added DIEA (350 mg, 2.71 mmol, 472 L, 3.0 eq) and HATU (858 mg, 2.26 mmol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with EtOAc (12 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl (S)-2-((2-fluoro-4-methyl-5-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (571 mg, 874 mol, 97% yield) was obtained as a brown oil. M56+H.sup.+=598.2 (LCMS).

Step 7: tert-Butyl(S)-2-((2-fluoro-4-methyl-5-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (400A-8)

[2005] To a solution of tert-butyl(S)-2-((2-fluoro-4-methyl-5-((1-(7-(((trifluoromethyl)sulfonyl) oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (571 mg, 874 mol, 184 L 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (135 mg, 874 mol, 1.0 eq) in a mixture of dioxane (30 mL) and H.sub.2O (6.0 mL) were added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (71.3 mg, 87.3 mol, 0.1 eq) and Na.sub.2CO.sub.3 (213 mg, 2.01 mmol, 2.3 eq). The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL), and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl(S)-2-((2-fluoro-4-methyl-5-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (280 mg, 527 mol, 60% yield) was obtained as a yellow oil. M56+H.sup.+=476.4 (LCMS).

Step 8: (S)-5-(Azetidin-2-ylmethoxy)-4-fluoro-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclo propyl)benzamide (400A-9)

[2006] To a solution of tert-butyl(S)-2-((2-fluoro-4-methyl-5-((1-(7-vinylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (280 mg, 527 mol, 1.0 eq) in DCM (10 mL) was added TFA (4.93 g, 43.3 mmol, 3.2 mL, 82 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude(S)-5-(azetidin-2-ylmethoxy)-4-fluoro-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (500 mg) as a yellow oil. M+H.sup.+=432.3 (LCMS).

Step 9: (S)-4-Fluoro-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 800)

[2007] To a solution of(S)-5-(azetidin-2-ylmethoxy)-4-fluoro-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (500 mg, 1.07 mmol, 1.0 eq, TFA salt) in MeOH (10 mL) was added TEA (0.1 L), followed by formaldehyde (173 mg, 2.14 mmol, 159 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBH.sub.3CN (134 mg, 2.14 mmol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (8030 mm, 3 m); flow rate: 60 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-4-Fluoro-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (54.0 mg, 107 mol, 10% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=446.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.78 (br d, J=3.3 Hz, 1H), 9.56-9.42 (m, 1H), 9.39-9.28 (m, 1H), 9.11 (br d, J=4.5 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.95-7.80 (m, 1H), 7.16-6.92 (m, 3H), 6.19 (d, J=17.6 Hz, 1H), 5.61 (d, J=11.0 Hz, 1H), 4.70-4.63 (m, 1H), 4.45-4.32 (m, 2H), 4.01-3.98 (m, 1H), 3.89-3.85 (m, 1H), 2.81 (d, J=4.9 Hz, 3H), 2.42-2.23 (m, 2H), 1.99 (s, 3H), 1.43 (br s, 2H), 1.34 (br s, 2H).

Example 401: (S)-4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 726)

##STR01251## ##STR01252##

Step 1: tert-Butyl(S)-2-((5-bromo-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (401A-1)

[2008] To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (500 mg, 2.14 mmol, 1.0 eq) in DMF (20 mL) were added Cs.sub.2CO.sub.3 (766 mg, 2.35 mmol, 1.1 eq) and tert-butyl(S)-2-(hydroxymethyl)azetidine-1-carboxylate (400 mg, 2.14 mmol, 1.0 eq). The resulting mixture was stirred at 60 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl(S)-2-((5-bromo-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (760 mg, 1.89 mmol, 89% yield) was obtained as a yellow solid. M56+H.sup.+=345.1 (LCMS).

Step 2: tert-Butyl(S)-2-((5-(methoxycarbonyl)-4-methyl-2-nitrophenoxy)methyl) azetidine-1-carboxylate (401A-2)

[2009] To a solution of tert-butyl(S)-2-((5-bromo-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (600 mg, 1.50 mmol, 1.0 eq) in MeOH (50 mL) were added Pd(PPh.sub.3).sub.2Cl.sub.2 (105 mg, 150 mol, 0.1 eq) and TEA (6.05 g, 59.8 mmol, 8.33 mL, 40 eq). The mixture was degassed and purged with CO three times, then stirred at 70 C. for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5 tert-Butyl(S)-2-((5-(methoxycarbonyl)-4-methyl-2-nitrophenoxy)methyl)azetidine-1-carboxylate (164 mg, 431 mol, 14% yield) was obtained as a yellow oil. M56+H.sup.+=325.2 (LCMS).

Step 3: (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (345A-3)

[2010] To a solution of tert-butyl(S)-2-((5-(methoxycarbonyl)-4-methyl-2-nitrophenoxy)methyl) azetidine-1-carboxylate (164 mg, 431 mol, 1.0 eq) in MeOH (11 mL) and THF (5.5 mL) was added NaOH (2 M aqueous, 1.0 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and washed with MTBE (5.0 mL2). The aqueous layer was acidified to pH 6 with HCl (1 M aqueous). The product was extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the product(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (110 mg, 300 mol, 70% yield) as a brown oil. M56+H.sup.+=311.2 (LCMS).

Step 4: tert-Butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (401A-3)

[2011] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoic acid (90.0 mg, 246 mol, 1.0 eq) and 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (73.5 mg, 221 mol, 0.9 eq) in DMF (6.0 mL) were added EDCI (70.6 mg, 369 mol, 1.5 eq), HOBt (49.8 mg, 369 mol, 1.5 eq) and TEA (49.7 mg, 491 mol, 68.4 L, 2.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.46). The crude product tert-butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (180 mg) was obtained as a yellow oil. M56+H.sup.+=625.3 (LCMS).

Step 5: tert-Butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-vinylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (401A-4)

[2012] To a solution of tert-butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-(((trifluoromethyl)sulfonyl)oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (170 mg, 250 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (38.5 mg, 250 mol, 42.4 L, 1.0 eq) in a mixture of dioxane (8.5 mL) and H.sub.2O (1.7 mL) were added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (20.4 mg, 25.0 mol, 0.1 eq) and Na.sub.2CO.sub.3 (60.9 mg, 574 mol, 2.3 eq). The resulting mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/0, R.sub.f=0.23). tert-Butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (115 mg, 206 mol, 82% yield) was obtained as a yellow solid. M+H.sup.+=559.4 (LCMS).

Step 6: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (401A-5)

[2013] To a solution of tert-butyl(S)-2-((4-methyl-2-nitro-5-((1-(7-vinylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (115 mg, 206 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.93 g, 16.9 mmol, 1.3 mL, 82 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the crude(S)-5-(azetidin-2-ylmethoxy)-2-methyl-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (240 mg, TFA salt) as a yellow solid. M+H.sup.+=459.3 (LCMS).

Step 7: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (401A-6)

[2014] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (240 mg, 419 mol, 1.0 eq, TFA salt) in MeOH (12 mL) was added TEA (2.4 mL), followed by formaldehyde (68.0 mg, 838 mol, 62.4 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. Then NaBH.sub.3CN (52.7 mg, 838 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.21). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (50.0 mg, 106 mol, 25% yield) was obtained as a yellow oil. M+H.sup.+=473.3 (LCMS).

Step 8: (S)-4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 726)

[2015] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-4-nitro-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (50.0 mg, 106 mol, 1.0 eq) in MeOH (2.5 mL) and H.sub.2O (0.5 mL) were added NH.sub.4Cl (28.3 mg, 529 mol, 5.0 eq) and iron powder (29.6 mg, 529 mol, 5.0 eq). The mixture was stirred at 80 C. for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (7.0 mL), and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna C18 (10030 mm, 5 m); flow rate: 60 mL/min; gradient: 1%-23% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-4-Amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (12.6 mg, 22.5 mol, 21% yield, TFA salt) was obtained as a white solid. M+H.sup.+=443.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.16 (br d, J=8.7 Hz, 1H), 9.00-8.88 (m, 1H), 8.74 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.62 (dd, J=4.4, 8.4 Hz, 1H), 7.00 (dd, J=10.9, 17.7 Hz, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 6.09 (d, J=17.2 Hz, 1H), 5.50 (d, J=10.9 Hz, 1H), 4.70-4.54 (m, 1H), 4.15 (br d, J=3.1 Hz, 1H), 4.10-4.01 (m, 1H), 3.92-3.82 (m, 2H), 2.87 (s, 3H), 2.39-2.30 (m, 2H), 2.00 (s, 3H), 1.35 (br s, 2H), 1.30-1.22 (m, 2H).

Example 402: (S)-4-Acetamido-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 746)

##STR01253##

Step 1: (S)-4-Acetamido-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 746)

[2016] To a solution of(S)-4-amino-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinyl quinolin-5-yl)cyclopropyl)benzamide (70.0 mg, 158 mol, 1.0 eq) in DCM (5.0 mL) were added TEA (64.0 mg, 633 mol, 8.1 L, 4.0 eq) and Ac.sub.2O (32.3 mg, 316 mol, 29.6 L, 2.0 eq). The mixture was stirred at 20 C. for 3 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-4-Acetamido-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (8.60 mg, 16.5 mol, 10% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=485.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.73-10.51 (m, 1H), 9.44 (s, 1H), 9.38-9.28 (m, 1H), 9.23-9.03 (m, 2H), 8.15 (s, 1H), 8.02 (s, 1H), 7.78 (br dd, J=3.8, 8.0 Hz, 1H), 7.62 (s, 1H), 7.04 (dd, J=10.8, 17.6 Hz, 1H), 6.82 (s, 1H), 6.16 (d, J=17.7 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.27 (d, J=4.4 Hz, 1H), 4.06-4.00 (m, 1H), 3.85 (br dd, J=6.7, 9.1 Hz, 2H), 2.83 (d, J=5.1 Hz, 3H), 2.42-2.33 (m, 2H), 2.15-2.06 (m, 3H), 1.99-1.95 (m, 3H), 1.44-1.37 (m, 2H), 1.31 (br s, 2H).

Example 403: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)benzamide (Compound 785)

##STR01254##

Step 1: (S)N-(1-(7-Methoxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (403A-1)

[2017] To a solution of(S)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (250 mg, 579 mol, 1.0 eq) in THF (35 mL) was added 10% palladium on carbon (750 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with THF (10 mL5). The combined filtrates were concentrated under vacuum to give(S)N-(1-(7-methoxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (500 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=436.1 (LCMS).

Step 2: (S)N-(1-(7-Hydroxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (403A-2)

[2018] To a solution of(S)N-(1-(7-Methoxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (500 mg) in DCM (20 mL) was added BBr.sub.3 (1.5 mL, 15 eq) dropwise at 78 C. under a N.sub.2 atmosphere. The mixture was stirred at 25 C. for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue. The residue was diluted with MeOH (5.0 mL) and adjusted to pH 8 with DIEA. The resulting mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 1/0 to 10/1. (S)N-(1-(7-Hydroxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (270 mg, 640 mol, 70% yield) was obtained as a yellow oil. M+H.sup.+=422.4 (LCMS).

Step 3: (S)-5-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (403A-3)

[2019] To a solution of(S)N-(1-(7-hydroxy-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (200 mg, 474 mol, 1.0 eq) in THF (7.0 mL) was added t-BuOK (53.0 mg, 474 mol, 1 eq) at 0 C. The mixture was stirred at this temperature for 30 min. To this mixture was added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (170 mg, 474 mol, 1.0 eq). Then the mixture was stirred at 25 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.7). (S)-5-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (100 mg, 181 mol, 38% yield) was obtained as a white solid. M+H.sup.+=554.2 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinyl-1,2,3,4-tetra hydroquinolin-5-yl)cyclopropyl)benzamide (Compound 785)

[2020] To a solution of(S)-5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (40.0 mg, 72.3 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.1 mg, 72.3 mol, 12.3 L, 1.0 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (0.1 mL) were added Na.sub.2CO.sub.3 (23.0 mg, 217 mol, 3.0 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (5.90 mg, 7.23 mol, 0.1 eq) under a N.sub.2 atmosphere. The resulting mixture was stirred at 80 C. for 5 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (2.0 mL), and extracted with EtOAc (2.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10040 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)benzamide (6.50 mg, 11.9 mol, 17% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=432.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.88 (br dd, J=3.8, 6.7 Hz, 1H), 8.71 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.99-6.91 (m, 2H), 6.78 (d, J=2.8 Hz, 1H), 6.61-6.49 (m, 2H), 5.60 (br d, J=17.4 Hz, 1H), 5.13 (br d, J=10.9 Hz, 1H), 4.69-4.58 (m, 1H), 4.28-4.22 (m, 2H), 4.04 (br dd, J=4.4, 9.4 Hz, 1H), 3.89-3.85 (m, 1H), 3.19 (br d, J=4.1 Hz, 2H), 2.93 (br t, J=6.1 Hz, 2H), 2.87 (d, J=4.9 Hz, 3H), 2.42-2.31 (m, 3H), 2.12 (s, 3H), 1.86-1.80 (m, 2H), 1.14-1.09 (m, 2H), 1.04 (br d, J=2.6 Hz, 2H).

Example 404: (S)-2-Methyl-N-(1-(1-methyl-7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 796)

##STR01255##

Step 1: (S)-2-Methyl-N-(1-(1-methyl-7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclo propyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 796)

[2021] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)benzamide (20.0 mg, 46.3 mol, 1.0 eq) in MeOH (2.0 mL) was added TEA (50.0 L), followed by formaldehyde (3.76 mg, 46.3 mol, 3.5 L, 37% purity in water, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (2.91 mg, 46.4 mol, 1.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (2.0 mL) and extracted with DCM (1.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10040 mm, 5 m); flow rate: 25 mL/min; gradient: 20%-50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-2-Methyl-N-(1-(1-methyl-7-vinyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-5-((1-methyl azetidin-2-yl)methoxy)benzamide (3.00 mg, 5.36 mol, 12% yield, TFA salt). M+H.sup.+=446.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.05-9.84 (m, 1H), 8.72 (s, 1H), 7.16-7.10 (m, 1H), 7.01 (s, 1H), 6.97-6.90 (m, 1H), 6.79-6.74 (m, 1H), 6.67-6.55 (m, 2H), 5.70 (d, J=17.6 Hz, 1H), 5.14 (d, J=11.0 Hz, 1H), 4.70-4.57 (m, 1H), 4.33-4.22 (m, 2H), 4.09-4.00 (m, 1H), 3.94-3.83 (m, 1H), 3.18 (t, J=5.7 Hz, 2H), 2.95 (br t, J=6.4 Hz, 2H), 2.89-2.81 (m, 6H), 2.41-2.30 (m, 2H), 2.12 (s, 3H), 1.89 (quin, J=5.9 Hz, 2H), 1.12 (br s, 2H), 1.03 (br s, 2H).

Example 405: (S)-2-Methyl-5-(2-(methylamino)propoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 660)

##STR01256##

Step 1: (S)-Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (405A-1)

[2022] To a solution of methyl 5-hydroxy-2-methylbenzoate (5.00 g, 30.1 mmol, 1.0 eq) and tert-butyl(S) (1-hydroxypropan-2-yl)carbamate (5.27 g, 30.1 mmol, 1.0 eq) in toluene (200 mL) were added TMAD (15.5 g, 90.3 mmol, 3.0 eq) and PPh.sub.3 (23.7 g, 90.3 mmol, 3.0 eq). The mixture was stirred at 100 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the 31% of the starting material remained and 23% of the desired product was detected. The mixture was allowed to cool to room temperature, then concentrated under vacuum to give a residue which was treated with water (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/19. (S)-Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (6.00 g, 18.5 mmol, 30% yield) was obtained as a white solid. M100+H.sup.+=224.1 (LCMS).

Step 2: (S)-Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoate (405A-2)

[2023] To a solution of methyl(S)-5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (3.00 g, 9.28 mmol, 1.0 eq) in THF (100 mL) were added NaH (556 mg, 13.9 mmol, 60% purity, 1.5 eq) and Mel (3.95 g, 27.8 mmol, 3.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the 27% of the starting material remained and 24% of the desired product was detected. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. (S)-Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoate (3.00 g, 8.90 mmol, 95% yield) was obtained as a white solid. M56+H.sup.+=282.2 (LCMS).

Step 3: (S)-5-(2-((tert-Butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoic acid (405A-3)

[2024] To a solution of methyl(S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoate (3.00 g, 8.89 mmol, 1.0 eq) in THF (10 mL), H.sub.2O (5.0 mL) and MeOH (7.5 mL) was added LiOH.Math.H.sub.2O (621 mg, 14.8 mmol, 3.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. THF and MeOH were concentrated under vacuum. The aqueous layer was adjusted to pH 5 with HCl (1 M aqueous), then extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give(S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoic acid (1.67 g, 5.01 mmol, 99% yield) as a white solid. M56+H.sup.+=268.2 (LCMS).

Step 4: (S)-5-(1-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (405A-4)

[2025] To a solution of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 902 mol, 1.0 eq) and(S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoic acid (291 mg, 902 mol, 1.0 eq) in DMF (4.0 mL) were added HATU (514 mg, 1.35 mmol, 1.5 eq) and DIEA (350 mg, 2.71 mmol, 3.0 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. (S)-5-(1-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 409 mol, 45% yield) was obtained as a white solid. M+H.sup.+=638.3 (LCMS).

Step 5: (S)-Methyl(1-(4-methyl-3-((1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (405A-5)

[2026] To a solution of(S)-5-(1-(5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (130 mg, 203 mol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (49.7 mg, 468 mol, 2.9 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (100 L) were added Na.sub.2CO.sub.3 (8.00 mg, 76.2 mol, 2.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (16.6 mg, 20.3 mol, 0.1 eq). The resulting mixture was stirred at 80 C. for 4 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature, then treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give(S)-methyl(1-(4-methyl-3-((1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)propan-2-yl)carbamate (130 mg, crude) as a yellow oil. M+H.sup.+==530.4 (LCMS).

Step 6: (S)-2-Methyl-5-(2-(methylamino)propoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 660)

[2027] To a solution of(S)-methyl(1-(4-methyl-3-((1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (130 mg, 472 mol, 1.0 eq) in EtOAc (500 L) was added HCl/EtOAc (4 M, 1.5 mL). The resulting mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 60 mL/min; gradient: 5%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-(2-(methylamino)propoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (25.5 mg, 54.5 mol, 22% yield) was obtained as a white solid. M+H.sup.+=430.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.68-9.40 (m, 1H), 9.29 (s, 1H), 9.17 (br s, 1H), 9.14-8.75 (m, 2H), 8.26 (s, 1H), 8.18 (br s, 1H), 7.95 (br d, J=4.3 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 5.83 (s, 1H), 5.48 (s, 1H), 4.13 (dd, J=4.0, 10.5 Hz, 1H), 4.06-4.01 (m, 1H), 3.44 (br s, 1H), 2.57-2.53 (m, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.46-1.38 (m, 2H), 1.38-1.31 (m, 2H), 1.27 (d, J=6.7 Hz, 3H).

Example 406: (S)N-(1-(7-Acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 638)

##STR01257##

Step 1: (S)N-(1-(7-(1-Ethoxyvinyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (406A-1)

[2028] To a solution of(S)-5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 546 mol, 1.0 eq) in DMF (6.0 mL) were added tributyl(1-ethoxyvinyl) stannane (394 mg, 1.09 mmol, 369 L, 2.0 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (38.3 mg, 54.6 mol, 0.1 eq). The mixture was stirred at 60 C. for 15 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL), and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give(S)N-(1-(7-(1-ethoxyvinyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy) benzamide (300 mg) as a brown oil, which was used in the next step without further purification. M+H.sup.+=472.3 (LCMS).

Step 2: (S)N-(1-(7-Acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 638)

[2029] A mixture of(S)N-(1-(7-(1-ethoxyvinyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (300 mg, 636 mol, 1.0 eq) and HCl/EtOAc (4 M, 4.0 mL, 25 eq) was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (52.4 mg, 105 mol, 17% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=444.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.31-9.21 (m, 2H), 9.11 (dd, J=1.4, 4.3 Hz, 1H), 8.62 (d, J=0.7 Hz, 1H), 8.35 (d, J=1.4 Hz, 1H), 7.83 (dd, J=4.3, 8.6 Hz, 1H), 7.13-7.06 (m, 1H), 6.95-6.87 (m, 1H), 6.75-6.68 (m, 1H), 4.66-4.54 (m, 1H), 4.30-4.18 (m, 2H), 4.01 (dt, J=5.1, 9.6 Hz, 1H), 3.85 (q, J=9.4 Hz, 1H), 2.82 (s, 3H), 2.76 (s, 3H), 2.39-2.28 (m, 2H), 1.93 (s, 3H), 1.42 (br s, 2H), 1.30-1.23 (m, 2H).

Example 407: N-(1-(7-(1-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (Compound 676)

##STR01258##

Step 1: N-(1-(7-(1-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (Compound 676)

[2030] To a solution of(S)N-(1-(7-acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (110 mg, 248 mol, 1.0 eq) in EtOH (10 mL) was added NaBH.sub.4 (18.8 mg, 496 mol, 2.0 eq) at 0 C. Then the mixture was stirred at 20 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into with NH.sub.4Cl aqueous (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(7-(1-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (27.0 mg, 55.5 mol, 22% yield, HCl salt) was obtained as a white solid. M+H.sup.+=446.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 10.13-9.93 (m, 1H), 9.34-9.18 (m, 1H), 8.45-8.32 (m, 1H), 8.29-8.22 (m, 1H), 8.21-8.14 (m, 1H), 7.19-7.09 (m, 1H), 7.04-6.95 (m, 1H), 6.92-6.82 (m, 1H), 5.18 (q, J=6.5 Hz, 1H), 4.77-4.68 (m, 1H), 4.38-4.15 (m, 3H), 3.98 (q, J=9.5 Hz, 1H), 2.96 (s, 3H), 2.62-2.51 (m, 2H), 2.03 (s, 3H), 1.67-1.55 (m, 5H), 1.48-1.43 (m, 2H).

Example 408: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 697)

##STR01259##

Step 1: 1-(7-((Trimethylsilyl) ethynyl)quinolin-5-yl)cyclopropan-1-amine (408A-1)

[2031] To a solution of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 602 mol, 1.0 eq) in acetonitrile (10 mL) were added TEA (82.7 mg, 1.81 mmol, 251 L, 3.0 eq), ethynyltrimethylsilane (118 mg, 1.20 mmol, 167 L, 2.0 eq), CuI (11.5 mg, 60.2 mol, 0.1 eq) and Pd(PPh.sub.3).sub.4 (69.6 mg, 60.2 mol, 0.1 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 1-(7-((Trimethylsilyl) ethynyl)quinolin-5-yl)cyclopropan-1-amine (115 mg, 410 mol, 68% yield) was obtained as a white solid.

Step 2: 1-(7-Ethynylquinolin-5-yl)cyclopropan-1-amine (408A-2)

[2032] To a solution of 1-(7-((trimethylsilyl) ethynyl)quinolin-5-yl)cyclopropan-1-amine (100 mg, 357 mol, 1.0 eq) in MeOH (2.0 mL) was added Cs.sub.2CO.sub.3 (232 mg, 713 mol, 2.0 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (1.0 mL) and extracted with DCM (1.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude 1-(7-ethynylquinolin-5-yl)cyclopropan-1-amine (100 mg) as a white solid.

Step 3: tert-Butyl(S)-2-((3-((1-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (408A-3)

[2033] To a solution of 1-(7-ethynylquinolin-5-yl)cyclopropan-1-amine (100 mg, 480 mol, 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (154 mg, 480 mol, 1.0 eq) in DMF (2.0 mL) were added DIEA (186 mg, 1.44 mmol, 251 L, 3.0 eq) and HATU (456 mg, 1.20 mmol, 2.5 eq). The resulting mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (10 mL) and extracted with EtOAc (2.0 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.4). tert-Butyl(S)-2-((3-((1-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 176 mol, 37% yield) was obtained as a white solid.

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 697)

[2034] To a solution of tert-butyl(S)-2-((3-((1-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 176 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (361 mg, 3.17 mmol, 234 L, 18 eq). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 C. to give a residue which was purified by preparative HPLC (Phenomenex C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (21.8 mg, 41.5 mol, 24% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=412.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.16 (s, 1H), 9.07 (d, J=8.8 Hz, 1H), 8.97 (dd, J=1.5, 4.1 Hz, 1H), 8.89-8.70 (m, 2H), 8.06 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.65 (dd, J=4.2, 8.6 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.72-4.57 (m, 1H), 4.46 (s, 1H), 4.29-4.19 (m, 1H), 4.17-4.09 (m, 1H), 4.02-3.88 (m, 1H), 3.87-3.79 (m, 1H), 2.47-2.41 (m, 1H), 2.38-2.29 (m, 1H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.30-1.21 (m, 2H).

Example 409: (S)N-(1-(7-Ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 620)

##STR01260##

Step 1: (S)N-(1-(7-Ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 620)

[2035] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (192 mg, 816 mol, 1.0 eq) and 1-(7-ethynyl-5-quinolyl)cyclopropanamine (170 mg, 816 mol, 1.0 eq) in DMF (3.0 mL) were added DIEA (316 mg, 2.45 mmol, 427 L, 3.0 eq) and HATU (776 mg, 2.04 mmol, 2.5 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was filtered. The filtrate obtained was purified by preparative HPLC (Xbridge BEH C18 (100 30 mm, 10 m); flow rate: 60 mL/min; gradient: 30%-50% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). The residue obtained was diluted with a mixture of acetonitrile (1.0 mL), H.sub.2O (4.0 mL), and HCl (1 M aqueous, 133 L). The resulting mixture was lyophilized to give(S)N-(1-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (51.4 mg, 103 mol, 13% yield, HCl salt) as a white solid. M+H.sup.+=426.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.78-10.35 (m, 1H), 9.21 (s, 1H), 9.07 (d, J=8.5 Hz, 1H), 8.96 (dd, J=1.3, 4.1 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.63 (dd, J=4.2, 8.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (br d, J=7.1 Hz, 1H), 6.72 (br s, 1H), 4.60 (br d, J=7.4 Hz, 1H), 4.46 (s, 1H), 4.37-4.28 (m, 1H), 4.26-4.17 (m, 1H), 4.04-3.95 (m, 1H), 3.92-3.79 (m, 1H), 2.81 (br s, 3H), 2.40-2.26 (m, 2H), 1.94 (s, 3H), 1.37 (br s, 2H), 1.25 (br s, 2H).

Example 410: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)benzamide (Compound 696)

##STR01261##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(prop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (410A-1)

[2036] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (100 mg, 157 mol, 1.0 eq) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68.7 mg, 330 mol, 2.1 eq) in a mixture of H.sub.2O (1.0 mL) and dioxane (6.0 mL) were added TEA (6.37 mg, 62.9 mol, 7.0 L, 0.3 eq), KF (27.4 mg, 472 mol, 3.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (38.5 mg, 47.2 mol, 0.3 eq) and CuI (4.49 mg, 23.6 mol, 0.15 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl(S)-2-((3-((1-(7-((tert-butoxycarbonyl)amino)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 152 mol, 48% yield) was obtained as a yellow solid. M+H.sup.+=526.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 9.02 (d, J=8.0 Hz, 1H), 8.91 (dd, J=1.6, 4.2 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.58 (dd, J=4.2, 8.6 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.88 (dd, J=2.8, 8.4 Hz, 1H), 6.66 (d, J=2.6 Hz, 1H), 4.42-4.34 (m, 1H), 4.14 (dd, J=4.8, 10.3 Hz, 1H), 4.00-3.96 (m, 1H), 3.77-3.69 (m, 2H), 2.33-2.25 (m, 1H), 2.13 (s, 3H), 2.10-2.03 (m, 1H), 1.93 (s, 3H), 1.39-1.25 (m, 13H).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(prop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 696)

[2037] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(1-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 152 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (800 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(prop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)benzamide (19.9 mg, 46.7 mol, 31% yield, TFA salt) was obtained as a white solid. M+H.sup.+=426.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.15 (s, 1H), 9.05 (d, J=8.4 Hz, 1H), 8.94 (dd, J=1.5, 4.1 Hz, 1H), 8.90-8.74 (m, 2H), 7.93 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.61 (dd, J=4.2, 8.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.69-4.60 (m, 1H), 4.26-4.20 (m, 1H), 4.16-4.11 (m, 1H), 3.93 (br s, 2H), 2.46-2.30 (m, 2H), 2.14 (s, 3H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.23 (br s, 2H).

Example 411: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(3,3,3-trifluoroprop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 803)

##STR01262##

Step 1: N-(1-(7-(1-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (Compound 803)

[2038] To a solution of CuI (3.58 mg, 18.8 mol, 0.2 eq), 1,10-phenanthroline (6.78 mg, 37.6 mol, 0.4 eq), K.sub.2CO.sub.3 (26.0 mg, 188 mol, 2.0 eq) and 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-113-benzo[d][1,2]iodaoxole (31.0 mg, 94.0 mol, 1.0 eq) in DCM (3.0 mL) was added dropwise a solution of(S)N-(1-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (40.0 mg, 94.0 mol, 1.0 eq) in DCM (1.0 mL). The mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(7-(1-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (18.1 mg, 33.8 mol, 36% yield, HCl salt) was obtained as a white solid. M+H.sup.+=494.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.76-10.43 (m, 1H), 9.27 (s, 1H), 9.15 (d, J=8.8 Hz, 1H), 9.06 (d, J=4.1 Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.76 (dd, J=4.2, 8.6 Hz, 1H), 7.13-7.06 (m, 1H), 6.97-6.89 (m, 1H), 6.78-6.71 (m, 1H), 4.68-4.56 (m, 1H), 4.33 (dd, J=7.8, 11.3 Hz, 1H), 4.25-4.17 (m, 1H), 4.06-3.94 (m, 1H), 3.90-3.79 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 2.40-2.28 (m, 2H), 1.93 (s, 3H), 1.43-1.35 (m, 2H), 1.30 (br s, 2H).

Example 412: (S)N-(1-(7-cyanoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (Compound 738)

##STR01263##

Step 1: tert-Butyl(S)-2-((3-((1-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (412A-1)

[2039] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 315 mol, 1.0 eq) in DMF (10 mL) were added Zn(CN).sub.2 (111 mg, 944 mol, 3.0 eq), BrettPhosPdG.sub.3 (28.5 mg, 31.5 mol, 0.1) and BrettPhos (33.8 mg, 62.9 mol, 0.2 eq). The mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl(S)-2-((3-((1-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 156 mol, 49% yield) was obtained as a white solid. M+H.sup.+=513.2 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-cyanoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (412A-2)

[2040] To a solution of tert-butyl(S)-2-((3-((1-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (40.0 mg, 78.0 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (0.2 mL). The mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-cyanoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (30.0 mg, TFA salt) as a white solid. M+H.sup.+=413.2 (LCMS).

Step 3: (S)N-(1-(7-Cyanoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 738)

[2041] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-cyanoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (30.0 mg, 56.9 mol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (5.77 mg, 56.9 mol, 7.93 L, 1.0 eq), followed by formaldehyde (3.42 mg, 113.9 mol, 3.14 L, 2.0 eq, 37% aqueous). The resulting mixture was adjusted to pH 6 with a small amount of AcOH (3.42 mg, 56.9 mol, 3.26 L, 1 eq). The mixture was stirred at 25 C. for 30 min, then NaBH.sub.3CN (17.9 mg, 284.90 mol, 5.0 eq) was added. The reaction mixture was stirred at 25 C. for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-30% B over 8 min; mobile phase A: 0.1% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Cyanoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (18.5 mg, 39.9 mol, 70% yield, HCl salt) was obtained as a white solid. M+H.sup.+=427.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.81-10.53 (m, 1H), 9.30 (s, 1H), 9.18 (d, J=8.5 Hz, 1H), 9.09 (dd, J=1.4, 4.1 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.81 (dd, J=4.1, 8.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.98-6.88 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.61 (br s, 1H), 4.42-4.14 (m, 2H), 4.04-3.79 (m, 2H), 2.85-2.64 (m, 3H), 2.41-2.24 (m, 2H), 1.93 (s, 3H), 1.43-1.28 (m, 4H).

Example 413: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 677)

##STR01264##

Step 1: tert-Butyl(S)-2-((3-((1-(7-ethylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (413A-1)

[2042] A solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (50.0 mg, 78.7 mol, 1.0 eq), potassium ethyltrifluoroborate (11.8 mg, 86.5 mol, 1.1 eq), Pd(OAc) 2 (1.77 mg, 7.87 mol, 0.1 eq), RuPhos (7.34 mg, 15.7 mol, 0.2 eq) and CS.sub.2CO.sub.3 (76.9 mg, 236 mol, 3.0 eq) in a mixture of toluene (3.0 mL) and H.sub.2O (0.3 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 110 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into H.sub.2O (5.0 mL) and extracted with EtOAc (4.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.5). tert-Buty(S)-2-((3-((1-(7-ethylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (63.0 mg, 122 mol, 78% yield) was obtained as a white solid. M+H.sup.+=516.3 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethylquinolin-5-yl)cyclopropyl)-2-methyl benzamide (Compound 677)

[2043] To a solution of tert-butyl(S)-2-((3-((1-(7-ethylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (63.0 mg, 122.18 mol, 1.0 eq) in DCM (3.0 mL) was added TFA (3.08 g, 27.0 mmol, 2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (30.0 mg, 56.7 mol, 47% yield, TFA salt) was obtained as a white solid. M+H.sup.+=416.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.45 (br d, J=8.6 Hz, 1H), 9.19 (s, 1H), 9.08 (dd, J=1.3, 4.8 Hz, 1H), 7.95 (s, 1H), 7.90-7.82 (m, 2H), 7.09 (d, J=8.6 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 4.69-4.58 (m, 1H), 4.28-4.17 (m, 1H), 4.16-4.08 (m, 1H), 3.98-3.77 (m, 2H), 2.89 (q, J=7.5 Hz, 2H), 2.48-2.42 (m, 1H), 2.40-2.28 (m, 1H), 1.95 (s, 3H), 1.40 (br s, 2H), 1.34-1.23 (m, 5H).

Example 414: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 692)

##STR01265##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (414A-1)

[2044] A mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 236 mol, 1.0 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (72.7 mg, 472 mol, 80.1 L, 2.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (19.3 mg, 23.6 mol, 0.1 eq), and Na.sub.2CO.sub.3 (57.5 mg, 543 mol, 2.3 eq) in a mixture of dioxane (6.0 mL) and H.sub.2O (1.0 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 156 mol, 66% yield) was obtained as a yellow oil. M+H.sup.+=514.3 (LCMS).

Step 2: tert-Butyl(S)-2-((3-((1-(7-ethyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (414A-2)

[2045] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 156 mol, 1.0 eq) in EtOAc (8.0 mL) was added 10% palladium on carbon (50.0 mg). The mixture was degassed and purged with H.sub.2 three times and stirred at 20 C. for 2 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL3). The combined organic layers were concentrated under vacuum to give the crude product tert-butyl(S)-2-((3-((1-(7-ethyl-1,2,3,4-tetrahydro quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (30.0 mg, 57.7 mol, 37% yield) as a white solid. M+H.sup.+=520.4 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.74 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.90 (dd, J=2.6, 8.3 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 6.68-6.39 (m, 1H), 4.46-4.38 (m, 1H), 4.18 (dd, J=4.8, 10.4 Hz, 1H), 4.03 (dd, J=2.8, 10.4 Hz, 1H), 3.81-3.67 (m, 3H), 3.30-3.23 (m, 3H), 3.03-2.86 (m, 3H), 2.32-2.23 (m, 1H), 2.10 (s, 3H), 1.94-1.86 (m, 2H), 1.34 (s, 9H), 1.17-1.11 (m, 5H), 1.03 (br s, 2H).

Step 3: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 692)

[2046] To a solution of tert-butyl(S)-2-((3-((1-(7-ethyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (20.0 mg, 38.5 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-ethyl-1,2,3,4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methylbenzamide (4.80 mg, 11.4 mol, 30% yield) was obtained as a white solid. M+H.sup.+=420.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.94-8.76 (m, 2H), 8.69 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.93 (dd, J=2.6, 8.4 Hz, 1H), 6.87-6.71 (m, 2H), 4.73-4.64 (m, 1H), 4.32-4.25 (m, 1H), 4.22-4.15 (m, 1H), 3.96-3.85 (m, 2H), 3.20 (br s, 2H), 2.92 (br t, J=5.9 Hz, 2H), 2.46-2.31 (m, 4H), 2.13 (s, 3H), 1.91-1.81 (m, 2H), 1.16-1.08 (m, 5H), 1.03-0.99 (m, 2H).

Example 415: (S)N-(1-(6-Methoxyquinolin-8-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 761)

##STR01266##

Step 1:6-Methoxyquinoline-8-carbonitrile (415A-2)

[2047] To a solution of 8-bromo-6-methoxyquinoline (13.0 g, 54.6 mmol, 1.0 eq) in DMF (250 mL) were added Zn(CN).sub.2 (12.8 mg, 109 mmol, 6.93 mL, 2.0 eq) and Pd(PPh.sub.3).sub.4 (6.31 g, 5.46 mmol, 0.1 eq) under a N.sub.2 atmosphere. The mixture was stirred at 100 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (400 mL), and extracted with EtOAc (200 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 6-Methoxyquinoline-8-carbonitrile (9.00 g, 48.9 mmol, 89% yield) was obtained as a white solid. M+H.sup.+=185.0 (LCMS).

Step 2: 1-(6-Methoxyquinolin-8-yl)cyclopropan-1-amine (415A-3)

[2048] A mixture of 6-methoxyquinoline-8-carbonitrile (1.00 g, 5.43 mmol, 1.0 eq) in anhydrous Et.sub.2O (100 mL) was degassed and purged with N.sub.2 three times. The mixture was cooled to 78 C. To this mixture was added Ti(i-PrO).sub.4 (2.31 g, 8.14 mmol, 2.4 mL, 15 eq) slowly, then EtMgBr (3 M in Et.sub.2O, 4.0 mL, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (1.54 g, 10.9 mmol, 1.34 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (50 mL) and MTBE (50 mL) and extracted with MTBE (50 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL6). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 0/1 to 10/1. 1-(6-Methoxyquinolin-8-yl)cyclopropan-1-amine (370 mg, 1.73 mmol, 32% yield) was obtained as a yellow oil. M+H.sup.+=215.2 (LCMS).

Step 3: (S)N-(1-(6-Methoxyquinolin-8-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 761)

[2049] To a mixture of 1-(6-methoxyquinolin-8-yl)cyclopropan-1-amine (100 mg, 467 mol, 1.0 eq) and(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (110 mg, 467 mol, 1.0 eq) in DMF (3.0 mL) were added HATU (444 mg, 1.17 mmol, 2.5 eq) and DIEA (181 mg, 1.40 mmol, 244 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (15 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 40 mm, 10 m); flow rate: 60 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(6-Methoxyquinolin-8-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (42.7 mg, 75.9 mol, 16% yield) was obtained as a white solid. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.54-9.94 (m, 1H), 9.19 (s, 1H), 9.07-8.96 (m, 1H), 8.77 (br d, J=8.3 Hz, 1H), 7.73-7.58 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.16-6.95 (m, 2H), 6.88 (s, 1H), 4.91-4.65 (m, 1H), 4.52-4.28 (m, 2H), 4.21-4.02 (m, 5H), 2.96-2.86 (m, 3H), 2.47-2.38 (m, 2H), 2.32 (s, 3H), 1.63-1.54 (m, 2H), 1.49-1.42 (m, 2H).

Example 416: 5-(2-(tert-Butylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 626)

##STR01267##

Step 1: 5-(2-Bromoethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (416A-1)

[2050] To a solution of 5-hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (150 mg, 431 mol, 1.0 eq) and 1,2-dibromoethane (809 mg, 4.31 mmol, 325 L, 10 eq) in acetone (5.0 mL) were added K.sub.2CO.sub.3 (137 mg, 990 mol, 2.3 eq) and 18-crown-6 (5.69 mg, 21.5 mol, 0.05 eq). The mixture was stirred at 60 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.38). 5-(2-Bromoethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (63.0 mg, 138 mol, 32% yield) was obtained as a yellow solid. M+H.sup.+=455.1 (LCMS).

Step 2: 5-(2-(tert-Butylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 626)

[2051] To a solution of 2-methylpropan-2-amine (101 mg, 1.38 mmol, 10 eq) in acetonitrile (5.0 mL) were added 5-(2-bromoethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (63.0 mg, 138 mol, 1.0 eq) and DIEA (53.7 mg, 415 mol, 72.3 L, 3.0 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Waters Xbridge BEH C18 (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 5-(2-(tert-Butylamino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (19.2 mg, 39.2 mol, 99% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=448.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.62 (br d, J=8.1 Hz, 1H), 9.33 (s, 1H), 9.16 (d, J=5.0 Hz, 1H), 8.97 (br s, 2H), 7.94 (br dd, J=5.4, 8.3 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.21 (br t, J=5.1 Hz, 2H), 4.02 (s, 3H), 3.22 (br s, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.31 (s, 11H).

Example 417: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy-d.SUB.2.)benzamide (Compound 797)

##STR01268##

Step 1: tert-Butyl(S)-2-(hydroxymethyl-d.SUB.2.)azetidine-1-carboxylate (417A-2)

[2052] To a solution of 1-(tert-butyl) 2-methyl(S)-azetidine-1,2-dicarboxylate (400 mg, 1.86 mmol, 1.0 eq) in THF (5.0 mL) was added LiAlD.sub.4 (77.9 mg, 1.86 mmol, 106 L, 1.0 eq) at 0 C. The mixture was stirred at 25 C. for 1 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated NH.sub.4Cl aqueous (10 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl(S)-2-(hydroxymethyl-d.sub.2)azetidine-1-carboxylate (300 mg, 1.59 mmol, 85% yield) as a yellow oil, which was used in the next step without any further purification. M56+H.sup.+=134.1. 1H NMR (400 MHZ, CDCl.sub.3) 4.44 (t, J=7.6 Hz, 1H), 3.93-3.84 (m, 1H), 3.79 (dt, J=4.8, 8.9 Hz, 1H), 2.18 (dtd, J=4.8, 8.7, 11.4 Hz, 1H), 1.94 (tdd, J=7.0, 9.3, 11.3 Hz, 1H), 1.46 (s, 9H).

Step 2: tert-Butyl(S)-2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl-d.SUB.2.)azetidine-1-carboxylate (417A-3)

[2053] To a solution of tert-butyl(S)-2-(hydroxymethyl-d.sub.2)azetidine-1-carboxylate (166 mg, 878 mol, 1.7 eq) and 5-hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (180 mg, 517 mol, 1.0 eq) in toluene (3.0 mL) were added added TMAD (267 mg, 1.55 mmol, 3.0 eq) and PPh.sub.3 (407 mg, 1.55 mmol, 3.0 eq) in one portion. The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl(S)-2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl-d.sub.2)azetidine-1-carboxylate (260 mg) as a yellow solid, which was used in the next step without any further purification. M+H.sup.+=520.3 (LCMS).

Step 3: (S)-5-(Azetidin-2-ylmethoxy-d.SUB.2.)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (417A-4)

[2054] To a solution of tert-butyl(S)-2-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl-d.sub.2)azetidine-1-carboxylate (260 mg, 450 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (250 L) at 0 C. The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 C. to give(S)-5-(azetidin-2-ylmethoxy-d.sub.2)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (180 mg, 429 mol, 95% yield, TFA salt) as a yellow solid, which was used in the next step without any further purification.

Step 4: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy-d.SUB.2.)benzamide (Compound 797)

[2055] To a solution of(S)-5-(azetidin-2-ylmethoxy-d.sub.2)N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (180 mg, 337 mmol, 1.0 eq, TFA) in MeOH (3.0 mL) was added TEA (50.0 L), followed by formaldehyde (54.8 mg, 675 mol, 50.2 L, 37% purity in water, 2.0 eq). The mixture was adjusted to pH 5 with a small amount of AcOH, then NaBH.sub.3CN (42.4 mg, 675 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH.sub.4Cl (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue, which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy-d.sub.2)benzamide (77.6 mg, 179 mol, 53% yield, TFA salt) was obtained as a white solid. M+H.sup.+=434.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.31 (br d, J=8.5 Hz, 1H), 9.22-9.16 (m, 1H), 9.01 (dd, J=1.3, 4.9 Hz, 1H), 7.72 (dd, J=4.9, 8.4 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.12-7.07 (m, 1H), 6.95-6.88 (m, 1H), 6.77-6.70 (m, 1H), 4.65-4.55 (m, 1H), 4.07-4.00 (m, 1H), 3.97 (s, 3H), 3.87 (q, J=9.5 Hz, 1H), 2.83 (s, 3H), 2.40-2.28 (m, 2H), 1.94 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H).

Example 418: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)benzamide (Compound 732)

##STR01269##

Step 1: Methyl(S)-2-methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)benzoate (418A-1)

[2056] To a solution of(S)-methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (200 mg, 573 mol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (100 L), followed by formaldehyde-d.sub.2 (107 mg, 687 mol, 94.6 L, 20% purity in D.sub.2O, 1.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBD.sub.3CN (36.0 mg, 573 mol, 1.0 eq) was added. The resulting mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 100/1 to 10/1. Methyl(S)-2-methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)benzoate (80.0 mg, 317 mol, 55% yield) was obtained as a yellow oil. M+H.sup.+=253.1 (LCMS).

Step 2: (S)-2-Methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)benzoic acid (418A-2)

[2057] A solution of methyl(S)-2-methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)benzoate (180 mg, 713 mol, 1.0 eq) in HCl (2 M aqueous, 10 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then adjusted to pH 6 with NaOH (2 M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V=10/1, 10 mL), then filtered. The filter cake was washed with MeOH/DCM (V/V=10/1, 10 mL2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give(S)-2-methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)benzoic acid (190 mg, crude) as a hydrophilic, white solid. M+H.sup.+=239.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.00-10.70 (m, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.16 (dd, J=2.8, 8.4 Hz, 1H), 4.79-4.65 (m, 1H), 4.54-4.47 (m, 1H), 4.40-4.33 (m, 1H), 4.14-4.02 (m, 1H), 3.97-3.84 (m, 1H), 2.56-2.55 (m, 3H), 2.47-2.37 (m, 2H).

Step 3: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)benzamide (Compound 732)

[2058] To a solution of(S)-2-methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)benzoic acid (190 mg, 797 mol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropan-1-amine (188 mg, 877 mol, 1.1 eq) in DMF (10 mL) were added DIEA (309 mg, 2.39 mmol, 417 L, 3.0 eq) and HATU (606 mg, 1.59 mmol, 2.0 eq). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL6). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)benzamide (52.3 mg, 120 mol, 15% yield) was obtained as a white solid. M+H.sup.+=435.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 9.00-8.90 (m, 1H), 8.86-8.79 (m, 1H), 7.48-7.39 (m, 2H), 7.31 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.7 Hz, 1H), 3.94-3.91 (m, 3H), 3.88-3.84 (m, 2H), 3.28-3.16 (m, 2H), 2.76-2.64 (m, 1H), 2.00-1.80 (m, 5H), 1.37-1.31 (m, 2H), 1.22-1.16 (m, 2H).

Example 419: tert-Butyl(6S,8aR)-6-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Compound 775) and tert-butyl(7S,9aR)-7-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy) octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (Compound 776)

##STR01270##

Step 1: tert-Butyl(6S,8aR)-6-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Compound 775) and tert-butyl(7S,9aR)-7-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy) octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (Compound 776)

[2059] To a mixture of 5-hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (150 mg, 431 mol, 1.0 eq) and tert-butyl(6S,8aR)-6-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (165 mg, 645 mol, 1.5 eq) in toluene (15 mL) was added CMBP (312 mg, 1.29 mmol, 3.0 eq) in glove box. The mixture was degassed and purged with N.sub.2 three times. The mixture was stirred at 100 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). tert-Butyl(6S,8aR)-6-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) hexa hydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (183 mg, 311 mol, 72% yield, eluent second) was obtained as a white solid. M+H.sup.+=587.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.94 (d, J=8.4 Hz, 1H), 8.81 (d, J=3.3 Hz, 1H), 7.51-7.35 (m, 2H), 7.31 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.5, 8.4 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 4.06-3.95 (m, 1H), 3.92 (s, 3H), 3.85-3.79 (m, 1H), 3.13 (br d, J=11.1 Hz, 1H), 2.83-2.53 (m, 3H), 2.05-1.91 (m, 5H), 1.90-1.80 (m, 1H), 1.78-1.66 (m, 1H), 1.61-1.12 (m, 17H). tert-Butyl(7S,9aR)-7-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphen oxy) octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (9.20 mg, 15.7 mol, 11% yield, eluent first) was obtained as a white solid. M+H.sup.+=587.3 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11 (s, 1H), 8.95 (d, J=7.5 Hz, 1H), 8.82 (dd, J=1.6, 4.1 Hz, 1H), 7.51-7.37 (m, 2H), 7.31 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.85 (dd, J=2.6, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 4.50-4.40 (m, 1H), 3.92 (s, 3H), 3.84-3.69 (m, 2H), 2.91 (br d, J=12.5 Hz, 1H), 2.57 (br s, 1H), 2.15 (br d, J=11.9 Hz, 1H), 1.96-1.76 (m, 6H), 1.55-1.31 (m, 16H), 1.22-1.14 (m, 2H).

Example 420: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-octahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 789) and N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (Compound 790)

##STR01271##

Step 1: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-octahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 789) and N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (Compound 790)

[2060] To a mixture of tert-butyl(6S,8aR)-6-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl) hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate and tert-butyl(7S,9aR)-7-(3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy) octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (70.0 mg, 119 mol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 2.19 mL). The resulting mixture was stirred at 20 C. for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-octahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (26.8 mg, 51.2 mol, 43% yield, HCl salt, eluent second) was obtained as a yellow solid. M+H.sup.+=487.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.62 (d, J=8.4 Hz, 1H), 9.30 (s, 1H), 9.18-9.08 (m, 1H), 7.94 (dd, J=5.4, 8.5 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.40-4.14 (m, 2H), 4.01 (s, 3H), 3.96-3.82 (m, 1H), 3.77-3.62 (m, 2H), 3.48-3.16 (m, 5H), 2.28-2.05 (m, 2H), 1.93 (s, 3H), 1.81-1.59 (m, 2H), 1.41 (br s, 2H), 1.30 (br d, J=3.4 Hz, 2H). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (11.7 mg, 22.4 mol, 19% yield, HCl salt, eluent first) was obtained as a yellow solid. M+H.sup.+=487.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.54 (d, J=8.4 Hz, 1H), 9.26 (s, 1H), 9.10 (d, J=5.1 Hz, 1H), 7.88 (dd, J=5.4, 8.5 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.02-6.92 (m, 1H), 6.80 (d, J=2.4 Hz, 1H), 4.74 (br s, 1H), 4.00 (s, 3H), 3.53-3.21 (m, 7H), 3.20-3.03 (m, 2H), 1.97-1.85 (m, 4H), 1.82-1.57 (m, 3H), 1.39 (br s, 2H), 1.29 (br s, 2H).

Example 421: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-2-methyloctahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 784) and N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-2-methyloctahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (Compound 783)

##STR01272##

Step 1: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-2-methyl octahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (Compound 783) and N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-2-methyloctahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 784)

[2061] To a mixture of N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-octahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide and N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (130 mg, 249 mol, 1.0 eq, HCl salt) in MeOH (5.0 mL) was added TEA (50 L), followed by formaldehyde (40.3 mg, 497 mol, 37.0 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBH.sub.3CN (31.2 mg, 497 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile). N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6S,8aR)-2-methyloctahydropyrrolo[1,2-a]pyrazin-6-yl)methoxy)benzamide (16.8 mg, 32.8 mol, 13% yield, eluent second) was obtained as a white solid. M+H.sup.+=501.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 9.00-8.87 (m, 1H), 8.81 (dd, J=1.6, 4.3 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 7.41 (dd, J=4.3, 8.4 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.95-3.87 (m, 4H), 3.78 (dd, J=5.4, 9.7 Hz, 1H), 3.10-3.01 (m, 1H), 2.81 (br d, J=10.3 Hz, 1H), 2.69-2.58 (m, 2H), 2.26-2.09 (m, 5H), 2.02-1.79 (m, 5H), 1.74-1.59 (m, 2H), 1.54-1.38 (m, 1H), 1.38-1.30 (m, 2H), 1.28-1.14 (m, 3H). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7S,9aR)-2-methyloctahydro-2H-pyrido[1,2-a]pyrazin-7-yl)oxy)benzamide (10.2 mg, 19.3 mol, 8% yield, eluent first) was obtained as a white solid. M+H.sup.+=501.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.94 (d, J=7.6 Hz, 1H), 8.82 (dd, J=1.5, 4.1 Hz, 1H), 7.49-7.37 (m, 2H), 7.31 (d, J=2.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 4.43 (br s, 1H), 3.92 (s, 3H), 2.88 (br d, J=12.5 Hz, 1H), 2.58 (br dd, J=10.1, 19.3 Hz, 3H), 2.18-1.88 (m, 10H), 1.82 (br d, J=13.0 Hz, 1H), 1.74-1.63 (m, 1H), 1.53-1.38 (m, 2H), 1.37-1.31 (m, 2H), 1.30-1.23 (m, 1H), 1.22-1.14 (m, 2H).

Example 422: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (Compound 799)

##STR01273## ##STR01274##

Step 1: tert-Butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (422A-2)

[2062] To a solution of (1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (200 mg, 1.23 mmol, 1.0 eq) in DCM (10 mL) were added TEA (450 mg, 4.44 mmol, 620 L, 3.6 eq) and Boc.sub.2O (321 mg, 1.47 mmol, 1.2 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (4.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. tert-Butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (320 mg, 1.22 mmol, 99% yield) was obtained as a yellow oil. M56+H.sup.+=208.2 (LCMS).

Step 2: tert-Butyl 3-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (422A-3)

[2063] To a solution of tert-butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 1.14 mmol, 1.0 eq) and methyl 5-hydroxy-2-methylbenzoate (189 mg, 1.14 mmol, 1.0 eq) in tolene (15 mL) were added TMAD (589 mg, 3.42 mmol, 3.0 eq) and PPh.sub.3 (896 mg, 3.42 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. tert-Butyl 3-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (366 mg, 890 mol, 78% yield) was obtained as a yellow oil. M56+H.sup.+=356.2 (LCMS).

Step 3: 5-((2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-2-methylbenzoic acid (422A-4)

[2064] To a solution of tert-butyl 3-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (366 mg, 890 mol, 1.0 eq) in MeOH (20 mL) and THF (10 mL) was added NaOH (2 M aqueous, 1.8 mL, 4.0 eq). The mixture was stirred at 70 C. for 16 h.

[2065] LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL), and washed with MTBE (15 mL2). The aqueous layer was acidified to pH 6 with HCl (1 M aqueous). The product was extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product 5-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-2-methylbenzoic acid (375 mg) as a yellow oil. M56+H.sup.+=342.2 (LCMS).

Step 4: tert-Butyl 3-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (422A-5)

[2066] To a solution of 1-(7-methoxyquinolin-5-yl)cyclopropan-1-amine (80.9 mg, 177 mol, 1.0 eq) and 5-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-2-methylbenzoicacid (150 mg, 377 mol, 1.0 eq) in DMF (8.0 mL) were added DIEA (146 mg, 1.13 mmol, 197 L, 3.0 eq) and HATU (359 mg, 943 mol, 2.5 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (8.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl 3-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (193 mg, 325 mol, 86% yield) was obtained as a yellow oil. M56+H.sup.+=538.4 (LCMS).

Step 5: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (422A-6)

[2067] To a solution of tert-butyl 3-((3-((1-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (193 mg, 325 mol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 7.4 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the product N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (160 mg, 302 mol, 93% yield, HCl salt) as a white solid. M+H.sup.+=494.3 (LCMS).

Step 6: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (Compound 799)

[2068] To a solution of N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (150 mg, 283 mol, 1.0 eq, HCl salt) in MeOH (10 mL) was added TEA (1.0 mL), followed by formaldehyde (45.9 mg, 566 mol, 42.1 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBH.sub.3CN (35.6 mg, 566 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (80 30 mm3 m); flow rate: 25 mL/min; gradient: 10%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)benzamide (65.1 mg, 120 mol, 42% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=508.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.82 (d, J=8.4 Hz, 1H), 9.34 (s, 1H), 9.07 (d, J=5.6 Hz, 1H), 8.03-7.87 (m, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.38-7.24 (m, 4H), 7.13 (d, J=8.4 Hz, 1H), 7.05-6.95 (m, 1H), 6.87 (d, J=2.6 Hz, 1H), 4.65-4.41 (m, 3H), 4.38-4.15 (m, 2H), 4.11 (s, 3H), 3.97 (br dd, J=4.6, 8.9 Hz, 1H), 3.46-3.35 (m, 1H), 3.09-2.87 (m, 3H), 2.03 (s, 3H), 1.62-1.54 (m, 2H), 1.49-1.39 (m, 2H).

Example 423: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl-2,2,3,3-d.SUB.4.)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 794)

##STR01275##

Step 1: (Ethyl-d.SUB.5.)magnesium bromide (423A-2)

[2069] A 50 mL Schlenk flask was charged with Mg (853 mg, 35.1 mmol, 2.0 eq), degassed, and purged with N.sub.2 three times. Dry THF (18 mL) was added via syringe, and the reaction was cooled to 0 C. I.sub.2 (5 mg, 19.7 mol) was added, followed by 1-bromoethane-1,1,2,2,2-d.sub.5 (2.00 g, 17.5 mmol, 3.42 mL, 1.0 eq) in portions. The reaction mixture was stirred at 0 C. for 2 h. The reaction mixture turned grey and most of the Mg was consumed. The reaction mixture was used into the next step without any further purification.

Step 2: 1-(7-Methoxyquinolin-5-yl)cyclopropan-2,2,3,3-d.SUB.4.-1-amine (423A-3)

[2070] A mixture of 7-methoxyquinoline-5-carbonitrile (50.0 mg, 271 mol, 1.0 eq) in anhydrous THF (5.0 mL) was degassed and purged with N.sub.2 three times. Then the white suspension was cooled to 78 C. To this mixture was added Ti(i-PrO).sub.4 (116 mg, 407 mol, 120 L, 1.5 eq) slowly during a period of 5 min and stirred at 78 C. for 10 min. (Ethyl-d.sub.5) magnesium bromide (1 M in THF, 2.0 mL, 7.4 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 10 min under a N.sub.2 atmosphere. The color of the mixture turned brown after the addition was complete. The resulting mixture was stirred at the same temperature for 10 min and then warmed to room temperature (between 15-20 C.) slowly over 1.5 h. The mixture turned black. To the mixture was added BF.sub.3.Math.Et.sub.2O (77.1 mg, 543 mol, 67.1 L, 2.0 eq) in portions at the same temperature and no obvious temperature changed was observed. The resulting mixture was stirred at room temperature for another 1 h. LCMS indicated that most of the starting material was consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=10/1, R.sub.f=0.4). 1-(7-Methoxyquinolin-5-yl)cyclopropan-2,2,3,3-d.sub.4-1-amine (20.0 mg, crude) was obtained as a brown gum. M+H.sup.+=219.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.85 (dd, J=1.6, 4.3 Hz, 1H), 8.68 (dd, J=0.9, 8.4 Hz, 1H), 7.39-7.33 (m, 2H), 7.24 (d, J=2.5 Hz, 1H), 3.95 (s, 3H).

Step 3: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl-2,2,3,3-d.SUB.4.)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 794)

[2071] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (37.7 mg, 160 mol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropan-2,2,3,3-d.sub.4-1-amine (35.0 mg, 160 mol, 1.0 eq) in DMF (1.0 mL) were added DIEA (62.2 mg, 481 mol, 83.8 L, 3.0 eq) and HATU (152 mg, 401 mol, 2.5 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered to give a filtrate which was purified by preparative HPLC (Phenomenex Luna column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl-2,2,3,3-d.sub.4)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (6.60 mg, 11.5 mol, 7% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=436.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.10-9.90 (m, 1H), 9.21-9.12 (m, 2H), 8.95 (d, J=3.5 Hz, 1H), 7.66-7.55 (m, 2H), 7.39 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.77-6.70 (m, 1H), 4.61 (br d, J=4.4 Hz, 1H), 4.23 (d, J=5.3 Hz, 2H), 4.02 (br dd, J=4.9, 9.7 Hz, 1H), 3.96 (s, 3H), 3.87 (br dd, J=6.0, 9.5 Hz, 1H), 2.84 (d, J=4.6 Hz, 3H), 2.41-2.27 (m, 2H), 1.95 (s, 3H).

Example 424: (S)-4-Hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 750)

##STR01276##

Step 1: tert-Butyl(S)-2-((2-methoxy-5-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (424A-2)

[2072] To a mixture of methyl 5-hydroxy-4-methoxy-2-methylbenzoate (500 mg, 2.54 mmol, 1.0 eq) and tert-butyl(S)-2-(hydroxymethyl)azetidine-1-carboxylate (578 mg, 2.54 mmol, 1.0 eq) in toluene (12 mL) were added TMAD (1.31 g, 7.64 mmol, 3.0 eq) and PPh.sub.3 (2.00 g, 7.64 mmol, 3.0 eq). The mixture was stirred at 100 C. for 16 h under a N.sub.2 atmosphere. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl(S)-2-((2-methoxy-5-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (900 mg, 2.46 mmol, 97% yield) was obtained as a yellow oil. M100+H.sup.+=266.1 (LCMS).

Step 2: Methyl(S)-5-(azetidin-2-ylmethoxy)-4-hydroxy-2-methylbenzoate (424A-3)

[2073] To a solution of tert-butyl(S)-2-((2-methoxy-5-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (450 mg, 1.23 mmol, 1.0 eq) in DCM (10 mL) was added a solution of BBr.sub.3 (1.54 g, 6.16 mmol, 593 L, 5.0 eq) in DCM (2.0 mL) dropwise at 78 C. The resulting mixture was stirred at the same temperature for 1 h, then warmed to 20 C. and stirred another 3 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude methyl(S)-5-(azetidin-2-ylmethoxy)-4-hydroxy-2-methylbenzoate (800 mg, 2.41 mmol, HBr salt) as a red oil, which was used in the next step without any further purification. M+H.sup.+=252.2 (LCMS).

Step 3: Methyl(S)-4-hydroxy-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (424A-4)

[2074] To a solution of methyl(S)-5-(azetidin-2-ylmethoxy)-4-hydroxy-2-methylbenzoate (400 mg, 1.20 mmol, 1.0 eq, HBr salt) in MeOH (10 mL) was added TEA (100 L), followed by formaldehyde (195 mg, 2.41 mmol, 179 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (151 mg, 2.41 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (20 mL) and extracted with DCM (30 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give methyl(S)-4-hydroxy-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=266.3 (LCMS).

Step 4: (S)-4-Hydroxy-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (424A-5)

[2075] A solution of methyl(S)-4-hydroxy-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoate (300 mg, 1.13 mmol, 1.0 eq) in HCl (2 M aqueous, 15 mL) was stirred at 100 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H.sub.2O (10 mL) and washed with MTBE (20 mL2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (20 mL5) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to give 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (150 mg) as a white solid, which was used in the next step without any further purification. M+H.sup.+=252.2 (LCMS).

Step 5: (S)-4-Hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 750)

[2076] To a solution of 2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (60.0 mg, 239 mol, 1.0 eq) and 1-(7-methoxyquinolin-5-yl)cyclopropan-1-amine (56.3 mg, 263 mol, 1.1 eq) in DMF (5.0 mL) were added DIEA (30.9 mg, 239 mol, 41.6 L, 1.0 eq) and HATU (27.0 mg, 71.6 mol, 0.3 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-4-Hydroxy-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (34.0 mg, 70.3 mol, 29% yield, HCl salt) was obtained as a brown solid. M+H.sup.+=448.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.55-9.45 (m, 1H), 9.11-8.98 (m, 2H), 7.87-7.77 (m, 1H), 7.70-7.62 (m, 1H), 7.50-7.42 (m, 1H), 6.87-6.80 (m, 1H), 6.64-6.59 (m, 1H), 4.74-4.51 (m, 1H), 4.31-4.18 (m, 2H), 4.07-3.80 (m, 5H), 2.93-2.81 (m, 3H), 2.41-2.32 (m, 2H), 2.01-1.95 (m, 3H), 1.41-1.36 (m, 2H), 1.30-1.24 (m, 2H).

Example 425: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-(methylamino)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 737)

##STR01277##

Step 1: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-(methylamino)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 737)

[2077] To a solution of(S)-4-amino-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (46.0 mg, 103 mol, 1.0 eq) in MeOH (5.0 mL) was added TEA (1.0 mL), followed by formaldehyde (8.36 mg, 103 mol, 7.68 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. Then NaBH.sub.3CN (9.72 mg, 155 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-20% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-(methylamino)-5-((1-methylazetidin-2-yl)methoxy)benzamide (14.5 mg, 29.2 mol, 28% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=461.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.59 (br s, 1H), 9.71 (br dd, J=2.0, 7.8 Hz, 1H), 9.14 (br d, J=5.6 Hz, 1H), 8.95 (s, 1H), 7.91 (br dd, J=4.1, 7.6 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 6.80 (s, 1H), 6.31 (br s, 1H), 4.73-4.51 (m, 1H), 4.32 (dd, J=5.9, 12.1 Hz, 1H), 4.18 (dd, J=2.6, 11.9 Hz, 1H), 4.04 (br dd, J=2.3, 5.9 Hz, 1H), 4.01 (s, 3H), 3.87-3.84 (m, 1H), 2.83 (s, 3H), 2.73-2.69 (m, 3H), 2.42-2.34 (m, 2H), 2.08 (s, 3H), 1.40 (br d, J=0.9 Hz, 2H), 1.31-1.24 (m, 2H).

Example 426: (S)N-(1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 625)

##STR01278##

Step 1: 5-Bromo-7-methoxy-2-methylquinoline (426A-2)

[2078] A mixture of 3-bromo-5-methoxyaniline (2.50 g, 12.4 mmol, 1.0 eq) and HCl (6 M aqueous, 10 mL) was heated to 105 C., then (E)-but-2-enal (1.73 g, 24.8 mmol, 2.1 mL, 2.0 eq) was added slowly. The resulting mixture was stirred at 105 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice-cold water (20 mL), treated with NH.sub.3H.sub.2O to adjust pH 8, and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. 5-Bromo-7-methoxy-2-methylquinoline (750 mg, 2.98 mmol, 24% yield) was obtained as a yellow solid. M+H.sup.+=252.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.25 (d, J=8.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.45-7.35 (m, 2H), 3.91 (s, 3H), 2.65 (s, 3H).

Step 2: 7-Methoxy-2-methylquinoline-5-carbonitrile (426A-3)

[2079] To a solution of 5-bromo-7-methoxy-2-methyl-quinoline (1.75 g, 6.94 mmol, 1.0 eq) in DMF (25 mL) were added Zn(CN).sub.2 (1.63 g, 13.9 mmol, 81 L, 2.0 eq) and Pd(PPh.sub.3).sub.4 (802 mg, 694 mol, 0.1 eq). The mixture was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 100 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice-cold water (30 mL), and extracted with EtOAc (25 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. 7-Methoxy-2-methylquinoline-5-carbonitrile (980 mg, 4.95 mmol, 73% yield) was obtained as a yellow solid. M+H.sup.+=199.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.27 (d, J=8.5 Hz, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 3.96 (s, 3H), 2.68 (s, 3H).

Step 3: 1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropanamine (426A-4)

[2080] A solution of 7-methoxy-2-methylquinoline-5-carbonitrile (1.30 g, 6.56 mmol, 1.0 eq) in Et.sub.2O (160 mL) was degassed and purged with N.sub.2 three times and cooled to 78 C. Ti(i-PrO).sub.4 (2.80 g, 9.84 mmol, 2.90 mL, 1.5 eq) was added slowly and the mixture was stirred for 5 min. EtMgBr (3.0 M in Et.sub.2O, 4.81 mL, 2.2 eq) was added dropwise at 78 C. to maintain the temperature at 78 C. under a N.sub.2 atmosphere. The mixture was stirred at same temperature for 10 min then warmed to 20 C. over 1 h. The mixture turned to black. To the mixture was added BF.sub.3.Math.Et.sub.2O (1.86 g, 13.1 mmol, 1.62 mL, 2.0 eq) in portions at the same temperature with no obvious temperature change. The resulting mixture was stirred at room temperature for another 1 h. LCMS showed some the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HCl (1 M aqueous, 100 mL) and MTBE (100 mL) and extracted with MTBE (80 mL2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropanamine (700 mg, 3.07 mmol, 47% yield) was obtained as a yellow oil. M+H.sup.+=229.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.56 (d, J=8.4 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 3.94 (s, 3H), 2.73 (s, 3H), 1.21-1.13 (m, 2H), 0.99 (d, J=2.1 Hz, 2H).

Step 4: (S)-tert-Butyl 2-((3-((1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (426A-5)

[2081] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (211 mg, 657 mol, 1.0 eq) in DMF (5.0 mL) was added 1-(7-methoxy-2-methylquinolin-5-yl)cyclopropanamine (150 mg, 657 mol, 1.0 eq), followed by DIEA (255 mg, 1.97 mmol, 343 L, 3.0 eq) and HATU (375 mg, 986 mol, 1.5 eq). The resulting mixture was stirred at 25 C. for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with ice-water (15 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (S)-tert-Butyl 2-((3-((1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (220 mg, 414 mol, 63% yield) was obtained as a yellow oil. M+H.sup.+=532.3 (LCMS).

Step 5: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (426A-6)

[2082] To a solution of(S)-tert-butyl 2-((3-((1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (370 mg, 696 mol, 1.0 eq) in DCM (12 mL) was added TFA (4.0 mL). The mixture was stirred at 25 C. for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give the crude(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (370 mg, crude, TFA salt) as a yellow oil. M+H.sup.+=432.2 (LCMS).

Step 6: (S)N-(1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 625)

[2083] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methylbenzamide (220 mg, 403 mol, 1.0 eq, TFA) in MeOH (3.0 mL) was added TEA (50 L), followed by HCHO (49.1 mg, 605 mol, 45 L, 37% purity, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (30.4 mg, 484 mol, 1.2 eq) was added. The resulting mixture was stirred at 25 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with NaHCO.sub.3 aqueous (1.0 mL) and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 60 mL/min; gradient: 25%-65% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile) to give a white solid. The solid was diluted with a mixture of acetonitrile (1.0 mL), H.sub.2O (4.0 mL), then 146 L HCl (1 M aqueous) was added slowly. The resulting mixture was lyophilized to give(S)N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoy)benzamide (70.1 mg, 145 mol, 31% yield, HCl salt) as a white solid. M+H.sup.+=446.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.82-10.52 (m, 1H), 9.42-9.02 (m, 2H), 7.57-7.39 (m, 2H), 7.16-7.03 (m, 1H), 6.97-6.89 (m, 1H), 6.80-6.62 (m, 1H), 4.69-4.52 (m, 1H), 4.45-4.28 (m, 1H), 4.22 (dd, J=3.2, 11.2 Hz, 1H), 4.06-3.90 (m, 4H), 3.85 (br dd, J=6.2, 9.5 Hz, 1H), 2.83-2.66 (m, 6H), 2.47-2.19 (m, 3H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.23 (br s, 2H).

Example 427: (S)-2-Fluoro-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 791)

##STR01279##

Step 1: (S)-tert-Butyl 2-((4-fluoro-3-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (427A-2)

[2084] To a solution of methyl 2-fluoro-5-hydroxybenzoate (500 mg, 2.94 mmol, 1.0 eq) and tert-butyl(S)-2-(hydroxyl methyl)azetidine-1-carboxylate (550 mg, 2.94 mmol, 1.0 eq) in toluene (10 mL) were added TMAD (759 mg, 4.41 mmol, 1.5 eq) and PPh.sub.3 (1.54 g, 5.88 mmol, 2.0 eq). The mixture was stirred at 110 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/3, R.sub.f=0.47). (S)-tert-Butyl 2-((4-fluoro-3-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (950 mg, 2.80 mmol, 95% yield) was obtained as a yellow oil. M+H.sup.+=340.2 (LCMS).

Step 2: (S)-5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-fluorobenzoic acid (427A-3)

[2085] To a solution of tert-butyl(S)-2-((4-fluoro-3-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (950 mg, 2.80 mmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 5.60 mL, 4.0 eq). The mixture was stirred at 70 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue. The residue was diluted with HCl (2 M aqueous) (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-fluorobenzoic acid (650 mg) as a yellow solid. M+H.sup.+=326.1 (LCMS).

Step 3: (S)-tert-Butyl 2-((4-fluoro-3-((1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (427A-4)

[2086] To a solution of(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-fluorobenzoic acid (50.0 mg, 154 mol, 1.0 eq) and 1-(7-methoxy-2-methylquinolin-5-yl)cyclopropanamine (35.1 mg, 154 mol, 1.0 eq) in DMF (1.0 mL) were added HATU (87.7 mg, 230 mol, 1.5 eq) and DIEA (59.6 mg, 461 mol, 80.3 L, 3.0 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was diluted with H.sub.2O (2.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were washed with brine (2.0 mL3), and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (S)-tert-Butyl 2-((4-fluoro-3-((1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (25.0 mg, 46.7 mol, 30% yield) was obtained as a yellow solid. M+H.sup.+=536.4 (LCMS).

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-2-fluoro-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)benzamide (427A-5)

[2087] To a solution of tert-butyl(25)-2-[4-fluoro-3-[1-(7-methoxy-2-methyl-5-quinolyl)cyclopropyl]carbamoyl]phenoxy]methyl]azetidine-1-carboxylate (30.0 mg, 56.0 mol, 1.0 eq) in DCM (1.0 mL) was added TFA (63.9 mg, 560 mol, 41.5 L, 10 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give(S)-5-(azetidin-2-ylmethoxy)-2-fluoro-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)benzamide (30.0 mg, TFA salt) as a yellow oil M+H.sup.+=436.2 (LCMS).

Step 5: 2-Fluoro-N-[1-(7-methoxy-2-methyl-5-quinolyl)cyclopropyl]-5-[[(2S)-1-methylazetidin-2-yl]methoxy]benzamide (Compound 791)

[2088] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-fluoro-N-(1-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl)benzamide (30.0 mg, 54.6 mol, 1.0 eq, TFA salt) and HCHO (8.86 mg, 109 mol, 8.13 L, 37% purity in H.sub.2O, 2.0 eq) in MeOH (1.0 mL) was added TEA (5.52 mg, 54.6 mol, 7.60 L, 1.0 eq) to adjust the pH to 8, then AcOH (3.28 mg, 54.6 mol, 3.12 L, 1.0 eq) was added to adjust the pH to 5. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (10.3 mg, 164 mol, 3.0 eq) was added, and the resulting mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Fluoro-N-[1-(7-methoxy-2-methyl-5-quinolyl)cyclopropyl]-5-[(2S)-1-methylazetidin-2-yl]methoxy]benzamide (7.60 mg, 15.5 mol, 28% yield, HCl salt) was obtained as a pale yellow gum. M+H.sup.+=450.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.10 (br s, 1H), 9.60-9.41 (m, 2H), 7.84 (br d, J=8.6 Hz, 1H), 7.76-7.61 (m, 2H), 7.21-7.15 (m, 1H), 7.13-7.06 (m, 1H), 7.06-7.01 (m, 1H), 4.70-4.59 (m, 1H), 4.50-4.40 (m, 1H), 4.25 (br dd, J=2.6, 11.0 Hz, 1H), 3.99 (s, 4H), 3.88-3.80 (m, 1H), 2.93 (s, 3H), 2.80 (br d, J=4.8 Hz, 3H), 2.38-2.26 (m, 2H), 1.42 (br s, 2H), 1.30 (br s, 2H).

Example 428: (S)N-(1-(7-Methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 817)

##STR01280##

Step 1: 5-Bromo-7-methoxyquinoline 1-oxide (428A-1)

[2089] To a solution of 5-bromo-7-methoxyquinoline (600 mg, 2.52 mmol, 1.0 eq) in DCM (10 mL) was added m-CPBA (665 mg, 3.28 mmol, 1.3 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with HCl (2 M aqueous, 10 mL) and extracted with DCM (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give 5-bromo-7-methoxyquinoline 1-oxide (650 mg, crude) as a yellow solid. M+H.sup.+=254.1/256.1 (LCMS).

Step 2: 5-Bromo-7-methoxy-2-(trifluoromethyl)quinoline (428A-2)

[2090] To a solution of 5-bromo-7-methoxyquinoline 1-oxide (650 mg, 2.56 mmol, 1.0 eq) in THF (10 mL) were added CsF (388 mg, 2.56 mmol, 1.0 eq) and TMSCF.sub.3 (1.46 g, 10.2 mmol, 4.0 eq) at 0 C. The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 5-Bromo-7-methoxy-2-(trifluoromethyl)quinoline (360 mg, 1.18 mmol, 45% yield) was obtained as a yellow solid. M+H.sup.+=306.1/308.1 (LCMS).

Step 3: 7-Methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (428A-3)

[2091] To a solution of 5-bromo-7-methoxy-2-(trifluoromethyl)quinoline (180 mg, 588 mol, 1.0 eq) in DMF (3.0 mL) were added Zn(CN).sub.2 (250 mg, 2.13 mmol, 3.6 eq) and Pd(PPh.sub.3).sub.4 (67.9 mg, 58.8 mol, 0.10 eq). The resulting mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 7-Methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (130 mg, 515 mol, 87% yield) was obtained as a yellow solid. M+H.sup.+=253.1 (LCMS).

Step 4: 1-(7-Methoxy-2-(trifluoromethyl)quinoline-5-yl)cyclopropan-1-amine (428A-4)

[2092] A solution of 7-methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (150 mg, 594 mol, 1.0 eq) in anhydrous Et.sub.2O (50 mL) was degassed and purged with N.sub.2 three times, The mixture was stirred with a mechanical stirrer at 78 C. To this mixture was added Ti(i-PrO).sub.4 (185 mg, 654 mol, 193 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 436 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (84.0 mg, 594 mol, 73.4 L, 1.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HCl (1 M aqueous, 5.0 mL) and MTBE (10 mL) and extracted with MTBE (10 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous) and extracted with DCM (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3 to give 1-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropan-1-amine (30.0 mg, 106 mol, 87% yield) as a yellow oil. M+H.sup.+=283.1 (LCMS).

Step 5: (S)N-(1-(7-Methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 817)

[2093] To a solution of 1-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropan-1-amine (20.0 mg, 70.8 mol, 1.0 eq) in DMF (2.0 mL) were added(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (16.6 mg, 70.8 mol, 1.0 eq), HATU (40.4 mg, 106 mol, 1.5 eq), and DIEA (27.4 mg, 212 mol, 37.0 L, 3.0 eq). The resulting mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 60 mL/min; gradient: 25%-55% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to give(S)N-(1-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (4.90 mg, 9.10 mol, 12% yield) as a white solid. M+H.sup.+=500.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.01-9.81 (m, 1H), 9.27-9.18 (m, 2H), 7.88 (d, J=8.7 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.49 (d, J=2.3 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.22 (d, J=5.3 Hz, 2H), 3.97 (s, 3H), 3.91-3.78 (m, 2H), 2.83 (d, J=5.0 Hz, 2H), 2.43-2.27 (m, 3H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.28-1.23 (m, 2H).

Example 429: (S)N-(1-(7-Hydroxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 809)

##STR01281##

Step 1: 5-(1-Aminocyclopropyl)-2-methylquinolin-7-ol (429A-1)

[2094] To a solution of 1-(7-methoxy-2-methylquinolin-5-yl)cyclopropan-1-amine (1.40 g, 6.13 mmol, 1.0 eq) in DCM (60 mL) was added a solution of BBr.sub.3 (23.0 g, 92.0 mmol, 8.86 mL, 15 eq) in DCM (10 mL) dropwise at 78 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at the same temperature for 2 h, then warmed to 20 C. and stirred another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with MeOH (20 mL) at 0 C. and treated with NH.sub.3H.sub.2O to adjust the pH 8. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1, followed by DCM/MeOH from 100/1 to 10/1. 5-(1-Aminocyclopropyl)-2-methylquinolin-7-ol (1.40 g, 6.53 mmol, crude) was obtained as a yellow solid. M+H.sup.+=215.1 (LCMS).

Step 2: (S)N-(1-(7-Hydroxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 809)

[2095] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (150 mg, 638 mol, 1.0 eq) and 5-(1-aminocyclopropyl)-2-methylquinolin-7-ol (137 mg, 638 mol, 1.0 eq) in DMF (10 mL) were added HATU (170 mg, 446 mol, 0.7 eq) and DIEA (82.4 mg, 638 mol, 111 L, 1.0 eq). The mixture was stirred at 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(1-(7-Hydroxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 147 mol, 23% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=432.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.40 (br d, J=8.5 Hz, 1H), 9.23-9.17 (m, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.31 (d, J=1.9 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.99-6.90 (m, 1H), 6.80-6.73 (m, 1H), 4.68-4.56 (m, 1H), 4.23 (d, J=5.3 Hz, 2H), 4.08-3.99 (m, 1H), 3.92-3.81 (m, 1H), 2.84 (d, J=3.1 Hz, 6H), 2.44-2.28 (m, 2H), 2.00-1.91 (m, 3H), 1.38 (br s, 2H), 1.29-1.12 (m, 2H).

Example 430: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 795)

##STR01282##

Step 1: (S)-tert-Butyl 2-((3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (430A-1)

[2096] To a mixture of 5-(1-aminocyclopropyl)quinolin-7-ol (300 mg, 1.50 mmol, 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (337 mg, 1.05 mmol, 0.7 eq) in DMF (5.0 mL) were added DIEA (194 mg, 1.50 mmol, 261 L, 1.0 eq) and HATU (399 mg, 1.05 mmol, 0.7 eq). The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL8). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum ether/EtOAc from 1/0 to 0/1. (S)-tert-Butyl 2-((3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (450 mg, 894 mol, 60% yield) was obtained as a yellow solid. M+H.sup.+=504.2 (LCMS).

Step 2: tert-Butyl(S)-2-((4-Methyl-3-((1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (430A-2)

[2097] To a mixture of tert-butyl(S)-2-((3-((1-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (200 mg, 397 mol, 1.0 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (92.2 mg, 397 mol, 1.0 eq) in DMF (10 mL) was added K.sub.2CO.sub.3 (110 mg, 794 mol, 2.0 eq). The mixture was degassed and purged with N.sub.2 three times, and the resulting mixture was stirred at 20 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum ether/EtOAc from 1/0 to 2/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2,2,2-trifluoroethoxy)quinolin-5yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-1-carboxylate (100 mg, 171 mol, 43% yield) was obtained as a white solid. M+H.sup.+=586.4 (LCMS).

Step 3: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (430A-3)

[2098] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(2,2,2-trifluoroethoxy)quinolin-5yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (100 mg, 171 mol, 43% yield) in DCM (5.0 mL) was added TFA (195 mg, 1.71 mmol, 126 L, 10 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (80 mg, crude, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=486.4 (LCMS)

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 795)

[2099] To a solution of(S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2,2,2-trifluoroethoxy) quinolin-5-yl)cyclopropyl)benzamide (80.0 mg, crude, TFA salt) in MeOH (5.0 mL) was added TEA (50.0 L), followed by formaldehyde (27.0 mg, 330 mol, 24.5 L, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (20.7 mg, 330 mol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H.sub.2O (5.0 mL) and extracted with DCM (1.0 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 40 mm, 5 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (23.7 mg, 23% yield, TFA salt) was obtained as a white solid. M+H.sup.+=500.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.94-9.82 (m, 1H), 9.20-9.12 (m, 1H), 9.03 (d, J=8.6 Hz, 1H), 8.90 (dd, J=1.3, 4.2 Hz, 1H), 7.59-7.50 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.98 (q, J=8.8 Hz, 2H), 4.64-4.57 (m, 1H), 4.25-4.20 (m, 2H), 4.07-4.00 (m, 1H), 3.87 (br dd, J=6.3, 9.8 Hz, 1H), 2.84 (d, J=5.0 Hz, 3H), 2.41-2.30 (m, 2H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.25 (br s, 2H).

Example 431: (S)-2-Methyl-N-(1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 815)

##STR01283##

Step 1: (3,3,3-Trifluoropropyl) zinc (II) iodide (431A-2)

[2100] To a solution of Zinc powder (876 mg, 13.4 mmol, 3.0 eq) in THF (3.0 mL) was added 1,2-dibromoethane (178 mg, 939 mol, 71.7 L, 0.21 eq). The mixture was stirred at 70 C. for 10 min under a N.sub.2 atmosphere, then cooled to 25 C., and TMSCl (28.3 mg, 260 mol, 33.0 L, 0.06 eq) was added. The mixture was stirred at 25 C. for 10 min. A solution of 1,1,1-trifluoro-3-iodopropane (1.00 g, 4.47 mmol, 524 L, 1.0 eq) in THF (2.0 mL) was added dropwise. The mixture was stirred at 25 C. until the reaction mixture turned gray. The mixture was used in the next step without any further purification.

Step 2: 5-(1-Aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (431A-3)

[2101] To a solution of 5-(1-aminocyclopropyl)-2-methylquinolin-7-ol (1.40 g, 6.53 mmol, 1.0 eq) in THF (60 mL) was added t-BuOK (1.47 g, 13.1 mmol, 2.0 eq) at 0 C. under a N.sub.2 atmosphere. The mixture was stirred at 0 C. for 15 min. 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (4.67 g, 13.1 mmol, 2.0 eq) was added in portions. The resulting reaction mixture was stirred at 20 C. for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-(1-Aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (850 mg, 2.45 mmol, 53% yield) was obtained as a yellow oil. M+H.sup.+=333.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.88 (d, J=8.8 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.63-7.57 (m, 2H), 2.76 (s, 3H), 1.25 (d, J=7.3 Hz, 2H), 1.07-1.03 (m, 2H).

Step 3: tert-Butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (431A-4)

[2102] To a solution of 5-(1-aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (850 mg, 2.45 mmol 1.0 eq) and(S)-5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (789 mg, 2.45 mmol, 1.0 eq) in DMF (20 mL) were added DIEA (952 mg, 7.36 mmol, 1.28 mL, 3.0 eq) and HATU (2.33 g, 6.14 mmol, 2.5 eq). The mixture was stirred at 20 C. for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (30 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. tert-Butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (1.30 g, 2.00 mmol, 82% yield) was obtained as a yellow gum. M+H.sup.+=650.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20 (s, 1H), 9.01 (d, J=8.7 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.6 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.89 (dd, J=2.7, 8.3 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.44-4.32 (m, 1H), 4.15 (dd, J=4.8, 10.3 Hz, 1H), 4.01-3.96 (m, 1H), 3.74 (br d, J=5.7 Hz, 2H), 2.70 (s, 3H), 2.30-2.24 (m, 1H), 2.10-2.03 (m, 1H), 1.94 (s, 3H), 1.42-1.26 (m, 13H).

Step 4: tert-Butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (431A-5)

[2103] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(((trifluoromethyl) sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 231 mol, 1.0 eq) and (3,3,3-trifluoropropyl) zinc (II) iodide (1 M, 693 L, 3.0 eq) in DMA (8.0 mL) were added Pd(C.sub.6H.sub.5CN).sub.2Cl.sub.2 (4.43 mg, 11.5 mol, 0.05 eq) and MePhos (8.42 mg, 23.1 mol, 0.1 eq). The mixture was stirred at 60 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL), and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (120 mg, 200 mol) was obtained as a brown oil. M+H.sup.+=598.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.06 (s, 1H), 8.92 (d, J=8.8 Hz, 1H), 7.72 (d, J=4.0 Hz, 2H), 7.42 (d, J=8.6 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.87 (dd, J=2.5, 8.4 Hz, 1H), 6.64 (d, J=2.5 Hz, 1H), 4.43-4.33 (m, 1H), 4.14 (dd, J=4.7, 9.9 Hz, 1H), 4.02-3.95 (m, 1H), 3.78-3.67 (m, 2H), 3.06-2.99 (m, 2H), 2.73-2.68 (m, 2H), 2.30-2.22 (m, 1H), 2.12-2.04 (m, 1H), 1.36-1.27 (m, 11H), 1.20 (br d, J=4.1 Hz, 2H).

Step 5: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)benzamide (431A-6)

[2104] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (110 mg, 184 mol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.0 mL, 73.4 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 20 C. to give the crude(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(2-methyl-7-(3,3,3-trifluoro propyl)quinolin-5-yl)cyclopropyl)benzamide (110 mg, 180 mol, TFA salt) as a brown oil. M+H.sup.+=498.2 (LCMS).

Step 6: (S)-2-Methyl-N-(1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 815)

[2105] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)benzamide (110 mg, 180 mol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (0.1 mL), followed by formaldehyde (110 mg, 1.36 mmol, 101 L, 37% purity in water, 7.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (33.9 mg, 540 mol, 3.0 eq) was added. The reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was diluted with saturated aqueous NaHCO.sub.3 (100 L) and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-N-(1-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (50.1 mg, 97.2 mol, 54% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=512.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.50-11.21 (m, 1H), 9.74-9.61 (m, 1H), 9.45-9.33 (m, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 8.02 (br d, J=8.8 Hz, 1H), 7.12-7.06 (m, 1H), 6.98-6.89 (m, 1H), 6.84-6.73 (m, 1H), 4.70-4.55 (m, 1H), 4.47 (dd, J=8.5, 11.0 Hz, 1H), 4.34-4.19 (m, 1H), 4.02-3.93 (m, 1H), 3.90-3.81 (m, 1H), 3.19-3.12 (m, 2H), 2.99 (s, 3H), 2.83-2.67 (m, 5H), 2.41-2.24 (m, 2H), 1.97 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 432: (S)N-(1-(7-Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (Compound 648)

##STR01284##

Step 1: (S)N-(1-(7-Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 648)

[2106] To a solution of(S)N-(1-(7-(cyclopent-1-en-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (90.0 mg, 192 mol, 1.0 eq) in EtOH (10 mL) was added 10% palladium on carbon (90.0 mg) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The resulting mixture was stirred at 20 C. for 16 h under a H.sub.2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the pad was washed with EtOH (5.0 mL3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (3.00 mg, 5.99 mol, 3% yield, HCl salt) was obtained as a white solid. M+H.sup.+=570.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.12-9.95 (m, 1H), 9.16-9.12 (m, 1H), 9.05-8.88 (m, 1H), 7.89 (s, 1H), 7.85-7.80 (m, 1H), 7.73-7.60 (m, 1H), 7.13-7.05 (m, 1H), 6.98-6.86 (m, 1H), 6.68 (s, 1H), 4.78-4.44 (m, 1H), 4.24 (br d, J=7.7 Hz, 2H), 4.07-3.92 (m, 1H), 3.91-3.70 (m, 1H), 2.84-2.82 (m, 2H), 2.64-2.59 (m, 2H), 2.16-2.11 (m, 2H), 2.09-2.07 (m, 2H), 2.00-1.96 (m, 3H), 1.88-1.81 (m, 2H), 1.75-1.64 (m, 4H), 1.43-1.33 (m, 2H), 1.24 (br s, 2H).

Example 433: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 683)

##STR01285##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (433A-1)

[2107] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (100 mg, 157 mol, 1.0 eq) and pyrrolidine (13.4 mg, 189 mol, 15.8 L, 1.2 eq) in 2-methylbutan-2-ol (2.0 mL) were added Cs.sub.2CO.sub.3 (103 mg, 315 mol, 2.0 eq) and XPhos Pd G3 (66.6 mg, 78.7 mol, 0.5 eq) at 20 C. The mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 75.5 mol, 48% yield) was obtained as a yellow oil. M+H.sup.+=557.4 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)benzamide (433A-2)

[2108] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 269 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.0 mL, 50 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (170 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=457.3 (LCMS).

Step 3: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 683)

[2109] To solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidin-1-a ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (150 mg, 328 mol, 1.0 eq) in MeOH (2.0 mL) were added HOAc (1.85 mg, 30.0 mol, 1.76 L, 0.1 eq) and formaldehyde (37.4 mg, 461 mol, 34.4 L, 37% purity in H.sub.2O, 1.5 eq) at 20 C. for 1 h. Then NaBH.sub.3CN (48.3 mg, 768 mol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC ((Phenomenex Gemini C18 column (15040 mm, 10 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 10 mM aqueous NH.sub.4HCO.sub.3, mobile phase B: acetonitrile)). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyrrolidin-1-yl)quinolin-5-yl)cyclopropyl)benzamide (3.00 mg, 6.37 mol, 2% yield) was obtained as a white solid. M+H.sup.+=471.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.07-9.00 (m, 1H), 8.75-8.83 (m, 1H), 8.64 (m, 1H), 7.38 (m, 1H), 7.15 (m, 1H), 6.98-7.06 (m, 1H), 6.83 (m, 1H), 6.75 (m, 1H), 6.59 (m, 1H), 3.82-3.90 (m, 2H), 3.40 (m, 4H), 3.17-3.25 (m, 3H), 2.69-2.76 (m, 1H), 2.17-2.24 (m, 3H), 1.91-2.05 (m, 8H), 1.80-1.89 (m, 1H), 1.29-1.38 (m, 2H), 1.12-1.21 (m, 2H).

Example 434: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 630)

##STR01286##

Step 1: 5-(1-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (434A-1)

[2110] To a solution of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 602 mol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (186 mg, 602 mol, 1.0 eq) in DMF (5.0 mL) were added DIEA (233 mg, 1.81 mmol, 315 L, 3.0 eq) and HATU (572 mg, 1.50 mmol, 2.5 eq). The mixture was stirred at 20 C. for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. 5-(1-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethane sulfonate (260 mg, 417 mol, 69% yield) was obtained as a brown oil. M+H.sup.+=624.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22 (s, 1H), 9.14 (br d, J=8.6 Hz, 1H), 9.08-9.01 (m, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.73 (dd, J=4.1, 8.6 Hz, 1H), 7.04 (br d, J=8.4 Hz, 1H), 6.85 (dd, J=2.5, 8.4 Hz, 1H), 6.63 (br s, 1H), 3.98 (br t, J=5.8 Hz, 2H), 3.46 (br t, J=5.6 Hz, 2H), 2.86-2.74 (m, 3H), 1.93 (s, 3H), 1.44-1.23 (m, 13H).

Step 2: tert-Butyl methyl(2-(4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (434A-2)

[2111] To a solution of 5-(1-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 320.70 mol, 1.0 eq) and thiophen-2-ylboronic acid (82.1 mg, 641 mol, 2.0 eq) in DMSO (5.0 mL) were added KOAc (94.4 mg, 962 mol, 3.0 eq), Pd(OAc).sub.2 (14.4 mg, 64.1 mol, 0.2 eq) and cataCxium A (46.0 mg, 128 mol, 0.4 eq). The mixture was degassed and purged with N.sub.2 three times, and the mixture was stirred at 80 C. for 15 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. tert-Butyl methyl(2-(4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (180 mg, 323 mol, crude) was obtained as a brown oil. M+H.sup.+=558.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.15 (s, 1H), 9.04 (br d, J=8.5 Hz, 1H), 8.92 (br d, J=3.4 Hz, 1H), 8.15 (s, 2H), 7.78 (d, J=3.3 Hz, 1H), 7.68 (d, J=5.0 Hz, 1H), 7.56 (dd, J=4.1, 8.5 Hz, 1H), 7.31-7.17 (m, 1H), 7.04 (br d, J=8.3 Hz, 1H), 6.84 (dd, J=2.3, 8.3 Hz, 1H), 6.61 (br s, 1H), 4.00-3.91 (m, 2H), 3.46 (br t, J=5.5 Hz, 2H), 2.81 (br d, J=8.0 Hz, 3H), 1.96 (s, 3H), 1.49-1.25 (m, 13H).

Step 3: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 630)

[2112] To a solution tert-butyl methyl(2-(4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (180 mg, 323 mol, 1.0 eq) in EtOH (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (70.1 mg, 141 mol, 44% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=458.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.46 (br d, J=8.4 Hz, 1H), 9.33 (s, 1H), 9.15 (d, J=4.0 Hz, 1H), 8.97 (br d, J=3.5 Hz, 2H), 8.33 (d, J=5.8 Hz, 2H), 7.94-7.84 (m, 2H), 7.79 (d, J=4.5 Hz, 1H), 7.29 (dd, J=3.8, 5.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.4 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.17 (t, J=5.0 Hz, 2H), 3.26-3.21 (m, 2H), 2.59-2.55 (m, 3H), 1.98 (s, 3H), 1.44 (br s, 2H), 1.38 (br s, 2H).

Example 435: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 608)

##STR01287##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (435A-1)

[2113] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 315 mol, 1.0 eq) and thiophen-2-ylboronic acid (80.5 mg, 629 mol, 2.0 eq) in DMSO (5.0 mL) were added KOAc (92.6 mg, 944 mol, 3.0 eq), Pd(OAc).sub.2 (14.1 mg, 62.9 mol, 0.2 eq) and cataCxium A (45.1 mg, 126 mol, 0.4 eq). The resulting mixture was stirred at 80 C. for 13 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (30 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl(S)-2-((4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (400 mg) as a brown oil, which was used in the next step without any further purification. M+H.sup.+=570.3 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 608)

[2114] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 263 mol, 1.0 eq) in DCM (1.5 mL) was added TFA (540 mg, 4.74 mmol, 351 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 30 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (74.3 mg, 127 mol, 48% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=470.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.18 (s, 1H), 9.09 (d, J=8.8 Hz, 1H), 8.96 (dd, J=1.4, 4.1 Hz, 1H), 8.89-8.66 (m, 2H), 8.18 (d, J=2.0 Hz, 2H), 7.86-7.77 (m, 1H), 7.71 (d, J=5.1 Hz, 1H), 7.62 (dd, J=4.3, 8.5 Hz, 1H), 7.25 (dd, J=3.8, 4.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.3 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.70-4.68 (m, 1H), 4.68-4.62 (m, 1H), 4.23 (dd, J=7.1, 11.1 Hz, 1H), 4.16-4.10 (m, 1H), 3.95-3.80 (m, 2H), 2.45-2.27 (m, 2H), 1.98 (s, 3H), 1.40 (br s, 2H), 1.33 (br s, 2H).

Example 436: (S)N-(1-(7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 753)

##STR01288##

Step 1: (S)N-(1-(7-(5-Formylthiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (436A-1)

[2115] A mixture of(S)-5-(1-(2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl) quinolin-7-yltrifluoromethanesulfonate (250 mg, 455 mol, 1.0 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (142 mg, 910 mol, 2.0 eq), KOAc (134 mg, 1.36 mmol, 3.0 eq), cataCxium A (32.6 mg, 91.0 mol, 0.2 eq) and Pd(OAc).sub.2 (10.2 mg, 45.5 mol, 0.1 eq) in DMSO (5.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (S)N-(1-(7-(5-Formylthiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (230 mg, 450 mol, 99% yield) was obtained as a yellow solid. M+H.sup.+=512.3 (LCMS).

Step 2: (S)N-(1-(7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 753)

[2116] To a stirred solution of(S)N-(1-(7-(5-formylthiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (40.0 mg, 78.2 mol, 1.0 eq) in MeOH (2.0 mL) was added NaBH.sub.4 (5.92 mg, 156 mol, 2.0 eq). The reaction mixture was stirred at 25 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (2.0 mL) and extracted with EtOAc (2.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (19.0 mg, 33.1 mol, 42% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=514.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.50-10.21 (m, 1H), 9.45-9.20 (m, 2H), 9.13-8.96 (m, 1H), 8.32-8.17 (m, 2H), 7.85-7.63 (m, 2H), 7.15-7.03 (m, 2H), 7.00-6.91 (m, 1H), 6.92-6.89 (m, 1H), 6.75-6.71 (m, 1H), 4.74-4.68 (m, 2H), 4.64-4.61 (m, 1H), 4.65-4.58 (m, 1H), 4.32-4.17 (m, 2H), 4.06-3.98 (m, 1H), 3.88-3.82 (m, 1H), 2.83-2.75 (m, 3H), 2.36-2.28 (m, 2H), 2.01-1.94 (m, 4H), 1.47-1.34 (m, 4H), 1.29-1.21 (m, 2H).

Example 437: 2-Methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 780)

##STR01289##

Step 1: tert-Butyl(S)-2-((3-((1-(7-(5-acetylthiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (437A-1)

[2117] A mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (100 mg, 157 mol, 1.0 eq), (5-acetyl-2-thienyl) boronic acid (53.5 mg, 314 mol, 2.0 eq), Pd(OAc).sub.2 (10.6 mg, 47.2 mol, 0.3 eq), KOAc (46.3 mg, 471 mol, 3.0 eq) and bis(1-adamantyl)-butyl-phosphane (11.3 mg, 31.5 mol, 0.2 eq) in DMSO (2.0 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenyl) ethynyl)azetidine-1-carboxylate (130 mg) was obtained as a colorless oil. M+H.sup.+=612.3 (LCMS).

Step 2: tert-Butyl(2S)-2-((4-methyl-3-((1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (437A-2)

[2118] To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenyl) ethynyl)azetidine-1-carboxylate (130 mg, 212 mol, 1.0 eq) in EtOH (1.0 mL) were added tetraisopropoxytitanium (603 mg, 2.13 mmol, 627 L, 10 eq) and pyrrolidine (75.6 mg, 1.06 mmol, 8.7 L, 5.0 eq). The mixture was stirred at 40 C. for 12 h. The reaction mixture was allowed to cool to room temperature, then NaBH.sub.4 (120 mg, 3.19 mmol, 15 eq) was added to the mixture. The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 40 mm, 5 m); flow rate: 25 mL/min; gradient: 30%-60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). tert-Butyl(2S)-2-((4-methyl-3-((1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (20.0 mg, 22.2 mol, 10% yield, TFA salt) was obtained as a white solid. M+H.sup.+=667.5 (LCMS).

Step 3: 5-(((S)-Azetidin-2-yl)methoxy)-2-methyl-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (437A-3)

[2119] To a solution of tert-butyl(25)-2-((4-methyl-3-((1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (20.0 mg, 29.9 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (86.6 mg, 759 mol, 56.3 L, 25 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product 5-(((S)-azetidin-2-yl)methoxy)-2-methyl-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (20.0 mg, TFA salt) as a colorless oil. M100+H.sup.+=567.3 (LCMS).

Step 4: 2-Methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 780)

[2120] To a of 5-(((S)-azetidin-2-yl)methoxy)-2-methyl-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (20.0 mg, 35.3 mol, 1.0 eq) in MeOH (2.0 mL) were added HOAc (211 g, 3.53 mol, 0.1 eq) and formaldehyde (4.30 mg, 52.9 mol, 3.94 L, 37% purity in H.sub.2O, 1.5 eq) at 20 C. for 1 h. Then NaBH.sub.3CN (5.54 mg, 8.2 mol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.04% HCl, mobile phase B: acetonitrile). 2-Methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (8.20 mg, 12.5 mol, 35% yield, 2 HCl salt) was obtained as a white solid. M+H.sup.+=581.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.55-11.40 (m, 1H), 10.89-10.73 (m, 1H), 9.51-9.28 (m, 2H), 9.13 (m, 1H), 8.43-8.24 (m, 2H), 7.93-7.82 (m, 2H), 7.56 (m, 1H), 7.14-7.06 (m, 1H), 6.96-6.87 (m, 1H), 6.74 (m, 1H), 4.96-4.84 (m, 1H), 4.71-4.57 (m, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 4.03-3.94 (m, 2H), 3.90-3.84 (m, 2H), 3.00-3.07 (m, 4H), 2.80 (m, 3H), 2.67 (m, 1H), 2.37-2.25 (m, 2H), 1.96 (m, 4H), 1.78 (m, 3H), 1.50-1.30 (m, 4H).

Example 438: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 669)

##STR01290##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (438A-1)

[2121] A mixture of 5-(1-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 314 mol, 1.0 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (58.9 mg, 377 mol, 1.2 eq), di(1-adamantyl)-N-butylphosphine hydroiodide (22.6 mg, 63.0 mol, 0.2 eq), Pd(OAc) 2 (7.10 mg, 31.0 mol, 0.1 eq) and KOAc (93.0 mg, 94.0 mol, 3.0 eq) in DMSO (3.0 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction was allowed to cool to room temperature. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 231 mol, 74% yield) was obtained as a white solid. M+H.sup.+=598.4 (LCMS).

Step 2: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (438A-2)

[2122] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 251 mol, 1.0 eq) in MeOH (2.0 mL) was added HOAc (1.51 mg, 25.0 mol, 1.44 L, 0.1 eq), pyrrolidine (26.8 mg, 376 mol, 31.0 L, 1.5 eq) at 20 C. for 1 h. Then NaBH.sub.3CN (39.4 mg, 627 mol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 0/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (160 mg, 237 mol, 95% yield) was obtained as a yellow oil. M+H.sup.+=653.4 (LCMS).

Step 3: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (438A-3)

[2123] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (160 mg, 245 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (708 mg, 6.21 mmol, 459 L, 25 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (170 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=553.4 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 669)

[2124] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (170 mg, 307 mol, 1.0 eq) in MeOH (2.0 mL) were added HOAc (1.85 mg, 30.0 mol, 1.76 L, 0.1 eq) and formaldehyde (37.4 mg, 461 mol, 34.4 L, 37% purity in H.sub.2O, 1.5 eq) at 20 C. for 1 h. Then NaBH.sub.3CN (48.3 mg, 768 mol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (64.5 mg, 94.8 mol, 31% yield, 2 HCl salt) was obtained as a yellow solid. M+H.sup.+=567.4 (LCMS); 1H NMR (400 MHZ, DMSO-d.sub.6) 11.26-11.11 (m, 1H), 11.07-10.87 (m, 1H), 9.60-9.41 (m, 1H), 9.36 (m, 1H), 9.16 (m, 1H), 8.40 (m, 1H), 8.32 (m, 1H), 7.94-7.88 (m, 1H), 7.87 (m, 1H), 7.54 (m, 1H), 7.09 (m, 1H), 6.92 (m, 1H), 6.75 (m, 1H), 4.66 (m, 3H), 4.40 (m, 1H), 4.25-4.18 (m, 1H), 4.05-3.93 (m, 1H), 3.89-3.77 (m, 1H), 3.50-3.38 (m, 2H), 3.18-3.06 (m, 2H), 2.80 (m, 3H), 2.37-2.24 (m, 2H), 2.03 (m, 2H), 1.97 (m, 3H), 1.94-1.87 (m, 2H), 1.48-1.43 (m, 2H), 1.40-1.35 (m, 2H).

Example 439: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 767)

##STR01291##

Step 1: tert-Butyl(S)-2-((3-((1-(7-(5-(methoxycarbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (439A-1)

[2125] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (120 mg, 188 mol, 1.0 eq) and (5-(methoxycarbonyl)thiophen-2-yl) boronic acid (70.2 mg, 377 mol, 2.0 eq) in DMSO (2.0 mL) were added Pd(OAc).sub.2 (12.7 mg, 56.6 mol, 0.30 eq), KOAc (55.6 mg, 566 mol, 3.0 eq) and bis(1-adamantyl)-butyl-phosphane (13.5 mg, 37.7 mol, 0.2 eq) at 20 C. and then the mixture was stirred at 80 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether 0/1 from to tert-Butyl(S)-2-((3-((1-(7-(5-1/1.(methoxycarbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (140 mg) was obtained as a yellow liquid. M+H.sup.+=628.3 (LCMS).

Step 2: (S)-5-(5-(1-(5-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl)thiophene-2-carboxylic acid (439A-2)

[2126] To a solution of tert-butyl(S)-2-((3-((1-(7-(5-(methoxycarbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (120 mg, 191 mol, 1.0 eq) in a mixture of H.sub.2O (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL) was added LiOH.Math.H.sub.2O (80.2 mg, 1.91 mmol, 10 eq). The mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with H.sub.2O (5.0 mL). The aqueous layer was adjusted to pH 6 with HCl (1 M aqueous), then extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude product(S)-5-(5-(1-(5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl)thiophene-2-carboxylic acid (92.0 mg) as a white solid. M+H.sup.+=614.3 (LCMS).

Step 3: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (439A-3)

[2127] To a solution of(S)-5-(5-(1-(5-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl)thiophene-2-carboxylic acid (92.0 mg, 149 mol, 1.0 eq) in DMF (5.0 mL) were added HATU (114 mg, 299 mol, 2.0 eq) and DIEA (58.1 mg, 449 mol, 78.33 L, 3.0 eq). The reaction mixture was stirred at 20 C. for 20 min. Then pyrrolidine (10.6 mg, 149 mol, 12.5 L, 1.0 eq) was added and the mixture was stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with EtOAc (5.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give tert-butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (99.6 mg 149 mol, 99% yield) as a brown gum. M+H.sup.+=667.4 (LCMS).

Step 4: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (439A-4)

[2128] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (99.6 mg, 149 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (70.0 mg) as a yellow gum. M+H.sup.+=567.3 (LCMS).

Step 5: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 767)

[2129] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (70.0 mg, 123 mol, 1.0 eq) in MeOH (2.0 mL) were added HOAc (1.85 mg, 30.0 mol, 1.76 L, 0.1 eq) and formaldehyde (20.0 mg, 247 mol, 18.3 L, 37% purity in H.sub.2O, 2.0 eq) at 20 C. The mixture was stirred at 20 C. for 1 h, then NaBH.sub.3CN (48.3 mg, 768 mol, 2.5 eq) was added. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (8030 mm, 3 m); flow rate: 25 mL/min; gradient: gradient: 10%-40% B over 8 min; mobile phase A: 0.04% HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (42.5 mg, 63.7 mol, 51% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=581.4 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.22 (s, 1H), 9.15 (br d, J=8.9 Hz, 1H), 9.00 (br d, J=3.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J=1.6 Hz, 1H), 7.82 (d, J=3.9 Hz, 1H), 7.75-7.63 (m, 2H), 7.10 (d, J=8.6 Hz, 1H), 6.98-6.87 (m, 1H), 6.72 (d, J=2.9 Hz, 1H), 4.66-4.51 (m, 1H), 4.31-4.18 (m, 2H), 4.06-3.95 (m, 1H), 3.90-3.77 (m, 4H), 2.82 (d, J=5.0 Hz, 3H), 2.72-2.63 (m, 1H), 2.42-2.23 (m, 2H), 1.95 (s, 5H), 1.91-1.83 (m, 2H), 1.46-1.26 (m, 4H).

Example 440: (S)N-(1-(7-(4-Chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 812)

##STR01292##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (440A-1)

[2130] To a stirred solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl) sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 315 mol, 1.0 eq) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole (106 mg, 472 mol, 1.5 eq) in a mixture of dioxane (8.0 mL) and H.sub.2O (0.8 mL) were added Na.sub.2CO.sub.3 (76.7 mg, 724 mol, 2.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (30.8 mg, 37.8 mol, 0.12 eq) in one portion. The mixture was degassed and purged with N.sub.2 three times and then stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (260 mg, 444 mol, 71% yield) was obtained as a yellow solid. M+H.sup.+=585.4 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25-9.15 (m, 1H), 8.99-8.91 (m, 1H), 8.21 (br d, J=14.6 Hz, 2H), 8.07 (s, 1H), 7.58-7.49 (m, 1H), 7.02 (s, 1H), 6.85 (s, 1H), 6.77 (br s, 1H), 4.47-4.36 (m, 1H), 4.24-4.17 (m, 1H), 4.05-3.99 (m, 1H), 3.90-3.81 (m, 2H), 2.78 (s, 3H), 2.35-2.22 (m, 2H), 2.17 (s, 3H), 1.32 (br s, 13H).

Step 2: tert-Butyl(S)-2-((3-((1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (440A-2)

[2131] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (210 mg, 360 mol, 1.0 eq) in acetonitrile (9.0 mL) was added NCS (57.0 mg, 432 mol, 1.2 eq). The mixture was stirred at 60 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/EtOAc=2/1, R.sub.f=0.4). tert-Butyl(S)-2-((3-((1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (40.0 mg, 64.6 mol, 18% yield) was obtained as a white solid. M+H.sup.+=619.4 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.19-9.11 (m, 1H), 8.97 (br d, J=2.9 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J=1.5 Hz, 1H), 7.58-7.50 (m, 1H), 7.05-7.01 (m, 1H), 6.86-6.82 (m, 1H), 6.80-6.75 (m, 1H), 4.49-4.38 (m, 1H), 4.25-4.17 (m, 1H), 4.06-3.98 (m, 1H), 3.92-3.82 (m, 2H), 2.75 (s, 3H), 2.35-2.20 (m, 2H), 2.16 (s, 3H), 1.33 (br s, 13H).

Step 3: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (440A-3)

[2132] To a solution of tert-butyl(S)-2-((3-((1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (80.0 mg, 130 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (221 mg, 1.04 mmol, 142 L, 15 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (80.0 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=519.3 (LCMS).

Step 4: (S)N-(1-(7-(4-Chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 812)

[2133] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (80.0 mg, 126 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (100 L), followed by formaldehyde (7.69 mg, 94.8 mol, 7.06 L, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (7.94 mg, 126 mol, 2.0 eq) was added. The resulting mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(4-Chloro-2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (30.0 mg, 51.4 mol, 41% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=533.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.33 (br d, J=8.1 Hz, 1H), 9.26 (s, 1H), 9.10 (d, J=3.4 Hz, 1H), 8.34 (d, J=0.9 Hz, 1H), 8.21 (d, J=1.5 Hz, 1H), 7.84 (dd, J=4.6, 8.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.7, 8.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.61 (br dd, J=3.0, 7.3 Hz, 1H), 4.34-4.18 (m, 2H), 4.01 (dt, J=4.5, 9.5 Hz, 1H), 3.86 (q, J=9.7 Hz, 1H), 2.82 (s, 3H), 2.75-2.69 (m, 3H), 2.43-2.25 (m, 2H), 1.97 (s, 3H), 1.43 (br s, 2H), 1.30 (br s, 2H).

Example 441: (S)N-(1-(8-Chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 814)

##STR01293##

Step 1: tert-Butyl(S)-2-((3-((1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (441A-1)

[2134] To a mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (210 mg, 360 mol, 1.0 eq) in acetonitrile (9.0 mL) was added NCS (57.0 mg, 432 mol, 1.2 eq). The mixture was stirred at 60 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL), and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/EtOAc=2/1, R.sub.f=0.4). tert-Butyl(S)-2-((3-((1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (100 mg, 161 mol, 45% yield) was obtained as a yellow solid. M+H.sup.+=619.3 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.21-9.15 (m, 1H), 9.13-9.07 (m, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.63-7.53 (m, 1H), 7.06-6.98 (m, 1H), 6.86-6.82 (m, 1H), 6.77-6.74 (m, 1H), 4.47-4.38 (m, 1H), 4.25-4.16 (m, 1H), 4.05-3.99 (m, 1H), 3.91-3.82 (m, 2H), 2.80 (s, 3H), 2.16 (s, 3H), 1.45 (br s, 13H).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (441A-2)

[2135] To a solution of tert-butyl(S)-2-((3-((1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-1-carboxylate (140 mg, 226 mol, 1.0 eq) in DCM (4.0 mL) was added TFA (251 L). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 C. to give(S)-5-(azetidin-2-ylmethoxy)-N-(1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (140 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=519.2 (LCMS).

Step 3: (S)N-(1-(8-Chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 814)

[2136] To a solution of(S)-5-(azetidin-2-ylmethoxy)-N-(1-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (140 mg, 221 mol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (200 L), followed by formaldehyde (27.0 mg, 332 mol, 24.9 L, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBH.sub.3CN (28.0 mg, 442 mol, 2.0 eq) was added. The reaction mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (20 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 30 mm, 3 m); flow rate: 25 mL/min; gradient: 15%-45% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(8-Chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (46.4 mg, 81.5 mol, 37% yield, HCl salt) was obtained as a green solid. M+H.sup.+=533.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.27-9.18 (m, 1H), 9.12-9.02 (m, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J=4.2, 8.5 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.72 (d, J=2.7 Hz, 1H), 4.63 (dq, J=2.9, 8.5 Hz, 1H), 4.36 (br dd, J=8.0, 11.3 Hz, 1H), 4.20 (br dd, J=3.1, 11.2 Hz, 1H), 3.99 (td, J=4.8, 9.5 Hz, 1H), 3.89-3.85 (m, 1H), 2.82-2.66 (m, 6H), 2.39-2.25 (m, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.34 (br s, 2H).

Example 442: (S)-2-Methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 782)

##STR01294##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (442A-1)

[2137] To a stirred solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 236 mol, 1.0 eq) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (98.7 mg, 472 mol, 2.0 eq) in a mixture of dioxane (5.0 mL) and H.sub.2O (0.5 mL) were added Na.sub.2CO.sub.3 (57.5 mg, 543 mol, 2.3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (28.9 mg, 35.4 mol, 0.2 eq). The mixture was degassed and purged with N.sub.2 three times and then stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (20 mL) and extracted with EtOAc (20 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/0, R.sub.f=0.3). tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (110 mg, 193 mol, 82% yield) was obtained as a yellow solid. M+H.sup.+=569.4 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.29-9.11 (m, 1H), 9.01-8.89 (m, 1H), 8.41-8.31 (m, 1H), 8.27-8.20 (m, 1H), 7.57-7.48 (m, 2H), 7.07-7.01 (m, 1H), 6.88-6.72 (m, 3H), 4.46-4.37 (m, 1H), 4.26-4.17 (m, 1H), 4.06-4.00 (m, 1H), 3.91-3.82 (m, 2H), 2.62-2.58 (m, 3H), 2.33-2.21 (m, 2H), 2.19-2.14 (m, 3H), 1.32 (br s, 13H).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (442A-2)

[2138] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (110 mg, 193 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (441 mg, 3.87 mmol, 286 L, 20 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give the crude(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (110 mg) as a yellow oil, which was used in the next step without any further purification. M+H.sup.+=469.3 (LCMS).

Step 3: (S)-2-Methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 782)

[2139] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (110 mg, 189 mol, 11.7 L, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (100 L), followed by formaldehyde-d.sub.2 (35.2 mg, 227 mol, 4.73 L, 20% purity in D.sub.2O, 1.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 C. for 30 min, then NaBD.sub.3CN (11.9 mg, 189 mol, 1.0 eq) was added. The reaction mixture was stirred at 20 C. for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-(methyl-d.sub.3)azetidin-2-yl)methoxy)-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (52.1 mg, 96.6 mol, 51% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=486.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.56-9.49 (m, 1H), 9.36-9.31 (m, 1H), 9.22-9.15 (m, 1H), 8.34-8.29 (m, 2H), 8.00-7.93 (m, 2H), 7.13-7.06 (m, 1H), 6.98 (s, 1H), 6.80-6.71 (m, 1H), 4.68-4.59 (m, 1H), 4.35-4.28 (m, 1H), 4.26-4.19 (m, 1H), 4.06-3.96 (m, 1H), 3.91-3.81 (m, 1H), 2.60-2.57 (m, 3H), 2.41 (br s, 2H), 1.99-1.94 (m, 3H), 1.44 (br s, 2H), 1.41-1.35 (m, 2H).

Example 443: (S)N-(1-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 806)

##STR01295##

Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)oxazole (443A-2)

[2140] To a solution of 1-(oxazol-2-yl) ethan-1-one (300 mg, 2.70 mmol, 1.0 eq) in toluene (3.0 mL) was added PTSA (23.3 mg, 135 mol, 0.05 eq) at 20 C. for 1 h. Then ethylene glycol (3.35 g, 54.0 mmol, 3.0 mL, 20 eq) was added and the mixture was stirred at 130 C. for 12 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 30 mm, 5 m); flow rate: 25 mL/min; gradient: 5%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(2-Methyl-1,3-dioxolan-2-yl)oxazole (200 mg, 1.25 mmol, 46% yield) was obtained as a yellow oil. M+H.sup.+=156 (LCMS).

Step 2: 5-Bromo-2-(2-methyl-1,3-dioxolan-2-yl)oxazole (443A-3)

[2141] To a solution of 2-(2-methyl-1,3-dioxolan-2-yl)oxazole (100 mg, 644 mol, 1.0 eq) in THF (3.0 mL) was added n-BuLi (2.5 M, 644 L, 2.5 eq) at 78 C., the mixture was stirred at 78 C. for 1 h. Then carbon tetrabromide (384 mg, 1.16 mmol, 1.8 eq) was added to the mixture at 78 C., and then the mixture was allowed to warm up to 20 C. and stirred at 20 C. for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into water (10 mL) and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 5-Bromo-2-(2-methyl-1,3-dioxolan-2-yl)oxazole (110 mg, 455 mol, 70% yield) was obtained as a yellow oil. M+H.sup.+=234.2/236.2 (LCMS).

Step 3: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-(2-methyl-1,3-dioxolan-2-yl)oxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (443A-4)

[2142] A mixture of tert-butyl(25)-2-[4-methyl-3-[1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-quinolyl]cyclopropyl]carbamoyl]phenoxy]methyl]azetidine-1-carboxylate (196 mg, 320 mol, 1.0 eq), 5-bromo-2-(2-methyl-1,3-dioxolan-2-yl)oxazole (90.0 mg, 384 mol, 1.2 eq), Pd(dppf)Cl.sub.2 (23.5 mg, 32.0 mol, 0.10 eq), and Na.sub.2CO.sub.3 (101 mg, 961 mol, 3.0 eq) in a mixture of dioxane (1.0 mL) and H.sub.2O (200 L) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. under a N.sub.2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(2-(2-methyl-1,3-dioxolan-2-yl)oxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 122 mol, 38% yield) was obtained as a white amorphous solid. M+H.sup.+=641.6 (LCMS).

Step 4: (S)N-(1-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (443A-5)

[2143] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(2-(2-methyl-1,3-dioxolan-2-yl)oxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (90.0 mg, 140 mol, 1.0 eq) in a mixture of DCM (2.0 mL) and H.sub.2O (1.0 mL) was added TFA (16.0 mg, 140 mol, 10.4 L, 1.0 eq). The mixture was stirred at 20 C. for 60 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 C. to give the crude product(S)N-(1-(7-(2-acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (80.0 mg, 128 mol, TFA salt) as a yellow solid. M+H.sup.+=497.3 (LCMS).

Step 5: (S)N-(1-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 806)

[2144] To a solution of(S)N-(1-(7-(2-acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (70 mg, 114 mol, 1.0 eq, TFA salt) in MeOH (2.0 mL) were added HOAc (688 g, 11.4 mol, 0.1 eq) and formaldehyde (13.9 mg, 171 mol, 12.8 L, 37% purity in H.sub.2O, 1.5 eq) at 20 C. for 1 h. Then NaBH.sub.3CN (7.20 mg, 114 mol, 1.0 eq) was added to the mixture. The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (8030 mm, 3 m); flow rate: 25 mL/min; gradient: 5%-35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (4.00 mg, 7.31 mol, 6% yield) was obtained as a white solid. M+H.sup.+=511.4 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 10.92-10.77 (m, 1H), 9.46-9.32 (m, 2H), 9.21-9.09 (m, 1H), 8.50 (m, 1H), 8.42-8.30 (m, 2H), 7.95-7.80 (m, 1H), 7.15-7.03 (m, 1H), 6.95-6.88 (m, 1H), 6.75 (m, 1H), 4.71-4.56 (m, 1H), 4.39 (m, 1H), 4.26-4.18 (m, 1H), 4.04-3.93 (m, 1H), 3.92-3.81 (m, 2H), 2.80 (m, 3H), 2.72-2.61 (m, 3H), 2.39-2.23 (m, 2H), 1.96 (m, 3H), 1.53-1.31 (m, 3H).

Example 444: (S)N-(1-(7-(1H-Pyrazol-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 619)

##STR01296##

Step 1: 5-Bromo-7-(1H-pyrazol-1-yl)quinoline (444A-1)

[2145] A solution of 5,7-dibromoquinoline (2.50 g, 8.71 mmol, 1.0 eq) in DMA (175 mL) was degassed and purged with N.sub.2 three times. To the mixture were added 1H-pyrazole (711 mg, 10.4 mmol, 1.2 eq), CuiBuCx.sub.2 (347 mg, 871 mol, 0.1 eq) and Cs.sub.2CO.sub.3 (5.68 g, 17.4 mmol, 2.0 eq) at 20 C. The resulting mixture was stirred at 120 C. for 14 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (200 mL), and extracted with EtOAc (100 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether=1/1, R.sub.f=0.3). 5-Bromo-7-(1H-pyrazol-1-yl)quinoline (400 mg, 1.46 mmol, 8% yield) was obtained as a colorless oil. M+H.sup.+=273.9 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.99-8.93 (m, 1H), 8.57-8.50 (m, 2H), 8.23 (d, J=1.6 Hz, 1H), 8.13 (d, J=2.5 Hz, 1H), 7.82 (s, 1H), 7.51 (dd, J=4.3, 8.5 Hz, 1H), 6.57 (t, J=2.1 Hz, 1H).

Step 2: 7-(1H-Pyrazol-1-yl)quinoline-5-carbonitrile (444A-2)

[2146] A solution of 5-bromo-7-(1H-pyrazol-1-yl)quinoline (900 mg, 3.28 mmol, 1.0 eq) in DMF (90 mL) was degassed and purged with N.sub.2 three times. To the mixture were added Zn(CN).sub.2 (771 mg, 6.57 mmol, 2.0 eq), Brettphos Pd G3 (595 mg, 657 mol, 0.2 eq) and Brettphos (353 mg, 657 mol, 0.2 eq) at 20 C. The resulting mixture was stirred at 80 C. for 1 h under a N.sub.2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (100 mL), and extracted with EtOAc (50 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. 7-(1H-Pyrazol-1-yl)quinoline-5-carbonitrile (200 mg, 908 mmol, 28% yield) was obtained as a white solid. .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.08 (dd, J=1.5, 4.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.62 (dd, J=4.3, 8.5 Hz, 1H), 6.66-6.58 (m, 1H).

Step 3: 1-(7-(1H-Pyrazol-1-yl)quinolin-5-yl)cyclopropan-1-amine (444A-3)

[2147] A mixture of 7-(1H-pyrazol-1-yl)quinoline-5-carbonitrile (50.0 mg, 227 mol, 1.0 eq) in anhydrous Et.sub.2O (5.0 mL) was degassed and purged with N.sub.2 three times, then cooled to 78 C. To this mixture was added Ti(i-PrO).sub.4 (71.0 mg, 250 mol, 73.7 L, 1.1 eq) slowly, and then EtMgBr (3 M in Et.sub.2O, 166 L, 2.2 eq) was added dropwise to maintain the temperature between 78 C. and 75 C. over 1 h under a N.sub.2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 C. over 1 h. BF.sub.3.Math.Et.sub.2O (64.5 mg, 454 mol, 48.3 mL, 2.0 eq) was added slowly with no obvious temperature change. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HCl (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH=1/1, R.sub.f=0.6). 1-(7-(1H-Pyrazol-1-yl)quinolin-5-yl)cyclopropan-1-amine (50.0 mg, 200 mol, 22% yield) was obtained as a yellow oil. M+H.sup.+=251.1 (LCMS).

Step 4: (S)N-(1-(7-(1H-Pyrazol-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 619)

[2148] To a solution of 1-(7-(1H-pyrazol-1-yl)quinolin-5-yl)cyclopropan-1-amine (40.0 mg, 160 mol, 3.0 eq) and(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (12.5 mg, 53.3 mol, 1.0 eq) in DMF (4 mL) were added HATU (50.6 mg, 133 mol, 2.5 eq) and DIEA (20.6 mg, 160 mol, 27.8 L, 3 eq). The mixture was stirred at 20 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (5.0 mL) and extracted with DCM (3.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (10030 mm, 10 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)N-(1-(7-(1H-Pyrazol-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (4.5 mg, 9.42 mol, 18% yield) was obtained as a yellow solid. M+H.sup.+=468.1 (LCMS); .sup.1H NMR (400 MHz, CD.sub.3OD) 9.86-9.77 (m, 1H), 9.19 (d, J=4.9 Hz, 1H), 8.78 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.11-8.00 (m, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.18-7.10 (m, 1H), 6.98 (dd, J=2.6, 8.3 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.75-6.68 (m, 1H), 4.72-4.66 (m, 1H), 4.35-4.14 (m, 3H), 4.02-3.90 (m, 1H), 2.95 (s, 3H), 2.60-2.51 (m, 2H), 2.04 (s, 3H), 1.63 (br s, 2H), 1.58-1.52 (m, 2H).

Example 445: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 653)

##STR01297##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (445A-1)

[2149] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (200 mg, 315 mol, 1.0 eq) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (64.5 mg, 315 mol, 1.0 eq) in a mixture of dioxane (20 mL) and H.sub.2O (6.0 mL) were added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (25.7 mg, 31.5 mol, 0.1 eq) and Na.sub.2CO.sub.3 (76.7 mg, 724 mol, 2.3 eq). The mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (15 mL), and extracted with EtOAc (6.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (140 mg, 248 mol, 79% yield) was obtained as a white solid. M+H.sup.+=565.5 (LCMS).

Step 2: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (445A-2)

[2150] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (140 mg, 248 mol, 1.0 eq) in DCM (7.0 mL) was added TFA (2.32 g, 20.4 mmol, 1.5 mL, 82 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (130 mg, TFA salt) as a yellow oil. M+H.sup.+=465.2 (LCMS).

Step 3: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 653)

[2151] To a solution of(S)-5-(azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (120 mg, 207 mol, 1.0 eq, TFA salt) in MeOH (10 mL) was added TEA (1.0 mL), followed by formaldehyde (415 mg, 415 mol, 38.1 L, 37% purity in water, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH 6, then NaBH.sub.3CN (26.1 mg, 415 mol, 2.0 eq) was added. The mixture was stirred at 20 C. for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 (7530 mm, 3 m); flow rate: 25 mL/min; gradient: 1%-25% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (36.6 mg, 61.5 mol, 30% yield, HCl salt) was obtained as a yellow solid. M+H.sup.+=479.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.27-9.13 (m, 3H), 9.03 (dd, J=1.5, 4.1 Hz, 1H), 8.75 (dd, J=1.4, 5.0 Hz, 1H), 8.50 (br d, J=8.0 Hz, 1H), 8.36 (d, J=1.4 Hz, 1H), 8.26 (d, J=1.8 Hz, 1H), 7.82-7.62 (m, 2H), 7.10 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.68-4.54 (m, 1H), 4.51-4.16 (m, 4H), 2.83 (d, J=4.6 Hz, 3H), 2.38-2.30 (m, 2H), 1.97 (s, 3H), 1.41 (s, 4H).

Example 446: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 689)

##STR01298##

Step 1: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (446A-1)

[2152] A mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (800 mg, 1.26 mmol, 1.0 eq), BPD (639 mg, 2.52 mmol, 2.0 eq), KOAc (308 mg, 3.15 mmol, 2.5 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (102 mg, 126 mol, 0.10 eq) in dioxane (20 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 2/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (420 mg, 376 mol, 30% yield) was obtained as a white solid. M82+H.sup.+=532.4 (LCMS).

Step 2: tert-Butyl(S)-2-((4-methyl-3-((1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (446A-2)

[2153] A mixture of tert-butyl(S)-2-((4-methyl-3-((1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (150 mg, 246 mol, 1.0 eq), 4-(5-bromo-3-pyridyl) morpholine (65.8 mg, 270 mol, 1.1 eq), Pd(OAc) 2 (16.6 mg, 73.8 mol, 0.3 eq), bis(1-adamantyl)-butyl-phosphane (17.6 mg, 49.2 mol, 0.2 eq) and KOAc (72.5 mg, 738 mol, 3.0 eq) in DMSO (2.0 mL) was degassed and purged with N.sub.2 three times. The resulting mixture was stirred at 80 C. for 16 h under a N.sub.2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL) and extracted with DCM (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 2/1. tert-Butyl(S)-2-((4-methyl-3-((1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (170 mg, 143 mol, 58% yield) was obtained as a white solid. M+H.sup.+=650.5 (LCMS).

Step 3: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 689)

[2154] To a solution of tert-butyl(S)-2-((4-methyl-3-((1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (170 mg, 261 mol, 1.0 eq) in DCM (2.0 mL) was added TFA (755 mg, 6.63 mmol, 490 L, 25 eq). The mixture was stirred at 20 C. for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 C. to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-28% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (22.5 mg, 33.9 mol, 13% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=550.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21 (m, 1H), 9.17-9.10 (m, 1H), 9.04-8.99 (m, 1H), 8.92-8.74 (m, 2H), 8.64 (m, 1H), 8.46 (m, 1H), 8.41 (m, 1H), 8.24-8.17 (m, 1H), 8.04 (m, 1H), 7.73-7.64 (m, 1H), 7.10 (m, 1H), 6.91 (m, 1H), 6.70 (m, 1H), 4.70-4.60 (m, 1H), 4.23 (m, 2H), 4.13 (m, 2H), 3.81 (m, 4H), 3.46-3.40 (m, 4H), 2.46-2.40 (m, 1H), 2.38-2.29 (m, 1H), 1.96 (m, 3H), 1.47-1.35 (m, 4H).

Example 447: (S)N-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 821)

##STR01299##

Step 1: N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (447A-1)

[2155] n-BuLi (2.5 M in Et.sub.2O, 139 L, 1.0 eq) was added dropwise to a solution of 5,7-dibromoquinoline (100 mg, 349 mol, 59.5 L, 1.0 eq) and 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (61.1 mg, 349 mol, 1.0 eq) in THF (2.0 mL) at 78 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at 78 C. for 1 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into NH.sub.4Cl aqueous (20 ml) and extracted with EtOAc (10 mL4). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (200 mg, 522 mol, 21% yield) was obtained as a yellow gum. .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.94 (dd, J=1.5, 4.1 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.41 (dd, J=4.1, 8.6 Hz, 1H), 5.53 (d, J=7.3 Hz, 1H), 5.26-5.15 (m, 3H), 1.11 (s, 10H).

Step 2: N-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (447A-2)

[2156] To a mixture of (5-acetylthiophen-2-yl) boronic acid (63.2 mg, 372 mol, 1.5 eq) and N-(3-(7-bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (95.0 mg, 248 mol, 1.0 eq) in DMSO (4.0 mL) were added KOAc (97.3 mg, 991 mol, 4.0 eq), cataCxium A (44.4 mg, 124 mol, 0.5 eq) and Pd(OAc).sub.2 (11.1 mg, 49.6 mol, 0.2 eq). The resulting mixture was stirred at 80 C. for 2 h under a N.sub.2 atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. N-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (160 mg, 373 mol, 75% yield) was obtained as a yellow solid. .sup.1H NMR (400 MHZ, CDCl.sub.3-d) 8.97 (dd, J=1.4, 4.1 Hz, 1H), 8.43 (s, 1H), 7.98-7.72 (m, 4H), 7.56 (d, J=4.0 Hz, 1H), 7.41 (dd, J=4.2, 8.6 Hz, 1H), 5.35-5.21 (m, 4H), 2.68-2.63 (m, 3H), 1.12 (s, 9H).

Step 3: 1-(5-(5-(3-Aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl) ethan-1-one (447A-3)

[2157] To a solution of N-(3-(7-(5-acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (150 mg, 350 mol, 1.0 eq) in MeOH (5.0 mL) was added HCl/dioxane (4 M, 637 L, 7.3 eq) at 0 C. The resulting mixture was stirred at 0 C. for 30 min. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the crude 1-(5-(5-(3-aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl) ethan-1-one (120 mg, 333 mol, 95% yield, HCl salt) as a yellow solid, which was used in the next step without any further purification. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.78 (br s, 3H), 9.21 (br d, J=3.6 Hz, 1H), 8.66 (br s, 1H), 8.47-8.31 (m, 1H), 8.26-8.00 (m, 3H), 7.96-7.78 (m, 1H), 5.44-5.31 (m, 4H), 2.60 (br s, 3H).

Step 4: (S)N-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 821)

[2158] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (78.2 mg, 333 mol, 1.0 eq) and 1-(5-(5-(3-aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl) ethan-1-one (120 mg, 333 mol, 1.0 eq, HCl salt) in DMF (5.0 mL) were added HATU (316 mg, 831 mol, 2.5 eq) and DIEA (129 mg, 998 mol, 174 L, 3.0 eq). The mixture was stirred at 25 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H.sub.2O (10 mL) and extracted with EtOAc (10 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (10030 mm, 5 m); flow rate: 25 mL/min; gradient: 10%-40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)N-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (21.6 mg, 32.9 mol, 10% yield) was obtained as a yellow solid. M+H.sup.+=542.4 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.96 (dd, J=1.4, 4.4 Hz, 1H), 8.36 (s, 1H), 8.31-8.24 (m, 2H), 7.95 (d, J=4.0 Hz, 1H), 7.83 (d, J=4.1 Hz, 1H), 7.63 (dd, J=4.4, 8.6 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.99 (dd, J=2.8, 8.5 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 5.47 (d, J=7.1 Hz, 2H), 5.35 (d, J=7.1 Hz, 2H), 4.74-4.63 (m, 1H), 4.35-4.16 (m, 3H), 4.02-3.92 (m, 1H), 3.00-2.92 (m, 3H), 2.62 (s, 3H), 2.58-2.48 (m, 2H), 2.04 (s, 3H).

Example 448: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(7-(2-methyloxazol-5-yl)quinolin-5-yl)oxetan-3-yl)benzamide (Compound 808)

##STR01300##

Step 1: N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (448A-1)

[2159] To a solution of 5,7-dibromoquinoline (500 mg, 1.74 mmol, 59.5 L, 1.0 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 697 L, 1.0 eq) dropwise at 78 C. under a N.sub.2 atmosphere. The resulting mixture was stirred at 78 C. for 1 h, then a solution of 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (305 mg, 1.74 mmol, 1.0 eq) in THF (1.0 mL) was added dropwise at 78 C. The resulting mixture was warmed to 25 C. for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (150 mg, 391 mol, 22% yield) was obtained as a yellow gum. M+H.sup.+=383.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.95 (d, J=4.3 Hz, 1H), 8.48-8.36 (m, 1H), 8.06-7.89 (m, 1H), 7.69 (br s, 1H), 7.52-7.40 (m, 1H), 5.53 (d, J=7.4 Hz, 1H), 5.30-5.08 (m, 3H), 1.11 (s, 9H).

Step 2:3-(7-Bromoquinolin-5-yl)oxetan-3-amine (448A-2)

[2160] To a solution of N-(3-(7-bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (150 mg, 391 mol, 1.0 eq) in MeOH (8 mL) was added HCl/dioxane (4 M, 712 L, 7.3 eq) at 0 C. The resulting mixture was stirred at 0 C. for 10 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 3-(7-bromoquinolin-5-yl)oxetan-3-amine (120 mg, 380 mol, 97% yield, HCl salt) as a yellow solid. M+H.sup.+=279.1 (LCMS).

Step 3: (S)N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (448A-3)

[2161] To a solution of(S)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzoic acid (82.0 mg, 349 mol, 1.0 eq) and 3-(7-bromo-5-quinolyl)oxetan-3-amine (110 mg, 349 mol, 1.0 eq, HCl salt) in DMF (5.0 mL) were added HATU (331 mg, 871 mol, 2.5 eq) and DIEA (135 mg, 1.05 mmol, 182 L, 3.0 eq). The mixture was stirred at 25 C. for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (S)N-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 161 mol, 46% yield) was obtained as a yellow gum. M+H.sup.+=496.3 (LCMS).

Step 4: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(7-(2-methyloxazol-5-yl)quinolin-5-yl)oxetan-3-yl)benzamide (Compound 808)

[2162] To a solution of(S)N-(3-(7-bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (60.0 mg, 121 mol, 1.0 eq) in a mixture of dioxane (6.0 mL) and H.sub.2O (0.6 mL) were added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (37.9 mg, 181 mol, 1.5 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (9.87 mg, 12.1 mol, 0.1 eq) and Na.sub.2CO.sub.3 (29.5 mg, 278 mol, 2.3 eq) under a N.sub.2 atmosphere. The resulting mixture was stirred at 80 C. for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL), and extracted with EtOAc (5.0 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (100 40 mm, 5 m); flow rate: 25 mL/min; gradient: 1%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(3-(7-(2-methyloxazol-5-yl)quinolin-5-yl)oxetan-3-yl)benzamide (6.40 mg, 9.89 mol, 8% yield, TFA salt) was obtained as a yellow solid. M+H.sup.+=499.4 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.96 (d, J=4.1 Hz, 1H), 8.30 (s, 1H), 8.26-8.19 (m, 2H), 7.78 (s, 1H), 7.62 (dd, J=4.3, 8.6 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.99 (dd, J=2.6, 8.4 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 5.46 (br d, J=7.0 Hz, 2H), 5.34 (d, J=7.0 Hz, 2H), 4.80-4.66 (m, 2H), 4.35-4.28 (m, 1H), 4.25-4.18 (m, 1H), 3.96 (q, J=9.8 Hz, 1H), 3.05-2.91 (m, 3H), 2.62 (s, 3H), 2.59-2.51 (m, 2H), 2.01 (s, 3H).

Example 449: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)benzamide (Compound 181)

##STR01301##

[2163] The synthesis of compound 181 was described in example 1 as intermediate 1A-8. M+H.sup.+=464.3.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 7.23 (d, J=7.1 Hz, 1H), 7.12-7.07 (m, 1H), 7.03-6.95 (m, 2H), 6.56-6.49 (m, 2H), 5.43-5.36 (m, 1H), 4.61-4.58 (m, 1H), 4.29-4.17 (m, 3H), 3.74-3.69 (m, 2H), 3.10-3.02 (m, 1H), 2.83-2.77 (m, 3H), 2.21-2.18 (m, 3H), 1.95-1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.48-1.46 (m, 1H), 1.46-1.45 (m, 9H), 1.31-1.30 (m, 1H).

Example 450: (R)-2-Methyl-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide (Compound 104)

##STR01302##

[2164] The synthesis of compound 104 was described in example 14 as intermediate 14A-3. M+H.sup.+=335.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.21 (d, J=8.5 Hz, 1H), 8.16-8.09 (m, 2H), 7.91 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.66-7.45 (m, 4H), 7.36 (d, J=8.3 Hz, 1H), 6.20-6.12 (m, 1H), 6.12-6.04 (m, 1H), 2.60-2.44 (m, 3H), 1.84 (d, J=6.5 Hz, 3H).

Example 451: tert-Butyl 3-((3-((1-([1,1-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxylate (Compound 188)

##STR01303##

[2165] The synthesis of compound 188 was described in example 201 as intermediate 201A-2. M+H.sup.+=398.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 7.61-7.52 (m, 4H), 7.44 (t, J=7.7 Hz, 4H), 7.41-7.32 (m, 3H), 7.08-6.99 (m, 1H), 4.28-4.22 (m, 2H), 4.21-4.14 (m, 1H), 3.78-3.71 (m, 2H), 2.32 (s, 3H), 1.46 (br s, 2H), 1.45 (s, 9H), 1.43 (br s, 2H).

Example 452: 2-(1-(Naphthalen-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (Compound 127)

##STR01304##

[2166] The synthesis of compound 127 was described in example 256 as intermediate 256A-1. M+H.sup.+=332.2 (LCMS); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.42 (br s, 1H), 8.02-7.94 (m, 1H), 7.93-7.86 (m, 2H), 7.80 (br d, J=8.1 Hz, 1H), 7.66 (br d, J=6.4 Hz, 1H), 7.53-7.42 (m, 3H), 7.23 (d, J=8.4 Hz, 1H), 4.36 (br s, 1H), 4.01 (br d, J=14.6 Hz, 1H), 3.73 (br d, J=14.9 Hz, 1H), 3.05-2.64 (m, 4H), 1.62 (br d, J=6.5 Hz, 3H).

Example 453: (S)-5-(1-(2-Methyl-5-((1-methylazetidin-2-yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (Compound 739)

##STR01305##

[2167] The synthesis of compound 739 was described in example 352 as intermediate 352A-1. M+H.sup.+=550.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.79-10.63 (m, 1H), 9.31 (s, 1H), 9.18 (d, J=8.6 Hz, 1H), 9.06 (dd, J=1.4, 4.1 Hz, 1H), 8.10 (d, J=2.5 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.76 (dd, J=4.3, 8.6 Hz, 1H), 7.12-7.06 (m, 1H), 6.98-6.86 (m, 1H), 6.82-6.70 (m, 1H), 4.70-4.54 (m, 1H), 4.36 (dd, J=7.9, 11.2 Hz, 1H), 4.21 (dd, J=3.2, 11.3 Hz, 1H), 4.08-3.93 (m, 1H), 3.84 (br dd, J=6.6, 9.6 Hz, 1H), 2.80 (d, J=5.0 Hz, 3H), 2.41-2.24 (m, 2H), 1.93 (s, 3H), 1.47-1.37 (m, 2H), 1.33-1.25 (m, 2H).

Example 454: 2-Methyl-N-(naphthalen-1-yl(oxetan-3-yl)methyl)-5-nitrobenzamide (Compound 110)

##STR01306##

[2168] Compound 110 was synthesized according to an analogous procedure to the one described for compound 105. M+H.sup.+=377.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.32 (d, J=8.5 Hz, 1H), 8.16-8.07 (m, 2H), 7.94-7.84 (m, 2H), 7.69-7.55 (m, 2H), 7.48-7.34 (m, 2H), 7.20 (d, J=7.1 Hz, 1H), 6.53 (t, J=8.8 Hz, 1H), 6.10 (br d, J=8.8 Hz, 1H), 5.13-5.00 (m, 2H), 4.89 (t, J=7.3 Hz, 1H), 4.51 (t, J=6.5 Hz, 1H), 4.00-3.79 (m, 1H), 3.50 (s, 2H), 2.54 (s, 3H).

Example 455: 2-Methyl-N-(naphthalen-1-yl(tetrahydrofuran-3-yl)methyl)-5-nitrobenzamide (Compound 123)

##STR01307##

[2169] Compound 123 was synthesized according to an analogous procedure to the one described for compound 105. M+H.sup.+=391.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.40-8.28 (m, 1H), 8.23-8.11 (m, 2H), 7.94 (dd, J=4.6, 7.3 Hz, 1H), 7.91-7.84 (m, 1H), 7.68-7.48 (m, 4H), 7.44-7.35 (m, 1H), 6.22-6.03 (m, 1H), 4.17-4.01 (m, 1H), 3.99-3.76 (m, 2H), 3.56-3.43 (m, 1H), 3.29-3.03 (m, 1H), 2.51 (d, J=9.8 Hz, 3H), 2.29 (q, J=7.3 Hz, 1H), 2.25-1.76 (m, 1H).

Example 456: N-(3-Methoxy-1-(naphthalen-1-yl) propyl)-2-methyl-5-nitrobenzamide (Compound 113)

##STR01308##

[2170] Compound 113 was synthesized according to an analogous procedure to the one described for compound 108. M+H.sup.+=379.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.35 (d, J=2.4 Hz, 1H), 8.22-8.15 (m, 2H), 7.91 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.62-7.46 (m, 4H), 7.45-7.37 (m, 2H), 6.21 (dt, J=4.6, 7.1 Hz, 1H), 3.58-3.42 (m, 2H), 3.40 (s, 3H), 2.55 (s, 3H), 2.51-2.20 (m, 2H).

Example 457: 5-Amino-2-methyl-N-(naphthalen-1-yl(oxetan-3-yl)methyl)benzamide (Compound 114)

##STR01309##

[2171] Compound 114 was synthesized according to an analogous procedure to the one described for compound 109. M+H.sup.+=347.0 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.33 (d, J=8.4 Hz, 1H), 7.94-7.80 (m, 2H), 7.64-7.53 (m, 2H), 7.44-7.35 (m, 1H), 7.13 (d, J=7.1 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.66-6.53 (m, 2H), 6.45 (t, J=8.7 Hz, 1H), 6.10 (br d, J=9.3 Hz, 1H), 5.11-4.91 (m, 2H), 4.83 (dd, J=6.6, 8.0 Hz, 1H), 4.52 (t, J=6.6 Hz, 1H), 3.94-3.71 (m, 1H), 2.34-2.24 (m, 3H).

Example 458: 5-Amino-N-(3-methoxy-1-(naphthalen-1-yl) propyl)-2-methylbenzamide (Compound 117)

##STR01310##

[2172] Compound 117 was synthesized according to an analogous procedure to the one described for compound 118. M+H.sup.+=349.2 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 8.20 (d, J=8.3 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.77 (br d, J=8.0 Hz, 1H), 7.59-7.37 (m, 4H), 7.18-7.04 (m, 1H), 6.92 (br d, J=7.6 Hz, 1H), 6.89-6.68 (m, 2H), 6.14 (br d, J=4.6 Hz, 1H), 3.49-3.37 (m, 2H), 3.33-3.28 (m, 3H), 2.33 (br d, J=6.6 Hz, 1H), 2.27 (s, 3H), 2.21 (br d, J=10.4 Hz, 1H).

Example 459: 5-(Azetidin-3-ylamino)-2-methyl-N-(1-(1,2,3,4-tetrahydro naphthalen-1-yl)ethyl)benzamide (Compound 182)

##STR01311##

[2173] Compound 182 was synthesized according to an analogous procedure to the one described for compound 172. M+H.sup.+=364.1 (LCMS); .sup.1H NMR (400 MHZ, CDCl.sub.3) 9.99-9.63 (m, 2H), 7.35-7.28 (m, 1H), 7.18-7.06 (m, 3H), 7.03-6.89 (m, 1H), 6.50-6.24 (m, 2H), 6.05-5.68 (m, 1H), 4.83-4.63 (m, 1H), 4.40-4.04 (m, 3H), 3.85-3.59 (m, 2H), 3.28-2.99 (m, 1H), 2.84 (br d, J=2.1 Hz, 1H), 2.26-1.87 (m, 5H), 1.83-1.47 (m, 2H), 1.36-1.10 (m, 3H).

Example 460: 2-(Aminomethyl)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-5-methylbenzofuran-6-carboxamide (Compound 607)

##STR01312##

[2174] Compound 607 was synthesized according to an analogous procedure to the one described for compound 197. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.96 (d, J=8.4 Hz, 1H), 8.83 (dd, J=1.4, 4.1 Hz, 1H), 7.48 (d, J=2.6 Hz, 1H), 7.44 (dd, J=4.2, 8.4 Hz, 1H), 7.34-7.28 (m, 2H), 7.20 (s, 1H), 6.60 (s, 1H), 3.93 (s, 3H), 3.79 (s, 2H), 2.11 (s, 3H), 1.40-1.32 (m, 2H), 1.23-1.18 (m, 2H).

Example 461: 2-((Dimethylamino)methyl)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-5-methylbenzofuran-6-carboxamide (Compound 606)

##STR01313##

[2175] Compound 606 was synthesized according to an analogous procedure to the one described for compound 198. M+H.sup.+=364.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =11.26 (br d, J=2.5 Hz, 1H), 9.62 (br d, J=8.6 Hz, 1H), 9.42 (s, 1H), 9.16 (d, J=5.0 Hz, 1H), 7.93 (dd, J=5.3, 8.4 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 2.73 (s, 6H), 2.13 (s, 3H), 1.44 (br s, 2H), 1.32 (br s, 2H).

Example 462: 5-(2-Aminoethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 513)

##STR01314##

[2176] Compound 513 was synthesized according to an analogous procedure to the one described for compound 215. M+H.sup.+=392.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12-9.07 (m, 1H), 8.94 (dd, J=1.0, 8.4 Hz, 1H), 8.82 (dd, J=1.6, 4.2 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.42 (dd, J=4.3, 8.5 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.7, 8.3 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.92 (s, 3H), 3.82 (t, J=5.8 Hz, 2H), 2.80 (t, J=5.8 Hz, 2H), 1.94 (s, 3H), 1.38-1.29 (m, 2H), 1.23-1.14 (m, 2H).

Example 463: 5-(Azetidin-3-ylmethoxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 430)

##STR01315##

[2177] Compound 430 was synthesized according to an analogous procedure to the one described for compound 263. M+H.sup.+=387.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.12-9.07 (m, 1H), 8.79-8.62 (m, 3H), 7.98-7.91 (m, 1H), 7.86-7.79 (m, 2H), 7.61-7.42 (m, 3H), 7.11-7.03 (m, 1H), 6.91-6.83 (m, 1H), 6.71-6.65 (m, 1H), 4.07-3.99 (m, 4H), 3.82-3.71 (m, 2H), 3.18-3.05 (m, 1H), 2.03-1.90 (m, 3H), 1.40-1.31 (m, 2H), 1.23-1.13 (m, 2H).

Example 464: 5-(((1R,2S)-2-Aminocyclohexyl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 428)

##STR01316##

[2178] Compound 428 was synthesized according to an analogous procedure to the one described for compound 263. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14-9.08 (m, 1H), 8.70-8.62 (m, 1H), 8.02-7.88 (m, 4H), 7.87-7.78 (m, 2H), 7.61-7.41 (m, 3H), 7.11-7.03 (m, 1H), 6.96-6.89 (m, 1H), 6.76-6.70 (m, 1H), 4.53-4.44 (m, 1H), 3.36 (br s, 1H), 2.01-1.93 (m, 3H), 1.92-1.84 (m, 1H), 1.77-1.65 (m, 3H), 1.50-1.32 (m, 6H), 1.22-1.12 (m, 2H).

Example 465: 5-(((1R,2R)-2-Aminocyclohexyl)oxy)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 429)

##STR01317##

[2179] Compound 429 was synthesized according to an analogous procedure to the one described for compound 263. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.15-9.09 (m, 1H), 8.69-8.62 (m, 1H), 8.02-7.78 (m, 6H), 7.63-7.41 (m, 3H), 7.11-7.03 (m, 1H), 6.95-6.88 (m, 1H), 6.71-6.64 (m, 1H), 4.14-3.97 (m, 1H), 3.20-3.07 (m, 1H), 2.12-2.03 (m, 1H), 1.98 (s, 4H), 1.74-1.61 (m, 2H), 1.38-1.15 (m, 8H).

Example 466: 5-(2-(Dimethylamino)ethoxy)-N-(1-(2-methoxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 277)

##STR01318##

[2180] Compound 277 was synthesized according to an analogous procedure to the one described for compound 271. M+H.sup.+=369.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.04-8.75 (m, 1H), 7.26-7.14 (m, 3H), 7.00-6.91 (m, 2H), 6.86 (d, J=8.9 Hz, 2H), 4.40-4.25 (m, 2H), 3.73 (s, 3H), 3.55-3.44 (m, 2H), 2.84 (s, 6H), 2.22 (s, 3H), 1.17 (br d, J=6.5 Hz, 4H).

Example 467: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-methoxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 278)

##STR01319##

[2181] Compound 278 was synthesized according to an analogous procedure to the one described for compound 271. M+H.sup.+=369.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 7.33 (d, J=8.8 Hz, 2H), 7.23-7.14 (m, 1H), 7.04-6.93 (m, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.43-4.26 (m, 2H), 3.78 (s, 3H), 3.66-3.51 (m, 2H), 2.98 (s, 6H), 2.27 (s, 3H), 1.17-1.34 (m, 4H).

Example 468: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(phenanthren-9-yl)cyclopropyl)benzamide (Compound 569)

##STR01320##

[2182] Compound 569 was synthesized according to an analogous procedure to the one described for compound 272. M+H.sup.+=451.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.80 (br d, J=7.6 Hz, 3H), 8.12 (s, 1H), 8.03-7.96 (m, 1H), 7.72-7.62 (m, 4H), 7.04 (d, J=8.5 Hz, 1H), 6.85 (br d, J=2.5 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H), 3.96 (br d, J=3.4 Hz, 2H), 2.89 (s, 2H), 2.73 (s, 2H), 2.40 (br s, 3H), 2.02-1.90 (m, 4H), 1.46-1.37 (m, 2H), 1.28 (br s, 2H).

Example 469: 2-Methyl-5-((1-methylazetidin-3-yl)methoxy)-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 427)

##STR01321##

[2183] Compound 427 was synthesized according to an analogous procedure to the one described for compound 283. M+H.sup.+=401.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.39-9.96 (m, 1H), 9.14-9.06 (m, 1H), 8.70-8.61 (m, 1H), 7.99-7.90 (m, 1H), 7.89-7.73 (m, 2H), 7.64-7.40 (m, 3H), 7.15-7.01 (m, 1H), 6.93-6.82 (m, 1H), 6.74-6.61 (m, 1H), 4.28-4.17 (m, 1H), 4.11-4.06 (m, 1H), 4.05-3.95 (m, 3H), 3.81-3.75 (m, 1H), 3.13-3.04 (m, 1H), 2.81-2.76 (m, 3H), 2.02-1.88 (m, 3H), 1.41-1.29 (m, 2H), 1.23 (br s, 1H).

Example 470: 5-(2-(Dimethylamino)ethoxy)-N-(1-(3-hydroxyphenyl)cyclopropyl)-2-methylbenzamide (Compound 306)

##STR01322##

[2184] Compound 306 was synthesized according to an analogous procedure to the one described for compound 294. M+H.sup.+=355.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.38-10.09 (m, 1H), 9.30 (br s, 1H), 8.91 (s, 1H), 7.18 (br d, J=8.0 Hz, 1H), 7.07 (br t, J=7.9 Hz, 1H), 7.07 (br t, J=7.9 Hz, 1H), 7.03-6.93 (m, 2H), 6.69 (s, 1H), 6.59 (br dd, J=7.9, 13.5 Hz, 2H), 4.35 (br t, J=4.6 Hz, 2H), 3.50 (br d, J=4.5 Hz, 2H), 2.84 (br d, J=4.4 Hz, 6H), 2.17-2.31 (m, 3H), 1.21 (br s, 4H).

Example 471: 5-(2-Amino-3-methylbutoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 572)

##STR01323##

[2185] Compound 572 was synthesized according to an analogous procedure to the one described for compound 324. M+H.sup.+=434.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.48 (br d, J=4.0 Hz, 1H), 9.28 (s, 1H), 9.10 (br d, J=5.0 Hz, 1H), 8.12 (br d, J=2.1 Hz, 3H), 7.88-7.80 (m, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.93 (dd, J=2.8, 8.4 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.15-4.10 (m, 1H), 4.00 (s, 3H), 3.98 (br s, 1H), 3.23 (br d, J=4.1 Hz, 1H), 2.05-1.98 (m, 1H), 1.95 (s, 3H), 1.39 (br s, 2H), 1.29 (br s, 2H), 0.99 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H).

Example 472: (S)-5-((1-(2-Fluoroethyl)azetidin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 567)

##STR01324##

[2186] Compound 567 was synthesized according to an analogous procedure to the one described for compound 348. M+H.sup.+=464.2. 1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 8.94 (br d, J=8.3 Hz, 1H), 8.81 (br d, J=3.4 Hz, 1H), 8.40-8.11 (m, 1H), 7.50-7.38 (m, 2H), 7.31 (d, J=1.8 Hz, 1H), 7.03 (br d, J=8.6 Hz, 1H), 6.93-6.78 (m, 1H), 6.60 (d, J=2.1 Hz, 1H), 4.42 (br t, J=4.6 Hz, 1H), 4.30 (br t, J=4.8 Hz, 1H), 4.02-3.76 (m, 6H), 2.97-2.73 (m, 3H), 2.59 (br d, J=3.0 Hz, 1H), 2.10-1.81 (m, 5H), 1.44-1.28 (m, 2H), 1.23-1.09 (m, 2H).

Example 473: 5-(2-((2-Fluoroethyl)(methyl)amino)ethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 571)

##STR01325##

[2187] Compound 571 was synthesized according to an analogous procedure to the one described for compound 348. M+H.sup.+=452.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.82-10.62 (m, 1H), 9.63-9.49 (m, 1H), 9.31 (s, 1H), 9.13 (br d, J=4.5 Hz, 1H), 7.97-7.82 (m, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.97-4.79 (m, 2H), 4.31 (s, 2H), 4.01 (s, 3H), 3.72-3.60 (m, 4H), 2.86 (br d, J=2.3 Hz, 3H), 1.96 (s, 3H), 1.44-1.36 (m, 2H), 1.30 (br s, 2H).

Example 474: N-(1-(7-Fluoronaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 444)

##STR01326##

[2188] Compound 444 was synthesized according to an analogous procedure to the one described for compound 365. M+H.sup.+=419.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.57-8.46 (m, 1H), 8.34-8.23 (m, 1H), 8.01-7.90 (m, 2H), 7.87-7.80 (m, 1H), 7.47-7.39 (m, 1H), 7.36-7.27 (m, 1H), 7.12-7.04 (m, 1H), 6.93-6.87 (m, 1H), 6.73-6.67 (m, 1H), 4.30-4.03 (m, 3H), 3.92-3.79 (m, 1H), 3.66-3.51 (m, 1H), 2.76-2.67 (m, 3H), 2.43-2.28 (m, 2H), 2.05-1.95 (m, 3H), 1.48-1.42 (m, 2H), 1.34-1.26 (m, 2H).

Example 475: 5-((Hexahydro-1H-pyrrolizin-7a-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 559)

##STR01327##

[2189] Compound 559 was synthesized according to an analogous procedure to the one described for compound 376. M+H.sup.+=472.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.99-8.94 (m, 1H), 8.81 (dd, J=1.6, 4.2 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.41 (dd, J=4.3, 8.5 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.82 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.92 (s, 3H), 3.52 (s, 2H), 2.93-2.82 (m, 2H), 2.58-2.51 (m, 2H), 1.93 (s, 3H), 1.85-1.63 (m, 6H), 1.56-1.47 (m, 2H), 1.38-1.30 (m, 2H), 1.21-1.16 (m, 2H).

Example 476: 5-(((2R,7aS)-2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 596)

##STR01328##

[2190] Compound 596 was synthesized according to an analogous procedure to the one described for compound 376. M+H.sup.+=490.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.83 (br d, J=8.1 Hz, 1H), 9.08 (d, J=5.5 Hz, 1H), 8.03-7.88 (m, 2H), 7.46 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.97 (br d, J=8.7 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.67-5.46 (m, 1H), 4.27-3.99 (m, 5H), 3.95-3.70 (m, 3H), 3.52-3.41 (m, 1H), 2.76-2.44 (m, 2H), 2.41-2.16 (m, 3H), 2.01 (d, J=2.1 Hz, 3H), 1.63-1.53 (m, 2H), 1.48-1.36 (m, 3H).

Example 477: N-(1-(Isoquinolin-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 454)

##STR01329##

[2191] Compound 454 was synthesized according to an analogous procedure to the one described for compound 384. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.25 (s, 1H), 8.82 (d, J=8.3 Hz, 1H), 8.38 (d, J=5.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.83-7.54 (m, 3H), 7.10-6.96 (m, 1H), 6.90-6.81 (m, 1H), 6.68 (d, J=2.7 Hz, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.31-3.24 (m, 2H), 2.78-2.70 (m, 1H), 2.24 (s, 3H), 2.02-1.82 (m, 5H), 1.62-1.46 (m, 2H), 1.43-1.27 (m, 2H).

Example 478: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide (Compound 473)

##STR01330##

[2192] Compound 473 was synthesized according to an analogous procedure to the one described for compound 384. M+H.sup.+=402.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20 (s, 1H), 8.87 (d, J=4.4 Hz, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J=4.4 Hz, 1H), 7.68-7.60 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 3.86 (d, J=5.4 Hz, 2H), 3.28-3.11 (m, 2H), 2.71 (br dd, J=1.3, 7.9 Hz, 1H), 2.21 (s, 3H), 2.03-1.94 (m, 1H), 1.93 (s, 3H), 1.91-1.78 (m, 1H), 1.38 (d, J=1.9 Hz, 2H), 1.25 (d, J=1.9 Hz, 2H).

Example 479: N-(1-(3-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 456)

##STR01331##

[2193] Compound 456 was synthesized according to an analogous procedure to the one described for compound 384. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.97 (s, 1H), 8.07-7.97 (m, 1H), 7.92 (d, J=8.25 Hz, 1H), 7.80 (s, 1H), 7.43-7.37 (m, 1H), 7.04 (d, J=8.38 Hz, 1H), 6.84 (dd, J=8.38, 2.75 Hz, 1H), 6.66 (d, J=2.63 Hz, 1H), 4.05 (s, 3H), 3.97-3.91 (m, 2H), 3.64-3.55 (m, 1H), 3.46 (td, J=7.66, 3.19 Hz, 1H), 3.04 (q, J=8.34 Hz, 1H), 2.49-2.40 (m, 3H), 2.14-2.06 (m, 2H), 2.01 (s, 3H), 1.49-1.43 (m, 2H), 1.30-1.26 (m, 2H).

Example 480: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(2-methylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 458)

##STR01332##

[2194] Compound 458 was synthesized according to an analogous procedure to the one described for compound 384. M+H.sup.+=415.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.99-8.82 (m, 2H), 7.80 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.59-7.49 (m, 1H), 7.47-7.39 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.96 (dd, J=2.8, 8.4 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 4.74-4.59 (m, 1H), 4.33-4.25 (m, 1H), 4.24-4.12 (m, 2H), 3.96 (q, J=9.6 Hz, 1H), 2.93 (d, J=13.6 Hz, 6H), 2.62-2.50 (m, 2H), 2.10 (s, 3H), 1.82-1.72 (m, 1H), 1.66-1.56 (m, 1H), 1.44-1.34 (m, 1H), 1.24-1.14 (m, 1H).

Example 481: N-(1-(Anthracen-9-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 507)

##STR01333##

[2195] Compound 507 was synthesized according to an analogous procedure to the one described for compound 384. M+H.sup.+=451.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.74 (s, 1H), 8.62 (s, 1H), 8.18-8.09 (m, 4H), 7.57-7.50 (m, 4H), 7.09-7.01 (m, 1H), 6.92-6.74 (m, 3H), 3.93-3.83 (m, 2H), 3.26 (br d, J=4.6 Hz, 1H), 2.30-2.15 (m, 7H), 2.05-1.79 (m, 3H), 1.25 (d, J=7.0 Hz, 4H).

Example 482: N-(1-(7-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 488)

##STR01334##

[2196] Compound 488 was synthesized according to an analogous procedure to the one described for compound 433. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.12 (s, 1H), 9.08 (s, 1H), 8.89 (d, J=7.9 Hz, 1H), 8.73 (dd, J=1.5, 4.3 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.32 (dd, J=4.2, 8.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.88 (d, J=5.4 Hz, 2H), 3.27 (br t, J=6.6 Hz, 2H), 2.84-2.72 (m, 1H), 2.23 (s, 3H), 2.01-1.78 (m, 5H), 1.37-1.30 (m, 2H), 1.20-1.11 (m, 2H).

Example 483: (S)N-(1-(2-Chloro-7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 617)

##STR01335##

[2197] Compound 617 was synthesized according to an analogous procedure to the one described for compound 436. M+H.sup.+=466.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11 (s, 1H), 8.99 (d, J=8.8 Hz, 1H), 7.49 (dd, J=3.1, 5.6 Hz, 2H), 7.29 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.92 (s, 3H), 3.87 (d, J=5.4 Hz, 2H), 3.28-3.19 (m, 2H), 2.78-2.68 (m, 1H), 2.21 (s, 3H), 1.99-1.80 (m, 5H), 1.33 (s, 2H), 1.25-1.17 (m, 2H).

Example 484: 5-(2-Aminopropoxy)-2-methyl-N-(1-(quinolin-5-yl)cyclopropyl)benzamide (Compound 498)

##STR01336##

[2198] Compound 498 was synthesized according to an analogous procedure to the one described for compound 445. M+H.sup.+=376.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22-9.13 (m, 2H), 8.98 (dd, J=4.25, 1.38 Hz, 1H), 8.01-7.86 (m, 5H), 7.78 (dd, J=8.38, 7.25 Hz, 1H), 7.68 (dd, J=8.63, 4.25 Hz, 1H), 7.08 (d, J=8.50 Hz, 1H), 6.89 (dd, J=8.38, 2.75 Hz, 1H), 6.67 (d, J=2.75 Hz, 1H), 4.02 (dd, J=10.26, 3.88 Hz, 1H), 3.85 (dd, J=10.38, 7.13 Hz, 1H), 3.60-3.48 (m, 1H), 1.95 (s, 3H), 1.41-1.34 (m, 2H), 1.26-1.18 (m, 5H).

Example 485: 5-(2-Aminopropoxy)-N-(1-(isoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 446)

##STR01337##

[2199] Compound 446 was synthesized according to an analogous procedure to the one described for compound 445. M+H.sup.+=376.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.63 (s, 1H), 9.25 (s, 1H), 8.68-8.82 (m, 2H), 8.25 (dd, J=7.69, 4.06 Hz, 2H), 7.97-8.11 (m, 3H), 7.83 (t, J=7.75 Hz, 1H), 7.08 (d, J=8.51 Hz, 1H), 6.90 (dd, J=8.38, 2.63 Hz, 1H), 6.70 (d, J=2.75 Hz, 1H), 4.03 (dd, J=10.26, 3.88 Hz, 1H), 3.87 (dd, J=10.19, 7.07 Hz, 1H), 3.48-3.62 (m, 1H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.19-1.28 (m, 5H).

Example 486: (S)N-(3-(7-Methoxyquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 566)

##STR01338##

[2200] Compound 566 was synthesized according to an analogous procedure to the one described for compound 450. M+H.sup.+=448.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.78 (dd, J=1.5, 4.4 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.43-7.32 (m, 2H), 7.06 (d, J=8.5 Hz, 1H), 6.87 (dd, J=2.6, 8.4 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 5.36-5.28 (m, 4H), 4.00 (s, 3H), 3.93 (d, J=5.5 Hz, 2H), 3.56-3.46 (m, 1H), 3.41 (dt, J=2.8, 7.8 Hz, 1H), 3.03-2.89 (m, 1H), 2.39 (s, 3H), 2.15-2.01 (m, 2H), 1.98 (s, 3H).

Example 487: 5-(3-Aminoazetidin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 464)

##STR01339##

[2201] Compound 464 was synthesized according to an analogous procedure to the one described for compound 463. M+H.sup.+=372.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.02 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.26 (br s, 3H), 7.98-7.89 (m, 1H), 7.86-7.77 (m, 2H), 7.60-7.42 (m, 3H), 6.95 (d, J=8.1 Hz, 1H), 6.41 (dd, J=2.4, 8.2 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 4.09-4.02 (m, 1H), 3.97 (t, J=7.7 Hz, 2H), 3.68-3.65 (m, 2H), 1.91 (s, 3H), 1.40-1.31 (m, 2H), 1.23-1.13 (m, 2H).

Example 488: 5-(3-Aminopyrrolidin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 485)

##STR01340##

[2202] Compound 485 was synthesized according to an analogous procedure to the one described for compound 463. M+H.sup.+=386.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.01 (s, 1H), 8.67 (d, J=8.3 Hz, 1H), 8.16 (br s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.85-7.78 (m, 2H), 7.61-7.43 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.48 (dd, J=2.6, 8.3 Hz, 1H), 6.25 (d, J=2.5 Hz, 1H), 3. 46-3.29 (m, 2H), 3.22-3.12 (m, 2H), 2.58-2.52 (m, 1H), 2.34-2.21 (m, 1H), 2.07-1.96 (m, 1H), 1.91 (s, 3H), 1.35 (s, 2H), 1.22-1.13 (m, 2H).

Example 489: 5-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-2-methyl-N-(1-(naphthalen-1-yl)cyclopropyl)benzamide (Compound 506)

##STR01341##

[2203] Compound 506 was synthesized according to an analogous procedure to the one described for compound 463. M+H.sup.+=414.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.54-9.30 (m, 1H), 9.05 (s, 1H), 8.91-8.63 (m, 2H), 7.93 (d, J=7.5 Hz, 1H), 7.82 (dd, J=7.6, 10.5 Hz, 2H), 7.60-7.41 (m, 3H), 7.03-6.97 (m, 1H), 6.91 (s, 1H), 6.64 (d, J=2.5 Hz, 1H), 3.67 (br d, J=11.4 Hz, 2H), 3.27 (br s, 2H), 2.56 (br t, J=11.9 Hz, 2H), 1.92 (s, 3H), 1.36 (s, 2H), 1.26 (d, J=6.4 Hz, 6H), 1.18 (br s, 2H).

Example 490: 5-(2-Aminopropoxy)-2-methyl-N-(1-(3-(5-methylthiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 479)

##STR01342##

[2204] Compound 479 was synthesized according to an analogous procedure to the one described for compound 470. M+H.sup.+=471.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.24 (s, 1H), 8.56-8.49 (m, 1H), 8.18 (d, J=1.88 Hz, 1H), 7.94 (d, J=1.50 Hz, 1H), 7.92-7.87 (m, 1H), 7.55-7.46 (m, 2H), 7.37 (d, J=3.50 Hz, 1H), 7.08 (d, J=8.50 Hz, 1H), 6.90 (dd, J=8.50, 2.75 Hz, 1H), 6.81 (dd, J=3.56, 1.06 Hz, 1H), 6.71 (d, J=2.63 Hz, 1H), 4.07 (dd, J=10.32, 3.56 Hz, 1H), 3.86 (dd, J=10.38, 7.25 Hz, 1H), 3.62 (td, J=6.88, 3.50 Hz, 1H), 2.53 (s, 3H), 2.04 (s, 3H), 1.47 (s, 2H), 1.39-1.30 (m, 5H).

Example 491: 5-(2-Aminopropoxy)-N-(1-(3-(5-chlorothiophen-2-yl)naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 502)

##STR01343##

[2205] Compound 502 was synthesized according to an analogous procedure to the one described for compound 470. M+H.sup.+=491.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12 (s, 1H), 8.67-8.59 (m, 1H), 8.06 (d, J=1.50 Hz, 1H), 8.02-7.95 (m, 2H), 7.61-7.51 (m, 3H), 7.23 (d, J=3.88 Hz, 1H), 7.02 (d, J=8.50 Hz, 1H), 6.83 (dd, J=8.32, 2.69 Hz, 1H), 6.60 (d, J=2.63 Hz, 1H), 3.67-3.56 (m, 2H), 3.11-3.00 (m, 1H), 1.96 (s, 3H), 1.38 (br s, 2H), 1.30-1.23 (m, 2H), 1.00 (d, J=6.50 Hz, 3H).

Example 492: 5-(2-Aminopropoxy)-N-(1-(3-(4-fluorophenyl)naphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 480)

##STR01344##

[2206] Compound 480 was synthesized according to an analogous procedure to the one described for compound 470. M+H.sup.+=469.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 8.60 (d, J=8.13 Hz, 1H), 8.23 (d, J=1.88 Hz, 1H), 8.06 (d, J=1.38 Hz, 1H), 8.03-7.97 (m, 1H), 7.85 (dd, J=8.75, 5.38 Hz, 2H), 7.65-7.53 (m, 2H), 7.25 (t, J=8.82 Hz, 2H), 7.11 (d, J=8.50 Hz, 1H), 6.94 (br d, J=2.75 Hz, 1H), 6.73 (d, J=2.63 Hz, 1H), 4.10 (dd, J=10.26, 3.50 Hz, 1H), 3.88 (s, 1H), 3.70-3.59 (m, 1H), 2.05 (s, 3H), 1.50 (br s, 2H), 1.44-1.38 (m, 2H), 1.36 (d, J=6.75 Hz, 3H).

Example 493: N-(1-(3-Ethoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 478)

##STR01345##

[2207] Compound 478 was synthesized according to an analogous procedure to the one described for compound 474. M+H.sup.+=445.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11-9.04 (m, 1H), 8.57-8.50 (m, 1H), 8.22-8.15 (m, 1H), 7.86-7.77 (m, 1H), 7.48-7.33 (m, 3H), 7.25-7.17 (m, 1H), 7.07-6.98 (m, 1H), 6.88-6.78 (m, 1H), 6.67-6.52 (m, 1H), 4.18-4.09 (m, 2H), 3.90-3.84 (m, 2H), 3.30-3.24 (m, 2H), 2.76 (br d, J=7.8 Hz, 1H), 2.23 (s, 3H), 2.03-1.78 (m, 5H), 1.44-1.38 (m, 3H), 1.35-1.29 (m, 2H), 1.19-1.12 (m, 2H).

Example 494: N-(1-(3-Isopropoxynaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methyl azetidin-2-yl)methoxy)benzamide (Compound 476)

##STR01346##

[2208] Compound 476 was synthesized according to an analogous procedure to the one described for compound 474. M+H.sup.+=459.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09-9.03 (m, 1H), 8.56-8.49 (m, 1H), 8.22-8.17 (m, 1H), 7.83-7.76 (m, 1H), 7.47-7.33 (m, 3H), 7.24-7.19 (m, 1H), 7.05-6.99 (m, 1H), 6.85-6.80 (m, 1H), 6.62-6.57 (m, 1H), 4.82-4.68 (m, 1H), 3.91-3.82 (m, 2H), 3.27-3.20 (m, 2H), 2.77-2.70 (m, 1H), 2.23-2.19 (m, 3H), 2.03-1.78 (m, 5H), 1.37-1.33 (m, 6H), 1.33-1.30 (m, 2H), 1.18-1.12 (m, 2H).

Example 495: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(neopentyloxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 787)

##STR01347##

[2209] Compound 787 was synthesized according to an analogous procedure to the one described for compound 474. M+H.sup.+=488.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.67-9.59 (m, 1H), 9.34-9.28 (m, 1H), 9.12-9.05 (m, 1H), 7.97-7.88 (m, 1H), 7.77-7.71 (m, 1H), 7.53-7.46 (m, 1H), 7.13-7.06 (m, 1H), 6.95-6.89 (m, 1H), 6.76-6.71 (m, 1H), 4.66-4.56 (m, 1H), 4.31-4.16 (m, 2H), 4.05-3.98 (m, 1H), 3.92-3.85 (m, 3H), 2.86-2.67 (m, 3H), 2.43-2.26 (m, 2H), 1.96-1.90 (m, 3H), 1.46-1.39 (m, 2H), 1.35-1.27 (m, 2H), 1.09-1.02 (m, 9H).

Example 496: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-(5-methylthiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 493)

##STR01348##

[2210] Compound 493 was synthesized according to an analogous procedure to the one described for compound 475. M+H.sup.+=497.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.91 (br s, 1H), 9.13 (s, 1H), 8.64-8.52 (m, 1H), 8.04-7.98 (m, 2H), 7.97-7.93 (m, 1H), 7.57-7.49 (m, 2H), 7.44 (d, J=3.5 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.94-6.85 (m, 2H), 6.69 (d, J=2.6 Hz, 1H), 4.63-4.51 (m, 1H), 4.27-4.17 (m, 2H), 4.05-3.96 (m, 1H), 3.84 (br dd, J=6.5, 9.4 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.50 (br s, 3H), 2.43-2.28 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.25 (br s, 2H).

Example 497: N-(1-(3-(5-Chlorothiophen-2-yl)naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 514)

##STR01349##

[2211] Compound 514 was synthesized according to an analogous procedure to the one described for compound 475. M+H.sup.+=517.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.38-10.11 (m, 1H), 9.15 (s, 1H), 8.66-8.61 (m, 1H), 8.07 (d, J=1.5 Hz, 1H), 8.03-7.98 (m, 2H), 7.59-7.54 (m, 3H), 7.24 (d, J=4.0 Hz, 1H), 7.08 (s, 1H), 6.93-6.87 (m, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.68-4.56 (m, 1H), 4.32-4.18 (m, 2H), 4.06-3.95 (m, 1H), 3.90-3.76 (m, 1H), 2.82 (d, J=5.1 Hz, 3H), 2.38-2.28 (m, 2H), 1.98 (s, 3H), 1.38 (br s, 2H), 1.28 (br s, 2H).

Example 498: N-(1-(3-(4-Fluorophenyl)naphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 518)

##STR01350##

[2212] Compound 518 was synthesized according to an analogous procedure to the one described for compound 475. M+H.sup.+=495.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.13 (s, 1H), 8.66 (d, J=7.9 Hz, 1H), 8.24-8.16 (m, 1H), 8.14-8.08 (m, 2H), 8.01 (br d, J=7.5 Hz, 1H), 7.87 (dd, J=5.9, 7.9 Hz, 2H), 7.65-7.50 (m, 2H), 7.37 (s, 2H), 7.08-6.97 (m, 1H), 6.89-6.76 (m, 1H), 6.60 (d, J=2.4 Hz, 1H), 3.86 (d, J=5.0 Hz, 2H), 3.26 (br d, J=1.1 Hz, 2H), 2.78-2.68 (m, 1H), 2.22 (s, 3H), 1.98 (s, 3H), 1.94 (br s, 2H), 1.38 (br s, 2H), 1.29 (br d, J=2.6 Hz, 2H).

Example 499: N-(1-(3-Acetamidonaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 500)

##STR01351##

[2213] Compound 500 was synthesized according to an analogous procedure to the one described for compound 482. M+H.sup.+=458.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.93-9.80 (m, 1H), 9.12 (s, 1H), 8.58-8.50 (m, 1H), 8.35 (d, J=1.50 Hz, 1H), 7.85-7.77 (m, 2H), 7.50-7.39 (m, 2H), 7.10 (d, J=8.38 Hz, 1H), 6.91 (dd, J=8.38, 2.75 Hz, 1H), 6.76-6.68 (m, 1H), 4.60 (br d, J=3.63 Hz, 1H), 4.28-4.14 (m, 2H), 4.07-3.96 (m, 1H), 3.92-3.80 (m, 1H), 2.83 (d, J=4.13 Hz, 3H), 2.43-2.27 (m, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 1.35 (br s, 2H), 1.16 (br s, 2H).

Example 500: 5-(((2R,4S)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 510)

##STR01352##

[2214] Compound 510 was synthesized according to an analogous procedure to the one described for compound 490. M+H.sup.+=449.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.04 (br d, J=8.0 Hz, 1H), 9.73-9.48 (m, 1H), 9.13 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.53-7.34 (m, 3H), 7.24 (d, J=2.5 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 5.62-5.30 (m, 1H), 4.27-4.20 (m, 1H), 4.19-4.10 (m, 1H), 4.09-3.98 (m, 1H), 3.87 (s, 3H), 3.50 (br s, 2H), 2.44-2.28 (m, 1H), 2.12-1.91 (m, 4H), 1.34 (br s, 2H), 1.16 (br s, 2H).

Example 501: 5-(((2S,4R)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 512)

##STR01353##

[2215] Compound 512 was synthesized according to an analogous procedure to the one described for compound 490. M+H.sup.+=450.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.26-10.11 (m, 1H), 9.88-9.68 (m, 2H), 9.44-9.36 (m, 1H), 9.22-9.14 (m, 1H), 8.02-7.94 (m, 1H), 7.76-7.69 (m, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 5.60-5.32 (m, 1H), 4.29-4.16 (m, 3H), 4.02 (s, 3H), 3.63-3.40 (m, 2H), 2.45-2.29 (m, 1H), 2.00 (br s, 1H), 1.99-1.95 (m, 3H), 1.45-1.40 (m, 2H), 1.35-1.28 (m, 2H).

Example 502: 5-(((2R,4S)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 556)

##STR01354##

[2216] Compound 556 was synthesized according to an analogous procedure to the one described for compound 490. M+H.sup.+=450.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.09 (s, 1H), 9.01-8.88 (m, 1H), 8.81 (dd, J=1.6, 4.2 Hz, 1H), 7.51-7.37 (m, 2H), 7.31 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.6, 8.4 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 5.34-5.10 (m, 1H), 3.92 (s, 3H), 3.82-3.68 (m, 2H), 3.60-3.48 (m, 1H), 3.02 (d, J=2.1 Hz, 1H), 2.97-2.90 (m, 1H), 2.15-1.98 (m, 1H), 1.94 (s, 3H), 1.77-1.52 (m, 1H), 1.42-1.29 (m, 2H), 1.21-1.12 (m, 2H).

Example 503: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-vinylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 517)

##STR01355##

[2217] Compound 517 was synthesized according to an analogous procedure to the one described for compound 508. M+H.sup.+=427.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.26-10.15 (m, 1H), 9.11 (s, 1H), 8.61 (d, J=7.5 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.84 (s, 1H), 7.53 (dquin, J=1.4, 6.9 Hz, 2H), 7.11-7.07 (m, 1H), 6.96-6.87 (m, 2H), 6.69 (d, J=2.8 Hz, 1H), 5.98 (d, J=17.5 Hz, 1H), 5.39 (d, J=11.4 Hz, 1H), 4.69-4.51 (m, 1H), 4.32-4.16 (m, 2H), 4.08-3.94 (m, 1H), 3.90-3.77 (m, 1H), 2.82 (d, J=4.9 Hz, 3H), 2.75-2.59 (m, 1H), 2.38-2.26 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.23 (br s, 2H).

Example 504: N-(1-(3-Allylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 503)

##STR01356##

[2218] Compound 503 was synthesized according to an analogous procedure to the one described for compound 508. M+H.sup.+=441.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.31-10.10 (m, 1H), 9.09 (s, 1H), 8.61 (br d, J=7.5 Hz, 1H), 7.90-7.84 (m, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.61 (s, 1H), 7.54-7.46 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.6, 8.3 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.06 (tdd, J=6.8, 10.1, 17.0 Hz, 1H), 5.23-5.07 (m, 2H), 4.65-4.54 (m, 1H), 4.32-4.16 (m, 2H), 4.05-3.94 (m, 1H), 3.90-3.79 (m, 1H), 3.54 (d, J=6.6 Hz, 2H), 2.81 (br s, 3H), 2.39-2.28 (m, 2H), 1.98 (s, 3H), 1.35 (br s, 2H), 1.21-1.12 (m, 2H).

Example 505: (S)-2-Methyl-N-(1-(7-(1-methyl-1H-pyrazol-5-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 578)

##STR01357##

[2219] Compound 578 was synthesized according to an analogous procedure to the one described for compound 508. M+H.sup.+=482.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.11 (br s, 1H), 9.76 (d, J=8.6 Hz, 1H), 9.55-9.41 (m, 1H), 9.32 (d, J=4.0 Hz, 1H), 8.50 (s, 1H), 8.28 (d, J=1.5 Hz, 1H), 8.12 (dd, J=5.1, 8.6 Hz, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.15-7.05 (m, 1H), 6.98-6.89 (m, 1H), 6.83-6.73 (m, 2H), 4.68-4.59 (m, 1H), 4.44 (dd, J=8.3, 11.2 Hz, 1H), 4.26-4.19 (m, 1H), 4.08-4.00 (m, 5H), 2.85-2.65 (m, 3H), 2.38-2.25 (m, 2H), 2.01-1.95 (m, 3H), 1.47 (br s, 2H), 1.39 (br s, 2H).

Example 506: (R)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 554)

##STR01358##

[2220] Compound 554 was synthesized according to an analogous procedure to the one described for compound 511. M+H.sup.+=418.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.72 (d, J=8.4 Hz, 1H), 9.35 (s, 1H), 9.17 (dd, J=1.2, 5.4 Hz, 1H), 7.99 (dd, J=5.4, 8.4 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.65 (dq, J=3.3, 7.9 Hz, 1H), 4.29 (dd, J=7.4, 11.2 Hz, 1H), 4.15 (dd, J=3.4, 11.3 Hz, 1H), 4.02 (s, 3H), 3.96-3.87 (m, 1H), 3.82 (dt, J=6.3, 9.9 Hz, 1H), 2.47-2.41 (m, 1H), 2.40-2.28 (m, 1H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.36-1.26 (m, 2H).

Example 507: N-(1-(3-Ethylnaphthalen-1-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 516)

##STR01359##

[2221] Compound 516 was synthesized according to an analogous procedure to the one described for compound 521. M+H.sup.+=429.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.56-10.43 (m, 1H), 9.09 (s, 1H), 8.65-8.53 (m, 1H), 7.89-7.82 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61 (s, 1H), 7.52-7.44 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.95-6.86 (m, 1H), 6.69 (br s, 1H), 4.60 (br d, J=4.3 Hz, 1H), 4.36-4.26 (m, 1H), 4.24-4.16 (m, 1H), 3.98 (br s, 1H), 3.88-3.73 (m, 1H), 2.84-2.72 (m, 5H), 2.40-2.25 (m, 2H), 1.98 (s, 3H), 1.35 (br s, 2H), 1.32-1.25 (m, 3H), 1.22-1.14 (m, 2H).

Example 508: 2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(3-propylnaphthalen-1-yl)cyclopropyl)benzamide (Compound 504)

##STR01360##

[2222] Compound 504 was synthesized according to an analogous procedure to the one described for compound 521. M+H.sup.+=443.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.45-10.35 (m, 1H), 9.08 (s, 1H), 8.64-8.56 (m, 1H), 7.89-7.82 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.60 (s, 1H), 7.52-7.44 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.67-4.55 (m, 1H), 4.36-4.26 (m, 1H), 4.24-4.17 (m, 1H), 4.05-3.94 (m, 1H), 3.84 (br dd, J=6.5, 9.6 Hz, 1H), 2.81 (d, J=5.1 Hz, 3H), 2.75-2.66 (m, 2H), 2.40-2.26 (m, 2H), 2.02-1.95 (m, 3H), 1.75-1.63 (m, 2H), 1.35 (br s, 2H), 1.17 (br s, 2H), 0.95 (t, J=7.4 Hz, 3H).

Example 509: (R)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 558)

##STR01361##

[2223] Compound 558 was synthesized according to an analogous procedure to the one described for compound 527. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.64 (br d, J=8.6 Hz, 1H), 9.31 (s, 1H), 9.15 (d, J=5.3 Hz, 1H), 7.95 (dd, J=5.4, 8.5 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.55 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.76 (d, J=2.8 Hz, 1H), 4.62 (dt, J=5.6, 8.0 Hz, 1H), 4.37-4.16 (m, 2H), 4.02 (s, 4H), 3.86 (d, J=9.6 Hz, 1H), 2.82 (s, 3H), 2.43-2.27 (m, 2H), 1.94 (s, 3H), 1.41 (br s, 2H), 1.31 (br s, 2H).

Example 510: 5-(((2R,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(3-methoxynaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 531)

##STR01362##

[2224] Compound 531 was synthesized according to an analogous procedure to the one described for compound 528. M+H.sup.+=463.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.30-11.07 (m, 1H), 9.13 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.50-7.34 (m, 3H), 7.24 (d, J=2.4 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.80-6.65 (m, 1H), 5.55-5.31 (m, 1H), 4.33 (br d, J=5.1 Hz, 2H), 4.10-3.98 (m, 2H), 3.91-3.87 (m, 3H), 3.55-3.38 (m, 1H), 2.97 (d, J=4.6 Hz, 3H), 2.49-2.37 (m, 1H), 2.22-2.03 (m, 1H), 1.97 (s, 3H), 1.34 (br s, 2H), 1.17 (br s, 2H).

Example 511: 5-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 532)

##STR01363##

[2225] Compound 532 was synthesized according to an analogous procedure to the one described for compound 528. M+H.sup.+=464.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.12-9.05 (m, 1H), 8.97-8.90 (m, 1H), 8.84-8.77 (m, 1H), 7.48-7.45 (m, 1H), 7.44-7.38 (m, 1H), 7.32-7.29 (m, 1H), 7.05-7.01 (m, 1H), 6.87-6.81 (m, 1H), 6.63-6.59 (m, 1H), 5.31-5.01 (m, 1H), 3.94-3.89 (m, 4H), 3.84-3.78 (m, 1H), 3.47-3.34 (m, 1H), 2.89-2.79 (m, 1H), 2.43-2.36 (m, 1H), 2.36-2.33 (m, 3H), 2.16-2.02 (m, 1H), 1.96-1.91 (m, 3H), 1.89-1.73 (m, 1H), 1.36-1.30 (m, 2H), 1.21-1.15 (m, 2H).

Example 512: 5-(((2R,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 557)

##STR01364##

[2226] Compound 557 was synthesized according to an analogous procedure to the one described for compound 528. M+H.sup.+=464.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 9.00-8.91 (m, 1H), 8.87-8.76 (m, 1H), 7.49-7.45 (m, 1H), 7.44-7.39 (m, 1H), 7.33-7.29 (m, 1H), 7.06-7.00 (m, 1H), 6.88-6.80 (m, 1H), 6.66-6.58 (m, 1H), 5.29-4.96 (m, 1H), 4.01-3.87 (m, 4H), 3.85-3.77 (m, 1H), 3.47-3.36 (m, 1H), 2.91-2.79 (m, 1H), 2.41 (br d, J=11.6 Hz, 1H), 2.34 (s, 3H), 2.18-1.99 (m, 1H), 1.94 (s, 3H), 1.91-1.70 (m, 1H), 1.34 (br s, 2H), 1.24-1.13 (m, 2H).

Example 513: (S)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylpiperidin-2-yl)methoxy)benzamide (Compound 553)

##STR01365##

[2227] Compound 553 was synthesized according to an analogous procedure to the one described for compound 528. M+H.sup.+=460.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.69 (d, J=8.4 Hz, 1H), 9.37 (s, 1H), 9.21-9.14 (m, 1H), 7.98 (dd, J=5.4, 8.4 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.97-6.88 (m, 1H), 6.81-6.74 (m, 1H), 4.27-4.13 (m, 2H), 4.02 (s, 3H), 3.35 (br s, 1H), 3.28-3.18 (m, 1H), 3.09-3.01 (m, 1H), 2.78-2.68 (m, 3H), 1.96 (s, 3H), 1.94-1.86 (m, 1H), 1.80-1.66 (m, 4H), 1.57-1.44 (m, 1H), 1.42 (br s, 2H), 1.31 (br s, 2H).

Example 514: (R)-5-(2-Aminopropoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 535)

##STR01366##

[2228] Compound 535 was synthesized according to an analogous procedure to the one described for compound 530. M+H.sup.+=406.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.24-9.14 (m, 2H), 8.97 (br d, J=4.38 Hz, 1H), 7.95 (br s, 3H), 7.63 (br dd, J=8.19, 4.69 Hz, 1H), 7.57 (d, J=2.38 Hz, 1H), 7.39 (d, J=2.13 Hz, 1H), 7.09 (d, J=8.50 Hz, 1H), 6.90 (dd, J=8.38, 2.75 Hz, 1H), 6.69 (d, J=2.63 Hz, 1H), 4.03 (dd, J=10.26, 3.88 Hz, 1H), 3.96 (s, 3H), 3.86 (dd, J=10.26, 7.25 Hz, 1H), 3.61-3.48 (m, 1H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.29-1.17 (m, 5H).

Example 515: (S)-5-(2-Aminopropoxy)-N-(1-(7-methoxyisoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 536)

##STR01367##

[2229] Compound 536 was synthesized according to an analogous procedure to the one described for compound 530. M+H.sup.+=406.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.45 (s, 1H), 9.22 (s, 1H), 8.63 (d, J=6.13 Hz, 1H), 8.55 (d, J=6.13 Hz, 1H), 7.96 (br s, 3H), 7.80 (d, J=2.63 Hz, 1H), 7.63 (d, J=2.25 Hz, 1H), 7.08 (d, J=8.50 Hz, 1H), 6.89 (dd, J=8.44, 2.69 Hz, 1H), 6.69 (d, J=2.63 Hz, 1H), 4.02 (br d, J=6.38 Hz, 1H), 3.95 (s, 3H), 3.85 (br d, J=3.13 Hz, 1H), 3.58-3.51 (m, 1H), 1.94 (s, 3H), 1.40-1.31 (m, 2H), 1.22 (br d, J=6.75 Hz, 5H).

Example 516: (R)-5-(2-Aminopropoxy)-N-(1-(7-methoxyisoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 537)

##STR01368##

[2230] Compound 537 was synthesized according to an analogous procedure to the one described for compound 530. M+H.sup.+=406.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.50 (s, 1H), 9.23 (s, 1H), 8.69 (d, J=6.13 Hz, 1H), 8.59 (d, J=6.25 Hz, 1H), 7.95 (br s, 3H), 7.84 (d, J=2.38 Hz, 1H), 7.68 (d, J=2.25 Hz, 1H), 7.09 (d, J=8.51 Hz, 1H), 6.90 (dd, J=8.38, 2.63 Hz, 1H), 6.70 (d, J=2.63 Hz, 1H), 4.05-4.02 (m, 1H), 3.97 (s, 3H), 3.88-3.84 (m, 1H), 3.56 (br dd, J=10.57, 5.69 Hz, 1H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.28-1.19 (m, 5H).

Example 517: (R)-5-(2-Aminopropoxy)-2-methyl-N-(1-(3-(thiophen-2-yl)naphthalen-1-yl)cyclopropyl)benzamide (Compound 543)

##STR01369##

[2231] Compound 543 was synthesized according to an analogous procedure to the one described for compound 539. M+H.sup.+=457.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21 (s, 1H), 8.71-8.59 (m, 1H), 8.16 (br s, 2H), 8.14-8.11 (m, 2H), 8.05-7.98 (m, 1H), 7.68 (dd, J=3.61, 0.92 Hz, 1H), 7.64 (dd, J=5.07, 0.92 Hz, 1H), 7.62-7.53 (m, 2H), 7.23 (dd, J=5.07, 3.61 Hz, 1H), 7.10 (d, J=8.44 Hz, 1H), 6.91 (dd, J=8.37, 2.63 Hz, 1H), 6.70 (d, J=2.57 Hz, 1H), 4.05 (dd, J=10.27, 3.91 Hz, 1H), 3.91 (dd, J=10.21, 7.03 Hz, 1H), 3.61-3.49 (m, 1H), 2.01 (s, 3H), 1.44-1.38 (m, 2H), 1.32-1.22 (m, 5H).

Example 518: (R)-5-(2-Aminopropoxy)-N-(1-(3-bromonaphthalen-1-yl)cyclopropyl)-2-methylbenzamide (Compound 540)

##STR01370##

[2232] Compound 540 was synthesized according to an analogous procedure to the one described for compound 541. M+H.sup.+=453.0 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22 (s, 1H), 8.64 (d, J=8.25 Hz, 1H), 8.18 (br s, 2H), 8.15 (d, J=1.38 Hz, 1H), 7.94 (d, J=8.00 Hz, 1H), 7.88 (d, J=1.88 Hz, 1H), 7.60 (dt, J=19.76, 7.00 Hz, 2H), 7.08 (d, J=8.38 Hz, 1H), 6.89 (dd, J=8.38, 2.63 Hz, 1H), 6.68 (d, J=2.50 Hz, 1H), 4.04 (dd, J=10.26, 4.00 Hz, 1H), 3.90 (dd, J=10.13, 7.13 Hz, 1H), 3.52 (br d, J=4.75 Hz, 1H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.29-1.18 (m, 5H).

Example 519: N-(3-Fluorobenzyl)-1-(1-(2-isopropylphenyl)ethyl)piperidine-4-carboxamide (Compound 552)

##STR01371##

[2233] Compound 552 was synthesized according to an analogous procedure to the one described for compound 549. M+H.sup.+=383.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.80 (br dd, J=1.8, 4.9 Hz, 1H), 8.62-8.48 (m, 1H), 7.83-7.71 (m, 1H), 7.53-7.26 (m, 4H), 7.12-6.94 (m, 3H), 4.72 (br t, J=7.1 Hz, 1H), 4.33-4.22 (m, 2H), 3.90 (br d, J=10.5 Hz, 1H), 3.39-3.35 (m, 1H), 3.21-3.08 (m, 1H), 2.95 (br d, J=11.4 Hz, 1H), 2.82-2.69 (m, 1H), 2.48-2.40 (m, 1H), 2.16-1.96 (m, 2H), 1.93-1.71 (m, 2H), 1.65-1.60 (m, 3H), 1.28-1.22 (m, 3H), 1.11 (d, J=6.8 Hz, 3H).

Example 520: N-(3-Fluorobenzyl)-1-(1-(7-methoxyquinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 593)

##STR01372##

[2234] Compound 593 was synthesized according to an analogous procedure to the one described for compound 549. M+H.sup.+=422.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 8.83-8.70 (m, 2H), 8.29 (br t, J=5.9 Hz, 1H), 7.39-7.30 (m, 2H), 7.27 (d, J=2.3 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 7.08-6.95 (m, 3H), 4.24 (d, J=5.4 Hz, 2H), 4.12 (q, J=6.4 Hz, 1H), 3.90 (s, 3H), 2.98 (br d, J=10.6 Hz, 1H), 2.78 (br d, J=11.1 Hz, 1H), 2.20-2.10 (m, 1H), 2.07-1.95 (m, 2H), 1.74-1.59 (m, 2H), 1.58-1.44 (m, 2H), 1.37 (d, J=6.6 Hz, 3H).

Example 521: N-(3-Fluorobenzyl)-1-(1-(3-(thiophen-2-yl)naphthalen-1-yl)ethyl)piperidine-4-carboxamide (Compound 599)

##STR01373##

[2235] Compound 599 was synthesized according to an analogous procedure to the one described for compound 549. M+H.sup.+=473.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.03-9.87 (m, 1H), 8.51 (br t, J=5.8 Hz, 1H), 8.45-8.33 (m, 2H), 8.27 (s, 1H), 8.11-8.05 (m, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.68-7.57 (m, 3H), 7.40-7.31 (m, 1H), 7.26-7.20 (m, 1H), 7.11-6.98 (m, 3H), 5.46-5.28 (m, 1H), 4.31-4.24 (m, 2H), 4.02 (br d, J=12.1 Hz, 1H), 3.29-3.14 (m, 1H), 3.11-3.00 (m, 1H), 2.96-2.85 (m, 1H), 2.47-2.40 (m, 1H), 2.13-2.01 (m, 2H), 1.85-1.77 (m, 5H).

Example 522: (R)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino)propoxy)benzamide (Compound 573)

##STR01374##

[2236] Compound 573 was synthesized according to an analogous procedure to the one described for compound 560. M+H.sup.+=420.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.59-9.49 (m, 1H), 9.35-9.28 (m, 1H), 9.15-9.00 (m, 2H), 8.98-8.87 (m, 1H), 7.94-7.84 (m, 1H), 7.69 (br s, 1H), 7.62-7.54 (m, 1H), 7.09 (d, J=8.50 Hz, 1H), 6.92 (dd, J=8.38, 2.63 Hz, 1H), 6.74 (s, 1H), 4.16-4.11 (m, 1H), 4.07-4.03 (m, 1H), 4.01 (s, 3H), 3.53-3.46 (m, 1H), 2.58-2.52 (m, 3H), 1.96 (s, 3H), 1.44-1.36 (m, 2H), 1.33-1.24 (m, 5H).

Example 523: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyridin-2-ylmethoxy)benzamide (Compound 562)

##STR01375##

[2237] Compound 562 was synthesized according to an analogous procedure to the one described for compound 561. M+H.sup.+=440.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.69 (d, J=8.4 Hz, 1H), 9.33 (s, 1H), 9.20 (dd, J=1.3, 5.4 Hz, 1H), 8.68 (d, J=4.5 Hz, 1H), 8.11 (br t, J=7.9 Hz, 1H), 7.99 (dd, J=5.4, 8.4 Hz, 1H), 7.79-7.64 (m, 3H), 7.64-7.55 (m, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.97 (dd, J=2.8, 8.4 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 5.26 (s, 2H), 4.02 (s, 3H), 1.98 (s, 3H), 1.46-1.39 (m, 2H), 1.35-1.29 (m, 2H).

Example 524: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(trifluoromethoxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 579)

##STR01376##

[2238] Compound 579 was synthesized according to an analogous procedure to the one described for compound 563. M+H.sup.+=486.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.36-10.25 (m, 1H), 9.26 (s, 1H), 9.16 (d, J=8.1 Hz, 1H), 9.03 (dd, J=1.4, 4.2 Hz, 1H), 7.94-7.79 (m, 2H), 7.72 (dd, J=4.3, 8.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.69-4.56 (m, 1H), 4.34-4.18 (m, 2H), 4.06-3.96 (m, 1H), 3.92-3.80 (m, 1H), 2.82 (d, J=5.0 Hz, 3H), 2.36-2.23 (m, 2H), 1.94 (s, 3H), 1.40 (br s, 2H), 1.32-1.24 (m, 2H).

Example 525: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 570)

##STR01377##

[2239] Compound 570 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=428.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.08 (br d, J=2.3 Hz, 1H), 9.62 (br d, J=8.6 Hz, 1H), 9.36 (s, 1H), 9.19 (d, J=4.4 Hz, 1H), 8.29-8.15 (m, 2H), 7.99 (br dd, J=5.1, 8.3 Hz, 1H), 7.17-7.01 (m, 2H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.23 (d, J=17.5 Hz, 1H), 5.66 (d, J=11.0 Hz, 1H), 4.66-4.59 (m, 1H), 4.46-4.38 (m, 1H), 4.24-4.18 (m, 1H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.79 (d, J=5.1 Hz, 3H), 2.41-2.23 (m, 2H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.35 (br s, 2H).

Example 526: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(2-methylprop-1-en-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 603)

##STR01378##

[2240] Compound 603 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=456.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.52 (br d, J=1.3 Hz, 1H), 9.25 (br s, 1H), 9.14 (br s, 1H), 8.06-7.86 (m, 3H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.7, 8.4 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.55 (s, 1H), 4.61 (br dd, J=2.8, 6.8 Hz, 1H), 4.36-4.16 (m, 2H), 4.02 (dt, J=4.6, 9.7 Hz, 1H), 3.86 (q, J=9.5 Hz, 1H), 2.90-2.73 (m, 3H), 2.46-2.29 (m, 2H), 2.09-1.90 (m, 9H), 1.41 (br s, 2H), 1.28 (br s, 2H).

Example 527: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(3,3,3-trifluoroprop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 650)

##STR01379##

[2241] Compound 650 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=496.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.31-9.15 (m, 2H), 9.04 (br d, J=3.8 Hz, 1H), 8.08 (br d, J=5.6 Hz, 2H), 7.74 (br dd, J=4.5, 8.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 6.42 (s, 1H), 6.32 (s, 1H), 4.70-4.55 (m, 1H), 4.35-4.17 (m, 2H), 4.09-3.94 (m, 1H), 3.93-3.81 (m, 1H), 2.69 (s, 3H), 2.34-2.28 (m, 2H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.30 (br s, 2H).

Example 528: (S)N-(1-(7-(3-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 668)

##STR01380##

[2242] Compound 668 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=518.2/520.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.72-10.46 (m, 1H), 9.44-9.23 (m, 2H), 9.10 (br s, 1H), 8.38 (br s, 1H), 8.26 (s, 1H), 7.90 (d, J=5.4 Hz, 1H), 7.83 (br d, J=3.6 Hz, 1H), 7.31 (d, J=5.4 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 4.70-4.54 (m, 1H), 4.38-4.30 (m, 1H), 4.22 (br dd, J=3.2, 11.2 Hz, 1H), 4.08-3.97 (m, 2H), 2.81 (d, J=5.0 Hz, 3H), 2.39-2.23 (m, 2H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.31 (br s, 2H).

Example 529: (S)N-(1-(7-(4-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 632)

##STR01381##

[2243] Compound 632 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=518.2/520.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.71-10.56 (m, 1H), 9.39 (br d, J=8.6 Hz, 1H), 9.30 (s, 1H), 9.12 (d, J=3.6 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J=1.6 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 7.85 (dd, J=4.6, 8.5 Hz, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 4.68-4.55 (m, 1H), 4.35 (dd, J=7.9, 11.3 Hz, 1H), 4.21 (dd, J=3.1, 11.3 Hz, 1H), 4.02-3.95 (m, 1H), 3.87-3.83 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 2.39-2.24 (m, 2H), 1.97 (s, 3H), 1.41 (br d, J=12.6 Hz, 4H).

Example 530: (S)N-(1-(7-(5-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 623)

##STR01382##

[2244] Compound 623 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=518.2/520.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.89-9.77 (m, 1H), 9.17 (s, 1H), 9.04 (br d, J=8.4 Hz, 1H), 8.94 (d, J=4.0 Hz, 1H), 8.10 (d, J=8.9 Hz, 2H), 7.69 (d, J=3.9 Hz, 1H), 7.60 (dd, J=4.6, 8.1 Hz, 1H), 7.27 (d, J=3.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.63-4.53 (m, 1H), 4.26-4.15 (m, 2H), 4.07-3.96 (m, 1H), 3.91-3.79 (m, 1H), 2.83 (d, J=4.9 Hz, 3H), 2.39-2.28 (m, 2H), 1.96 (s, 3H), 1.42-1.29 (m, 4H).

Example 531: N-(1-(7-(Furan-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 604)

##STR01383##

[2245] Compound 604 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=4.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.50 (br d, J=8.4 Hz, 1H), 9.29 (s, 1H), 9.20-9.12 (m, 1H), 8.37 (d, J=1.4 Hz, 1H), 8.32 (s, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.92 (dd, J=4.9, 8.6 Hz, 1H), 7.42 (d, J=3.4 Hz, 1H), 7.12-7.07 (m, 1H), 6.98-6.88 (m, 1H), 6.79-6.75 (m, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.70-4.56 (m, 1H), 4.33-4.17 (m, 2H), 4.01 (dt, J=4.6, 9.6 Hz, 1H), 3.86 (q, J=9.5 Hz, 1H), 2.84-2.68 (m, 3H), 2.42-2.22 (m, 2H), 1.95 (s, 3H), 1.48-1.33 (m, 4H).

Example 532: (S)N-(1-(7-(1H-Pyrazol-4-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 652)

##STR01384##

[2246] Compound 652 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.04 (m, 2H), 8.94 (d, J=4.1 Hz, 1H), 8.31 (br s, 2H), 8.19-8.06 (m, 2H), 7.67-7.49 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.69-4.53 (m, 1H), 4.22 (br d, J=3.0 Hz, 2H), 4.06-3.99 (m, 1H), 3.94-3.85 (m, 1H), 2.88-2.79 (m, 3H), 2.48-2.43 (m, 1H), 2.35 (br s, 1H), 1.98 (s, 3H), 1.50-1.25 (m, 4H).

Example 533: (S)-2-Methyl-N-(1-(7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 670)

##STR01385##

[2247] Compound 670 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=482.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.45-10.28 (m, 1H), 9.46-9.33 (m, 1H), 9.25 (s, 1H), 9.08 (br d, J=2.1 Hz, 1H), 8.50 (s, 1H), 8.20 (br d, J=18.0 Hz, 2H), 8.13 (s, 1H), 7.86-7.77 (m, 1H), 7.14-7.07 (m, 1H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 4.66-4.57 (m, 1H), 4.36-4.19 (m, 2H), 4.06-3.98 (m, 1H), 3.95 (s, 3H), 3.86 (br dd, J=6.5, 9.6 Hz, 1H), 2.82 (d, J=4.9 Hz, 3H), 2.34-2.26 (m, 2H), 1.98 (s, 3H), 1.40 (br d, J=16.6 Hz, 4H).

Example 534: (S)N-(1-(7-(1H-Pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 633)

##STR01386##

[2248] Compound 633 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=468.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.59-10.39 (m, 1H), 9.45 (br d, J=5.5 Hz, 1H), 9.28 (s, 1H), 9.17-9.02 (m, 1H), 8.49 (br d, J=17.9 Hz, 2H), 7.95-7.77 (m, 2H), 7.17-7.06 (m, 1H), 6.99 (d, J=2.1 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.81-6.67 (m, 1H), 4.72-4.55 (m, 1H), 4.39-4.27 (m, 1H), 4.26-4.15 (m, 1H), 4.03-3.96 (m, 1H), 3.85 (br dd, J=6.7, 9.7 Hz, 1H), 2.81 (d, J=4.9 Hz, 3H), 2.42-2.34 (m, 1H), 2.32-2.22 (m, 1H), 1.97 (s, 3H), 1.44 (br s, 2H), 1.35 (br s, 2H).

Example 535: (S)-2-Methyl-N-(1-(7-(5-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 651)

##STR01387##

[2249] Compound 651 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=482.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 12.73 (s, 1H), 9.11 (s, 1H), 9.04 (br d, J=8.4 Hz, 1H), 8.94-8.85 (m, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.52 (dd, J=4.3, 8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.8, 8.3 Hz, 1H), 6.66 (s, 1H), 6.61 (d, J=2.6 Hz, 1H), 3.86 (d, J=5.4 Hz, 2H), 3.27-3.16 (m, 2H), 2.76-2.66 (m, 1H), 2.32 (s, 3H), 2.23-2.17 (m, 3H), 1.98-1.92 (m, 4H), 1.88-1.80 (m, 1H), 1.39 (br s, 2H), 1.33-1.20 (m, 2H).

Example 536: (S)-2-Methyl-N-(1-(7-(1-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 582)

##STR01388##

[2250] Compound 582 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=482.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.64 (br d, J=8.8 Hz, 1H), 9.36-9.29 (m, 1H), 9.20 (d, J=4.9 Hz, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.48 (s, 1H), 7.99 (dd, J=5.1, 8.4 Hz, 1H), 7.90 (d, J=2.3 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.00 (d, J=2.3 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.62 (br dd, J=2.9, 7.8 Hz, 1H), 4.39-4.28 (m, 1H), 4.25-4.18 (m, 1H), 4.04-3.95 (m, 4H), 3.85 (d, J=9.8 Hz, 1H), 2.84-2.68 (m, 3H), 2.36 (br s, 2H), 1.96 (s, 3H), 1.46 (br s, 2H), 1.35 (br s, 2H).

Example 537: (S)N-(1-(7-(1-(Difluoromethyl)-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 644)

##STR01389##

[2251] Compound 644 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=518.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.47 (br d, J=8.4 Hz, 1H), 9.29 (s, 1H), 9.18-9.10 (m, 1H), 8.55 (s, 2H), 8.44 (d, J=2.8 Hz, 1H), 8.15-7.78 (m, 2H), 7.32 (d, J=2.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 4.62 (br dd, J=3.3, 7.7 Hz, 1H), 4.37-4.17 (m, 2H), 4.00 (td, J=4.9, 9.5 Hz, 1H), 3.94-3.79 (m, 1H), 2.88-2.67 (m, 3H), 2.39-2.28 (m, 2H), 1.96 (s, 3H), 1.45 (br s, 2H), 1.34 (br s, 2H).

Example 538: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(1-phenyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 659)

##STR01390##

[2252] Compound 659 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=544.3 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.15 (d, J=8.5 Hz, 1H), 8.89 (dd, J=1.5, 4.3 Hz, 1H), 8.65 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.60 (dd, J=4.3, 8.5 Hz, 1H), 7.54 (t, J=8.0 Hz, 2H), 7.40-7.33 (m, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.88 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.06-3.97 (m, 2H), 3.85 (br d, J=1.1 Hz, 1H), 3.62 (td, J=3.9, 7.9 Hz, 1H), 3.28-3.21 (m, 1H), 2.54 (s, 3H), 2.25-2.14 (m, 2H), 2.02 (s, 3H), 1.57-1.52 (m, 2H), 1.48-1.40 (m, 2H).

Example 539: (S)N-(1-(7-(Cyclopent-1-en-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 609)

##STR01391##

[2253] Compound 609 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=468.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.29-9.16 (m, 2H), 9.06-8.97 (m, 1H), 8.22-8.16 (m, 1H), 7.90 (br d, J=5.8 Hz, 1H), 7.65 (br d, J=1.3 Hz, 1H), 7.13-7.05 (m, 1H), 6.97-6.87 (m, 1H), 6.72-6.69 (m, 1H), 6.67-6.64 (m, 1H), 4.65-4.50 (m, 1H), 4.33-4.17 (m, 2H), 4.06-3.94 (m, 1H), 3.90-3.75 (m, 2H), 2.85-2.75 (m, 5H), 2.62-2.57 (m, 2H), 2.37-2.25 (m, 2H), 2.12-2.01 (m, 2H), 1.95 (s, 3H), 1.38 (br s, 2H), 1.31-1.23 (m, 2H).

Example 540: (S)N-(1-(7-(Benzo[b]thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 621)

##STR01392##

[2254] Compound 621 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=534.2 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.90 (br d, J=8.3 Hz, 1H), 9.43 (br s, 1H), 9.22 (br d, J=5.5 Hz, 1H), 8.80 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.18-8.08 (m, 1H), 7.97 (dd, J=3.2, 6.0 Hz, 2H), 7.46 (dd, J=3.1, 6.1 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.98 (dd, J=2.7, 8.3 Hz, 1H), 6.88 (s, 1H), 4.74-4.65 (m, 1H), 4.38-4.14 (m, 3H), 4.02-3.88 (m, 1H), 2.95 (s, 3H), 2.62-2.48 (m, 2H), 2.07 (s, 3H), 1.66 (br s, 2H), 1.59-1.52 (m, 2H).

Example 541: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-phenylquinolin-5-yl)cyclopropyl)benzamide (Compound 594)

##STR01393##

[2255] Compound 594 was synthesized according to an analogous procedure to the one described for compound 568. M+H.sup.+=478.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.50 (br d, J=8.0 Hz, 1H), 9.29 (s, 1H), 9.19-9.11 (m, 1H), 8.39-8.27 (m, 2H), 7.97-7.84 (m, 3H), 7.66-7.58 (m, 2H), 7.55-7.49 (m, 1H), 7.18-7.05 (m, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.81-6.71 (m, 1H), 4.68-4.56 (m, 1H), 4.34-4.17 (m, 2H), 4.01 (dt, J=4.6, 9.6 Hz, 1H), 3.85 (q, J=9.3 Hz, 1H), 2.84-2.69 (m, 3H), 2.40-2.28 (m, 2H), 1.97 (s, 3H), 1.48-1.36 (m, 4H).

Example 542: (R)-5-(2-(Dimethylamino)propoxy)-N-(1-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 574)

##STR01394##

[2256] Compound 574 was synthesized according to an analogous procedure to the one described for compound 575. M+H.sup.+=434.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.87-10.59 (m, 1H), 9.77 (d, J=8.51 Hz, 1H), 9.42 (m, 1H), 9.20 (m, 1H), 8.00 (m, 1H), 7.84-7.61 (m, 2H), 7.09 (d, J=8.50 Hz, 1H), 6.93 (m, 1H), 6.80 (d, J=2.63 Hz, 1H), 4.20 (m, 2H), 4.02 (m, 3H), 3.74-3.68 (m, 1H), 2.76-2.69 (m, 6H), 1.97 (m, 3H), 1.43 (m, 2H), 1.31 (d, J=6.75 Hz, 5H).

Example 543: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-phenoxyquinolin-5-yl)cyclopropyl)benzamide (Compound 592)

##STR01395##

[2257] Compound 592 was synthesized according to an analogous procedure to the one described for compound 581. M+H.sup.+=494.2. 1H NMR (400 MHZ, DMSO-d.sub.6) 9.15 (s, 1H), 9.07-8.95 (m, 1H), 8.88-8.75 (m, 1H), 7.76-7.61 (m, 1H), 7.55-7.43 (m, 3H), 7.35-7.13 (m, 4H), 7.09-6.98 (m, 1H), 6.91-6.77 (m, 1H), 6.69-6.56 (m, 1H), 3.95-3.78 (m, 2H), 3.26-3.19 (m, 2H), 2.76-2.69 (m, 1H), 2.24-2.18 (m, 3H), 2.03-1.90 (m, 4H), 1.88-1.79 (m, 1H), 1.42-1.29 (m, 2H), 1.25-1.20 (m, 2H).

Example 544: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(thiazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 590)

##STR01396##

[2258] Compound 590 was synthesized according to an analogous procedure to the one described for compound 588. M+H.sup.+=485.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.59-10.41 (m, 1H), 9.38-9.24 (m, 2H), 9.09 (d, J=3.3 Hz, 1H), 8.58-8.46 (m, 2H), 8.08 (d, J=3.1 Hz, 1H), 7.97 (d, J=3.3 Hz, 1H), 7.80 (dd, J=4.3, 8.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.69-4.54 (m, 1H), 4.39-4.19 (m, 2H), 4.04-3.93 (m, 1H), 3.88-3.81 (m, 1H), 2.81 (d, J=4.9 Hz, 3H), 2.40-2.25 (m, 2H), 1.97 (s, 3H), 1.45 (br s, 2H), 1.32 (br s, 2H).

Example 545: (S)N-(1-(7-(2-Methoxyethoxy)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 591)

##STR01397##

[2259] Compound 591 was synthesized according to an analogous procedure to the one described for compound 598. M+H.sup.+=476.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.48-10.28 (m, 1H), 9.39 (br dd, J=2.5, 4.8 Hz, 1H), 9.30-9.20 (m, 1H), 9.05 (br d, J=4.3 Hz, 1H), 7.85-7.72 (m, 1H), 7.62 (s, 1H), 7.50-7.43 (m, 1H), 7.14-7.06 (m, 1H), 6.98-6.89 (m, 1H), 6.72 (s, 1H), 4.67-4.55 (m, 1H), 4.36-4.27 (m, 3H), 4.26-4.19 (m, 1H), 4.03-3.96 (m, 1H), 3.90-3.84 (m, 1H), 3.79-3.76 (m, 2H), 2.82 (d, J=5.0 Hz, 3H), 2.72-2.63 (m, 2H), 2.42-2.24 (m, 3H), 1.95 (s, 3H), 1.42-1.36 (m, 2H), 1.28 (br s, 2H).

Example 546: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 612)

##STR01398##

[2260] Compound 612 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=414.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.27 (d, J=8.5 Hz, 1H), 9.19 (s, 1H), 9.04 (dd, J=1.2, 4.4 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H), 8.00 (s, 1H), 7.75 (dd, J=4.6, 8.6 Hz, 1H), 7.12-6.98 (m, 2H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 6.15 (d, J=17.6 Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 4.70-4.60 (m, 1H), 4.28-4.19 (m, 1H), 4.17-4.09 (m, 1H), 3.99-3.79 (m, 2H), 2.44-2.30 (m, 2H), 1.96 (s, 3H), 1.39 (br s, 2H), 1.31 (br s, 2H).

Example 547: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 613)

##STR01399##

[2261] Compound 613 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=428.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.32 (d, J=8.5 Hz, 1H), 9.19 (s, 1H), 9.07 (dd, J=1.4, 4.6 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.04 (s, 1H), 7.79 (dd, J=4.6, 8.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 5.79 (s, 1H), 5.42 (s, 1H), 4.65 (dq, J=3.4, 7.8 Hz, 1H), 4.27-4.19 (m, 1H), 4.17-4.10 (m, 1H), 3.96-3.88 (m, 1H), 3.82 (dt, J=6.3, 10.0 Hz, 1H), 2.45-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.27 (s, 3H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.31 (br s, 2H).

Example 548: (S,E)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(2-cyclopropylvinyl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 667)

##STR01400##

[2262] Compound 667 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=454.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (br d, J=6.1 Hz, 2H), 9.00-8.74 (m, 3H), 7.96 (br d, J=3.9 Hz, 1H), 7.80 (s, 1H), 7.69-7.57 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.78-6.66 (m, 2H), 6.24-6.09 (m, 1H), 4.73-4.60 (m, 1H), 4.26-4.09 (m, 2H), 3.92 (br d, J=6.1 Hz, 1H), 3.85-3.81 (m, 1H), 2.46-2.30 (m, 2H), 1.97 (s, 3H), 1.76-1.64 (m, 1H), 1.41-1.23 (m, 4H), 0.92-0.85 (m, 2H), 0.70-0.60 (m, 2H).

Example 549: (S,E)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(3-methylstyryl)quinolin-5-yl)cyclopropyl)benzamide (Compound 704)

##STR01401##

[2263] Compound 704 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=504.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.48 (d, J=8.3 Hz, 1H), 9.02 (dd, J=1.3, 4.8 Hz, 1H), 8.51 (d, J=1.3 Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J=4.9, 8.5 Hz, 1H), 7.65-7.57 (m, 1H), 7.55-7.42 (m, 3H), 7.31 (t, J=7.7 Hz, 1H), 7.18 (br d, J=7.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.96 (dd, J=2.7, 8.5 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 4.80-4.75 (m, 1H), 4.26-4.19 (m, 2H), 4.09-3.94 (m, 2H), 2.65-2.52 (m, 2H), 2.41 (s, 3H), 2.04 (s, 3H), 1.60-1.51 (m, 2H), 1.50-1.43 (m, 2H).

Example 550: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-methylthiophen-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 640)

##STR01402##

[2264] Compound 640 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=484.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.10 (m, 2H), 8.97 (dd, J=1.3, 4.3 Hz, 1H), 8.95-8.69 (m, 2H), 8.26-8.17 (m, 2H), 7.91 (d, J=1.5 Hz, 1H), 7.64 (dd, J=4.3, 8.6 Hz, 1H), 7.47 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.70-4.61 (m, 1H), 4.27-4.19 (m, 1H), 4.17-4.10 (m, 1H), 3.98-3.87 (m, 2H), 2.55 (d, J=0.8 Hz, 3H), 2.44-2.29 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.37-1.31 (m, 2H).

Example 551: (S)N-(1-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 643)

##STR01403##

[2265] Compound 643 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=512.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 9.08 (d, J=8.7 Hz, 1H), 8.98 (dd, J=1.6, 4.1 Hz, 1H), 8.82-8.75 (m, 1H), 8.32 (d, J=1.4 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.65 (dd, J=4.3, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.26-4.19 (m, 1H), 4.17-4.10 (m, 1H), 3.96-3.88 (m, 1H), 3.86-3.79 (m, 1H), 2.69-2.65 (m, 1H), 2.59 (s, 3H), 2.34-2.31 (m, 1H), 1.98 (s, 3H), 1.43-1.38 (m, 2H), 1.35 (br s, 2H).

Example 552: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(5-cyanothiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 658)

##STR01404##

[2266] Compound 658 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=495.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.20 (s, 1H), 9.08 (d, J=8.6 Hz, 1H), 8.99 (dd, J=1.4, 4.2 Hz, 1H), 8.89-8.71 (m, 2H), 8.33 (d, J=1.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.10 (d, J=4.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 1H), 7.66 (dd, J=4.2, 8.6 Hz, 1H), 7.13-7.06 (m, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.70-4.57 (m, 1H), 4.28-4.18 (m, 1H), 4.17-4.09 (m, 1H), 3.98-3.78 (m, 2H), 2.48-2.42 (m, 1H), 2.48-2.40 (m, 2H), 2.24 (s, 1H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.35 (br s, 2H).

Example 553: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 673)

##STR01405##

[2267] Compound 673 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=486.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (s, 1H), 9.16 (d, J=8.5 Hz, 1H), 9.03 (dd, J=1.4, 4.1 Hz, 1H), 9.00-8.73 (m, 2H), 8.48 (d, J=1.8 Hz, 1H), 8.42 (d, J=1.1 Hz, 1H), 7.72 (dd, J=4.2, 8.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.65 (br d, J=5.1 Hz, 1H), 4.28-4.19 (m, 1H), 4.18-4.09 (m, 1H), 3.96-3.89 (m, 1H), 3.86-3.80 (m, 1H), 2.84 (s, 3H), 2.48-2.28 (m, 2H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.31 (br s, 2H).

Example 554: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(furan-3-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 645)

##STR01406##

[2268] Compound 645 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=454.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.25-9.09 (m, 2H), 9.03-8.71 (m, 3H), 8.48 (s, 1H), 8.27-8.06 (m, 2H), 7.86 (t, J=1.6 Hz, 1H), 7.65 (dd, J=4.3, 8.5 Hz, 1H), 7.18 (d, J=1.1 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.65 (br d, J=4.0 Hz, 1H), 4.23 (br dd, J=7.1, 11.2 Hz, 2H), 4.13 (br dd, J=3.3, 11.2 Hz, 2H), 2.45-2.24 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.35 (br s, 2H).

Example 555: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(2,5-dimethylfuran-3-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 641)

##STR01407##

[2269] Compound 641 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=482.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.09 (m, 2H), 8.96 (br d, J=4.0 Hz, 1H), 8.87-8.71 (m, 2H), 8.03 (s, 1H), 7.93 (s, 1H), 7.63 (br dd, J=3.9, 8.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.51 (s, 1H), 4.71-4.60 (m, 1H), 4.27-4.19 (m, 1H), 4.16-4.10 (m, 1H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 2.54 (s, 3H), 2.39-2.32 (m, 2H), 2.31 (s, 3H), 1.99 (s, 3H), 1.39 (br s, 2H), 1.32-1.25 (m, 2H).

Example 556: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-methylfuran-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 646)

##STR01408##

[2270] Compound 646 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.17 (s, 1H), 9.09 (br d, J=8.3 Hz, 1H), 9.00-8.64 (m, 3H), 8.24-8.05 (m, 2H), 7.60 (dd, J=4.3, 8.5 Hz, 1H), 7.15 (d, J=3.1 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 6.32 (dd, J=0.9, 3.2 Hz, 1H), 4.74-4.57 (m, 1H), 4.31-4.18 (m, 1H), 4.17-4.06 (m, 1H), 4.00-3.87 (m, 1H), 3.86-3.77 (m, 1H), 2.43 (s, 3H), 2.40-2.21 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.30 (br s, 2H).

Example 557: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(oxazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 694)

##STR01409##

[2271] Compound 694 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=455.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.22 (s, 1H), 9.14 (d, J=7.9 Hz, 1H), 9.02 (dd, J=1.5, 4.1 Hz, 1H), 8.95-8.77 (m, 2H), 8.50 (s, 2H), 8.36 (s, 1H), 7.70 (dd, J=4.2, 8.6 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 4.67-4.63 (m, 1H), 4.23 (dd, J=7.1, 11.2 Hz, 1H), 4.17-4.11 (m, 1H), 3.97-3.77 (m, 2H), 2.48-2.41 (m, 1H), 2.39-2.29 (m, 1H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.29 (br s, 2H).

Example 558: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 698)

##STR01410##

[2272] Compound 698 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=469.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.24-9.17 (m, 2H), 9.01 (dd, J=1.2, 4.3 Hz, 1H), 8.20 (s, 2H), 7.86 (s, 1H), 7.72 (dd, J=4.4, 8.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.69 (d, J=2.8 Hz, 1H), 4.70-4.53 (m, 1H), 4.27-4.18 (m, 1H), 4.16-4.08 (m, 1H), 3.98-3.88 (m, 1H), 3.86-3.77 (m, 1H), 2.56 (s, 3H), 2.47-2.30 (m, 2H), 1.95 (s, 3H), 1.45-1.37 (m, 2H), 1.35-1.29 (m, 2H), 1.65-1.67 (m, 1H).

Example 559: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-methyl-1,3,4-oxadiazol-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 680)

##STR01411##

[2273] Compound 680 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=470.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23 (s, 1H), 9.15 (d, J=8.3 Hz, 1H), 9.05 (dd, J=1.4, 4.1 Hz, 1H), 8.90-8.77 (m, 2H), 8.48 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 7.74 (dd, J=4.1, 8.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.65 (br d, J=5.5 Hz, 1H), 4.28-4.19 (m, 1H), 4.18-4.11 (m, 1H), 4.00-3.87 (m, 2H), 2.66 (s, 3H), 2.46 (br s, 1H), 2.37-2.29 (m, 1H), 1.95 (s, 3H), 1.43 (br s, 2H), 1.29 (br s, 2H).

Example 560: (S)N-(1-(7-(1H-Pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 636)

##STR01412##

[2274] Compound 636 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=454.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23-9.15 (m, 2H), 8.99 (d, J=3.5 Hz, 1H), 8.88-8.71 (m, 2H), 8.43 (s, 1H), 8.35 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.67 (dd, J=4.5, 8.6 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.91 (dd, J=2.5, 8.5 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.71-4.60 (m, 1H), 4.23 (dd, J=6.9, 11.1 Hz, 1H), 4.16-4.11 (m, 1H), 3.96-3.86 (m, 2H), 2.44-2.29 (m, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.31 (br s, 2H).

Example 561: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(5-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 635)

##STR01413##

[2275] Compound 635 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.40 (d, J=8.5 Hz, 1H), 9.22 (s, 1H), 9.09 (dd, J=1.3, 4.8 Hz, 1H), 8.47 (d, J=1.4 Hz, 1H), 8.35 (s, 1H), 7.83 (dd, J=4.8, 8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.91 (dd, J=2.7, 8.4 Hz, 1H), 6.76-6.68 (m, 2H), 4.65 (dq, J=3.2, 7.8 Hz, 1H), 4.28-4.19 (m, 1H), 4.17-4.10 (m, 1H), 3.98-3.88 (m, 1H), 3.82 (dt, J=6.3, 10.0 Hz, 1H), 2.47-2.41 (m, 1H), 2.39-2.29 (m, 4H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 562: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(1-methyl-1H-pyrazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 649)

##STR01414##

[2276] Compound 649 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22 (s, 1H), 9.18-9.11 (m, 1H), 9.05-8.98 (m, 1H), 8.95-8.77 (m, 2H), 8.15-8.02 (m, 2H), 7.78-7.65 (m, 1H), 7.61-7.52 (m, 1H), 7.16-7.05 (m, 1H), 6.97-6.87 (m, 1H), 6.78-6.69 (m, 1H), 6.67-6.59 (m, 1H), 4.76-4.58 (m, 1H), 4.28-4.19 (m, 1H), 4.17-4.09 (m, 1H), 4.00 (s, 3H), 3.97-3.81 (m, 2H), 2.47-2.41 (m, 1H), 2.39-2.31 (m, 1H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.32 (br s, 2H).

Example 563: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(1-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 634)

##STR01415##

[2277] Compound 634 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.14 (m, 2H), 8.98 (dd, J=1.4, 4.4 Hz, 1H), 8.88-8.78 (m, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.65 (dd, J=4.4, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.91 (dd, J=2.7, 8.4 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 4.71-4.60 (m, 1H), 4.28-4.19 (m, 1H), 4.17-4.10 (m, 1H), 3.97 (s, 3H), 3.88-3.78 (m, 2H), 2.45-2.30 (m, 2H), 1.98 (s, 3H), 1.41 (br s, 2H), 1.29 (br s, 2H).

Example 564: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(1-(difluoromethyl)-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 656)

##STR01416##

[2278] Compound 656 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=504.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19 (s, 1H), 9.14 (d, J=8.4 Hz, 1H), 8.98 (dd, J=1.5, 4.3 Hz, 1H), 8.88-8.73 (m, 2H), 8.48-8.43 (m, 2H), 8.40 (d, J=2.8 Hz, 1H), 8.13-7.80 (m, 1H), 7.65 (dd, J=4.2, 8.6 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.23 (dd, J=7.1, 11.3 Hz, 2H), 4.13 (br dd, J=3.3, 11.1 Hz, 2H), 2.45-2.28 (m, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.30 (br s, 2H).

Example 565: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(1-phenyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 664)

##STR01417##

[2279] Compound 664 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=530.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.24-9.15 (m, 2H), 9.00 (dd, J=1.4, 4.3 Hz, 1H), 8.96-8.72 (m, 2H), 8.68 (d, J=2.5 Hz, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8.04-7.95 (m, 2H), 7.67 (dd, J=4.3, 8.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 2H), 7.43-7.34 (m, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.65 (br d, J=3.4 Hz, 1H), 4.27-4.19 (m, 1H), 4.17-4.10 (m, 1H), 4.00-3.89 (m, 2H), 2.45-2.28 (m, 2H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.34 (br s, 2H).

Example 566: (S)N-(1-(7-(1H-Pyrazol-4-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 642)

##STR01418##

[2280] Compound 642 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=454.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.24-9.08 (m, 2H), 8.98-8.91 (m, 1H), 8.85-8.69 (m, 2H), 8.32 (br s, 2H), 8.21-8.10 (m, 2H), 7.67-7.54 (m, 1H), 7.17-7.02 (m, 1H), 6.96-6.87 (m, 1H), 6.75-6.65 (m, 1H), 4.72-4.58 (m, 1H), 4.25 (s, 1H), 4.17-4.11 (m, 1H), 3.94-3.90 (m, 1H), 3.86-3.80 (m, 1H), 2.47-2.42 (m, 1H), 2.33 (br s, 1H), 1.98 (s, 3H), 1.43-1.32 (m, 4H).

Example 567: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 665)

##STR01419##

[2281] Compound 665 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.19-9.07 (m, 2H), 8.95 (dd, J=1.4, 4.4 Hz, 1H), 8.93-8.75 (m, 2H), 8.44 (s, 1H), 8.13-8.08 (m, 3H), 7.62 (dd, J=4.4, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.23 (dd, J=7.1, 11.2 Hz, 2H), 4.13 (br dd, J=3.3, 11.3 Hz, 2H), 3.93 (s, 3H), 2.48-2.29 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.36-1.29 (m, 2H).

Example 568: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(benzo[b]thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 695)

##STR01420##

[2282] Compound 695 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=520.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21 (s, 1H), 9.09 (d, J=7.7 Hz, 1H), 8.98 (dd, J=1.3, 4.1 Hz, 1H), 8.89-8.67 (m, 2H), 8.34 (d, J=1.9 Hz, 1H), 8.28-8.14 (m, 2H), 8.09-8.01 (m, 1H), 7.96 (dd, J=1.8, 6.5 Hz, 1H), 7.64 (dd, J=4.2, 8.6 Hz, 1H), 7.50-7.37 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.97-6.87 (m, 1H), 6.71 (d, J=2.8 Hz, 1H), 4.69-4.59 (m, 1H), 4.28-4.20 (m, 1H), 4.18-4.11 (m, 1H), 3.94-3.88 (m, 1H), 3.83 (br dd, J=5.3, 10.5 Hz, 1H), 2.46-2.25 (m, 2H), 2.00 (s, 3H), 1.42 (br s, 2H), 1.37 (br s, 2H).

Example 569: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(benzo[d]oxazol-2-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 711)

##STR01421##

[2283] Compound 711 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=505.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.26 (s, 1H), 9.18 (d, J=8.3 Hz, 1H), 9.07 (dd, J=1.5, 4.1 Hz, 1H), 8.94-8.76 (m, 2H), 8.73 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96-7.88 (m, 2H), 7.75 (dd, J=4.1, 8.5 Hz, 1H), 7.49 (dquin, J=1.5, 7.3 Hz, 2H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.71-4.58 (m, 1H), 4.28-4.19 (m, 1H), 4.18-4.11 (m, 1H), 3.96-3.77 (m, 2H), 2.48-2.40 (m, 1H), 2.38-2.28 (m, 1H), 1.98 (s, 3H), 1.46 (br s, 2H), 1.34 (br s, 2H).

Example 570: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(cyclohex-1-en-1-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 662)

##STR01422##

[2284] Compound 662 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.24-9.11 (m, 2H), 9.02-8.96 (m, 1H), 8.95-8.76 (m, 2H), 8.11 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.68 (dd, J=4.5, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.69 (d, J=2.8 Hz, 1H), 6.54 (br s, 1H), 4.72-4.60 (m, 1H), 4.27-4.19 (m, 1H), 4.17-4.10 (m, 1H), 4.02-3.81 (m, 4H), 2.44-2.18 (m, 4H), 1.97 (s, 3H), 1.86-1.77 (m, 2H), 1.72-1.63 (m, 2H), 1.37 (br s, 2H), 1.28 (br s, 2H).

Example 571: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(4-fluorophenyl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 675)

##STR01423##

[2285] Compound 675 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=482.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23-9.12 (m, 2H), 8.99 (br d, J=3.9 Hz, 1H), 8.90-8.74 (m, 2H), 8.20 (s, 2H), 7.94 (dd, J=5.5, 8.6 Hz, 2H), 7.66 (dd, J=4.2, 8.5 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (dd, J=2.4, 8.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 4.65 (br d, J=4.3 Hz, 1H), 4.23 (br dd, J=7.2, 11.1 Hz, 1H), 4.17-4.09 (m, 1H), 3.95-3.89 (m, 1H), 3.85-3.79 (m, 1H), 2.47-2.28 (m, 2H), 1.98 (s, 3H), 1.38 (br d, J=15.4 Hz, 4H).

Example 572: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(3-chloro-4-fluorophenyl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 666)

##STR01424##

[2286] Compound 666 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=516.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.23-9.13 (m, 2H), 9.00 (dd, J=1.5, 4.3 Hz, 1H), 8.97-8.76 (m, 2H), 8.26 (d, J=1.4 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.13 (dd, J=2.3, 7.1 Hz, 1H), 7.92 (ddd, J=2.4, 4.7, 8.6 Hz, 1H), 7.68 (dd, J=4.3, 8.5 Hz, 1H), 7.61 (t, J=8.9 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.65 (br d, J=6.3 Hz, 1H), 4.23 (dd, J=7.2, 11.2 Hz, 1H), 4.17-4.09 (m, 1H), 3.97-3.78 (m, 2H), 2.48-2.26 (m, 2H), 1.98 (s, 3H), 1.40 (br s, 4H).

Example 573: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(6-oxo-1,6-dihydropyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 674)

##STR01425##

[2287] Compound 674 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=481.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.19-9.09 (m, 2H), 8.97 (dd, J=1.3, 4.3 Hz, 1H), 8.95-8.71 (m, 2H), 8.16-7.94 (m, 4H), 7.64 (dd, J=4.4, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.53 (d, J=9.5 Hz, 1H), 4.65 (br d, J=4.8 Hz, 1H), 4.30-4.18 (m, 1H), 4.17-4.08 (m, 1H), 3.99-3.73 (m, 2H), 2.47-2.42 (m, 1H), 2.38-2.28 (m, 1H), 1.98 (s, 3H), 1.37 (br s, 4H).

Example 574: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 637)

##STR01426##

[2288] Compound 637 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=465.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.28-9.16 (m, 3H), 9.07-9.01 (m, 1H), 8.78 (dd, J=1.3, 5.1 Hz, 1H), 8.63-8.56 (m, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 7.82 (dd, J=5.2, 7.8 Hz, 1H), 7.73 (dd, J=4.3, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.65 (br dd, J=2.7, 8.0 Hz, 1H), 4.27-4.18 (m, 1H), 4.16-4.09 (m, 1H), 3.97-3.77 (m, 2H), 2.41-2.25 (m, 2H), 1.96 (s, 3H), 1.41 (br s, 4H).

Example 575: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(pyrimidin-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 682)

##STR01427##

[2289] Compound 682 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=466.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.26-9.13 (m, 2H), 9.08-9.01 (m, 3H), 9.00-8.92 (m, 2H), 8.90-8.71 (m, 2H), 7.71 (dd, J=4.2, 8.6 Hz, 1H), 7.57 (t, J=4.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.3 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.71-4.59 (m, 1H), 4.27-4.19 (m, 1H), 4.17-4.10 (m, 1H), 4.18-4.10 (m, 1H), 3.96-3.88 (m, 1H), 3.86-3.78 (m, 1H), 2.47-2.29 (m, 2H), 1.98 (s, 3H), 1.45 (br s, 2H), 1.30 (br s, 2H).

Example 576: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-(2-(piperidin-1-yl)pyrimidin-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 688)

##STR01428##

[2290] Compound 688 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=549.5 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.10 (m, 2H), 8.99-8.96 (m, 1H), 8.90 (s, 2H), 8.88-8.70 (m, 2H), 8.18 (dd, J=1.6, 19.5 Hz, 2H), 7.64 (dd, J=4.4, 8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.70 (d, J=2.8 Hz, 1H), 4.70-4.61 (m, 1H), 4.21 (br d, J=7.3 Hz, 1H), 4.15 (br d, J=3.4 Hz, 1H), 3.97-3.88 (m, 2H), 3.86-3.83 (m, 4H), 2.48-2.40 (m, 1H), 2.40-2.27 (m, 1H), 1.98 (s, 3H), 1.72-1.64 (m, 2H), 1.57 (br d, J=3.9 Hz, 4H), 1.39 (br s, 4H).

Example 577: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(imidazo[1,2-a]pyridin-6-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 686)

##STR01429##

[2291] Compound 686 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=504.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.54 (s, 1H), 9.25 (s, 1H), 9.12 (d, J=8.7 Hz, 1H), 9.02 (dd, J=1.5, 4.0 Hz, 1H), 8.97-8.77 (m, 2H), 8.51 (dd, J=1.3, 9.6 Hz, 1H), 8.43-8.37 (m, 2H), 8.30-8.22 (m, 2H), 8.15-8.09 (m, 1H), 7.74-7.66 (m, 1H), 7.12 (s, 1H), 6.95-6.89 (m, 1H), 6.72-6.67 (m, 1H), 4.66 (br d, J=6.1 Hz, 1H), 4.27-4.20 (m, 1H), 4.16-4.10 (m, 1H), 3.95-3.90 (m, 1H), 3.85-3.81 (m, 1H), 2.47-2.41 (m, 1H), 2.39-2.31 (m, 1H), 1.97 (s, 3H), 1.45-1.36 (m, 4H).

Example 578: (S)N-(1-(7-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 685)

##STR01430##

[2292] Compound 685 was synthesized according to an analogous procedure to the one described for compound 608. M+H.sup.+=505.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.60 (s, 1H), 9.20 (s, 1H), 9.16 (d, J=8.3 Hz, 1H), 9.01 (dd, J=1.3, 4.2 Hz, 1H), 8.94-8.73 (m, 2H), 8.61 (s, 1H), 8.39 (d, J=1.4 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.27-8.23 (m, 1H), 8.08-8.01 (m, 1H), 7.71-7.64 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.68-4.62 (m, 1H), 4.26-4.20 (m, 1H), 4.16-4.10 (m, 1H), 3.93-3.79 (m, 2H), 2.49-2.41 (m, 1H), 2.38-2.27 (m, 1H), 1.98 (s, 3H), 1.43 (br d, J=14.2 Hz, 4H).

Example 579: (S)N-(1-(7-Ethynyl-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 822)

##STR01431##

[2293] Compound 822 was synthesized according to an analogous procedure to the one described for compound 620. M+H.sup.+=440.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.44-10.12 (m, 1H), 9.33-9.16 (m, 2H), 8.11 (s, 1H), 7.92 (s, 1H), 7.80 (br d, J=8.1 Hz, 1H), 7.15-7.05 (m, 1H), 6.99-6.90 (m, 1H), 6.82-6.68 (m, 1H), 4.62 (br s, 2H), 4.31-4.20 (m, 2H), 4.03-3.98 (m, 1H), 3.88-3.85 (m, 1H), 2.86-2.78 (m, 6H), 2.41-2.27 (m, 2H), 1.96 (s, 3H), 1.38 (br s, 2H), 1.27 (br s, 2H).

Example 580: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 615)

##STR01432##

[2294] Compound 615 was synthesized according to an analogous procedure to the one described for compound 630. M+H.sup.+=402.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.47-9.42 (m, 1H), 9.27-9.24 (m, 1H), 9.18-9.03 (m, 1H), 8.25-8.15 (m, 1H), 8.12-8.00 (m, 1H), 7.96-7.79 (m, 1H), 7.12-6.99 (m, 2H), 6.93-6.87 (m, 1H), 6.71-6.67 (m, 1H), 6.19 (d, J=17.5 Hz, 1H), 5.62 (d, J=11.0 Hz, 1H), 4.13 (t, J=5.0 Hz, 2H), 3.25 (t, J=4.9 Hz, 2H), 2.58 (s, 3H), 1.95 (s, 3H), 1.40 (br s, 2H), 1.33 (br s, 2H).

Example 581: 2-Methyl-5-(2-(methylamino)ethoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 616)

##STR01433##

[2295] Compound 616 was synthesized according to an analogous procedure to the one described for compound 630. M+H.sup.+=416.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.62-9.50 (m, 1H), 9.34-9.26 (m, 1H), 9.22-9.14 (m, 1H), 8.31-8.25 (m, 1H), 8.19-8.13 (m, 1H), 8.02-7.93 (m, 1H), 7.14-7.06 (m, 1H), 6.95-6.86 (m, 1H), 6.77-6.65 (m, 1H), 5.84 (s, 1H), 5.49 (s, 1H), 4.15 (t, J=5.0 Hz, 2H), 3.26 (br t, J=4.9 Hz, 2H), 2.58 (s, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.34 (br s, 2H).

Example 582: 2-Methyl-N-(1-(7-(1-methyl-1H-pyrazol-5-yl)quinolin-5-yl)cyclopropyl)-5-(2-(methylamino)ethoxy)benzamide (Compound 639)

##STR01434##

[2296] Compound 639 was synthesized according to an analogous procedure to the one described for compound 630. M+H.sup.+=456.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.22 (s, 1H), 9.15 (br d, J=8.5 Hz, 1H), 9.02 (d, J=4.1 Hz, 1H), 8.11 (d, J=1.0 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.71 (dd, J=4.2, 8.6 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 4.12 (t, J=4.9 Hz, 2H), 4.00 (s, 3H), 3.27 (br t, J=4.7 Hz, 2H), 2.60 (s, 3H), 1.97 (s, 3H), 1.39 (br s, 2H), 1.32 (br s, 2H).

Example 583: 2-Methyl-N-(1-(7-(1-methyl-1H-pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-5-(2-(methylamino)ethoxy)benzamide (Compound 647)

##STR01435##

[2297] Compound 647 was synthesized according to an analogous procedure to the one described for compound 630. M+H.sup.+=456.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.46-9.32 (m, 1H), 9.26 (s, 1H), 9.08 (br d, J=3.5 Hz, 1H), 8.76 (br dd, J=1.3, 7.4 Hz, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.84-7.75 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.15 (t, J=4.9 Hz, 2H), 3.99 (s, 3H), 3.27 (br d, J=5.3 Hz, 2H), 2.59 (t, J=5.4 Hz, 3H), 1.98 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 584: (S)N-(1-(2,7-Dimethylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 802)

##STR01436##

[2298] Compound 802 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=430.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.48 (d, J=8.8 Hz, 1H), 9.22 (s, 1H), 7.96-7.79 (m, 3H), 7.09 (br d, J=8.5 Hz, 1H), 6.92 (dd, J=2.4, 8.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 4.66-4.56 (m, 1H), 4.21 (br d, J=5.1 Hz, 2H), 4.03 (dt, J=4.6, 9.5 Hz, 1H), 3.86 (br d, J=9.6 Hz, 1H), 2.85 (d, J=16.0 Hz, 6H), 2.60 (s, 3H), 2.43-2.28 (m, 2H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H).

Example 585: (S)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 717)

##STR01437##

[2299] Compound 717 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=442.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.64-9.49 (m, 1H), 9.36-9.28 (m, 1H), 9.18 (br s, 1H), 8.25 (s, 1H), 8.13 (br s, 1H), 8.04-7.84 (m, 1H), 7.13-6.98 (m, 2H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.23 (d, J=17.6 Hz, 1H), 5.66 (br d, J=10.8 Hz, 1H), 4.29-4.16 (m, 2H), 3.80-3.64 (m, 1H), 3.60-3.55 (m, 1H), 3.14-3.04 (m, 1H), 2.89 (s, 3H), 2.28-2.14 (m, 1H), 2.06-1.85 (m, 5H), 1.81-1.72 (m, 1H), 1.43 (br s, 2H), 1.34 (br s, 2H).

Example 586: (S)-2-Methyl-N-(1-(2-methyl-7-vinylquinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 813)

##STR01438##

[2300] Compound 813 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=442.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.92 (br d, J=3.4 Hz, 1H), 9.63-9.23 (m, 2H), 8.35-7.76 (m, 3H), 7.15-7.00 (m, 2H), 6.92 (dd, J=2.7, 8.4 Hz, 1H), 6.83-6.73 (m, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.65 (br d, J=11.0 Hz, 1H), 4.68-4.58 (m, 1H), 4.40 (dd, J=8.2, 11.2 Hz, 1H), 4.22 (dd, J=3.1, 11.3 Hz, 1H), 4.05-3.93 (m, 1H), 3.91-3.77 (m, 1H), 2.92 (s, 3H), 2.83-2.66 (m, 3H), 2.40-2.26 (m, 2H), 1.98 (s, 3H), 1.42 (br s, 2H), 1.33 (br s, 2H).

Example 587: (S)-2-Methyl-5-((1-methylpyrrolidin-2-yl)methoxy)-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 719)

##STR01439##

[2301] Compound 719 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=456.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.44-9.33 (m, 1H), 9.27-9.19 (m, 1H), 9.13-9.03 (m, 1H), 8.26-8.19 (m, 1H), 8.09-8.04 (m, 1H), 7.88-7.78 (m, 1H), 7.12-7.05 (m, 1H), 6.98-6.88 (m, 1H), 6.77-6.67 (m, 1H), 5.86-5.73 (m, 1H), 5.52-5.28 (m, 1H), 4.27-4.10 (m, 2H), 3.84-3.69 (m, 1H), 3.16-3.03 (m, 1H), 2.92-2.84 (m, 3H), 2.29-2.16 (m, 4H), 2.10-1.69 (m, 7H), 1.44-1.38 (m, 2H), 1.34-1.27 (m, 2H).

Example 588: (S,E)-N-(1-(7-(2-Cyclopropylvinyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 684)

##STR01440##

[2302] Compound 684 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=468.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.04-9.84 (m, 1H), 9.22-9.09 (m, 2H), 8.99-8.90 (m, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.63 (dd, J=4.4, 8.5 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.00-6.87 (m, 1H), 6.80-6.67 (m, 2H), 6.17 (dd, J=9.4, 15.8 Hz, 1H), 4.65-4.58 (m, 1H), 4.23 (br d, J=5.7 Hz, 2H), 4.03-3.99 (m, 1H), 3.89-3.84 (m, 1H), 2.94-2.76 (m, 3H), 2.40-2.31 (m, 2H), 1.97 (s, 3H), 1.76-1.64 (m, 1H), 1.41-1.22 (m, 3H), 0.93-0.84 (m, 2H), 0.69-0.62 (m, 2H).

Example 589: (S,E)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(3-methylstyryl)quinolin-5-yl)cyclopropyl)benzamide (Compound 690)

##STR01441##

[2303] Compound 690 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=518.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.59-10.46 (m, 1H), 9.43-9.34 (m, 1H), 9.27 (s, 1H), 9.08 (br d, J=3.9 Hz, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.81 (br dd, J=3.3, 7.5 Hz, 1H), 7.61 (s, 1H), 7.57 (s, 2H), 7.57-7.53 (m, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.5, 8.3 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 4.66-4.58 (m, 1H), 4.33 (dd, J=7.8, 11.3 Hz, 1H), 4.25-4.19 (m, 1H), 4.03-3.98 (m, 1H), 3.88-3.84 (m, 1H), 2.81 (d, J=5.1 Hz, 3H), 2.41-2.25 (m, 5H), 1.98 (s, 3H), 1.43 (br s, 2H), 1.40-1.35 (m, 2H).

Example 590: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(prop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 721)

##STR01442##

[2304] Compound 721 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=440.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.10-9.89 (m, 1H), 9.16 (s, 1H), 9.09 (br d, J=8.4 Hz, 1H), 8.96 (br d, J=3.4 Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.65 (dd, J=4.3, 8.5 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (dd, J=2.3, 8.4 Hz, 1H), 6.77-6.67 (m, 1H), 4.60 (br d, J=5.3 Hz, 1H), 4.22 (br d, J=5.1 Hz, 2H), 4.08-3.97 (m, 1H), 3.86 (br dd, J=5.6, 9.1 Hz, 1H), 2.88-2.68 (m, 3H), 2.43-2.25 (m, 2H), 2.14 (s, 3H), 1.94 (s, 3H), 1.35 (br s, 2H), 1.24 (br s, 2H).

Example 591: (S)N-(1-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 657)

##STR01443##

[2305] Compound 657 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=526.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.91 (br s, 1H), 9.23-9.16 (m, 1H), 9.09 (d, J=8.6 Hz, 1H), 8.98 (dd, J=1.4, 4.1 Hz, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.65 (dd, J=4.3, 8.5 Hz, 1H), 7.14-7.07 (m, 1H), 6.92 (dd, J=2.7, 8.4 Hz, 1H), 6.77-6.68 (m, 1H), 4.60 (br d, J=4.4 Hz, 1H), 4.25-4.20 (m, 2H), 3.87 (br dd, J=3.1, 9.4 Hz, 2H), 2.83 (d, J=4.9 Hz, 3H), 2.59 (s, 3H), 2.42-2.27 (m, 2H), 1.97 (s, 3H), 1.45-1.31 (m, 4H).

Example 592: (S)N-(1-(7-(5-Cyanothiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 754)

##STR01444##

[2306] Compound 754 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=509.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.67 (br d, J=4.0 Hz, 1H), 9.33-9.23 (m, 2H), 9.08 (d, J=3.3 Hz, 1H), 8.39 (s, 1H), 8.24 (d, J=1.8 Hz, 1H), 8.11 (d, J=4.0 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.79 (dd, J=4.4, 8.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.8, 8.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.69-4.56 (m, 1H), 4.42-4.30 (m, 1H), 4.21 (dd, J=3.2, 11.3 Hz, 1H), 4.04-3.95 (m, 1H), 3.89-3.80 (m, 1H), 2.80 (d, J=5.0 Hz, 3H), 2.38-2.26 (m, 2H), 1.96 (s, 3H), 1.45-1.40 (m, 2H), 1.37 (br s, 2H).

Example 593: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(2-methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 764)

##STR01445##

[2307] Compound 764 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=499.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 1.31-1.44 (m, 4H), 1.91-1.97 (m, 3H), 2.27-2.40 (m, 2H), 2.72-2.76 (m, 3H), 2.79-2.84 (m, 3H), 3.81-3.89 (m, 1H), 3.97-4.06 (m, 1H), 4.17-4.24 (m, 2H), 4.53-4.67 (m, 1H), 6.68-6.73 (m, 1H), 6.89-6.94 (m, 1H), 7.05-7.13 (m, 1H), 7.72-7.79 (m, 1H), 8.13 (s, 1H), 8.20 (s, 1H), 8.33 (s, 1H), 8.95-9.08 (m, 1H), 9.25 (br d, J=9.4 Hz, 1H).

Example 594: (S)-2-Methyl-N-(1-(7-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 691)

##STR01446##

[2308] Compound 691 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=500.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.03-9.83 (m, 1H), 9.22 (s, 1H), 9.14 (d, J=8.5 Hz, 1H), 9.02 (dd, J=1.4, 4.1 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.41 (d, J=1.3 Hz, 1H), 7.71 (dd, J=4.2, 8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 4.60 (br d, J=4.0 Hz, 1H), 4.27-4.17 (m, 2H), 4.08-3.99 (m, 1H), 3.93-3.82 (m, 1H), 2.86-2.80 (m, 6H), 2.41-2.28 (m, 2H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.31 (br s, 2H).

Example 595: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-methylfuran-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 654)

##STR01447##

[2309] Compound 654 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=482.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.63-10.46 (m, 1H), 9.39 (br d, J=4.3 Hz, 1H), 9.28 (s, 1H), 9.09 (br d, J=4.8 Hz, 1H), 8.25 (d, J=11.5 Hz, 2H), 7.92-7.72 (m, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.17-7.02 (m, 1H), 6.92 (dd, J=2.5, 8.4 Hz, 1H), 6.74 (d, J=2.6 Hz, 1H), 6.38 (d, J=3.0 Hz, 1H), 4.68-4.58 (m, 1H), 4.37-4.28 (m, 1H), 4.26-4.18 (m, 1H), 3.99 (br dd, J=4.6, 9.0 Hz, 1H), 3.88-3.81 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 2.44 (s, 3H), 2.37-2.29 (m, 2H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.35 (br s, 2H).

Example 596: (S)N-(1-(7-(Furan-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 655)

##STR01448##

[2310] Compound 655 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=468.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.70 (br d, J=8.4 Hz, 1H), 9.36 (s, 1H), 9.22 (d, J=5.1 Hz, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.05 (dd, J=5.3, 8.5 Hz, 1H), 7.91 (s, 1H), 7.17 (s, 1H), 7.14-7.03 (m, 1H), 6.92 (dd, J=2.6, 8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.62 (br dd, J=2.9, 7.4 Hz, 1H), 4.40-4.26 (m, 1H), 4.25-4.14 (m, 1H), 4.01 (dt, J=4.4, 9.6 Hz, 1H), 3.85 (q, J=9.7 Hz, 1H), 2.81 (s, 3H), 2.42-2.23 (m, 2H), 1.96 (s, 3H), 1.45 (br s, 2H), 1.42 (br s, 2H).

Example 597: (S)N-(1-(7-(2,5-Dimethylfuran-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 671)

##STR01449##

[2311] Compound 671 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=496.1 (LCMS); .sup.1H NMR (400 MHZ, CD.sub.3OD) 9.60 (d, J=8.5 Hz, 1H), 9.07 (dd, J=1.3, 5.1 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.06 (s, 1H), 7.91 (dd, J=5.1, 8.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (dd, J=2.6, 8.3 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 6.47 (s, 1H), 4.74-4.61 (m, 1H), 4.31-4.26 (m, 1H), 4.24-4.14 (m, 2H), 4.00-3.90 (m, 1H), 2.95 (s, 3H), 2.61 (s, 3H), 2.57-2.51 (m, 2H), 2.34 (s, 3H), 2.03 (s, 4H), 1.60-1.53 (m, 2H), 1.48-1.41 (m, 2H).

Example 598: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(2-methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 716)

##STR01450##

[2312] Compound 716 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=483.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.19-11.07 (m, 1H), 9.83-9.63 (m, 1H), 9.47-9.39 (m, 1H), 9.24 (d, J=4.3 Hz, 1H), 8.57-8.28 (m, 2H), 8.13-7.96 (m, 2H), 7.21-7.03 (m, 1H), 6.91 (dd, J=2.6, 8.3 Hz, 1H), 6.77 (d, J=2.6 Hz, 1H), 4.70-4.60 (m, 1H), 4.43 (br dd, J=8.3, 11.2 Hz, 1H), 4.23-4.19 (m, 1H), 3.83 (br d, J=6.9 Hz, 2H), 2.84-2.65 (m, 3H), 2.59 (s, 3H), 2.39-2.25 (m, 1H), 2.42-2.17 (m, 2H), 2.10-1.90 (m, 3H), 1.60-1.24 (m, 4H).

Example 599: (S)-2-Methyl-N-(1-(7-(5-methyl-1,3,4-oxadiazol-2-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 693)

##STR01451##

[2313] Compound 693 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=484.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.95-9.82 (m, 1H), 9.27-9.18 (m, 1H), 9.16 (s, 1H), 9.05 (dd, J=1.5, 4.1 Hz, 1H), 8.48 (s, 1H), 8.44 (d, J=1.8 Hz, 1H), 7.74 (dd, J=4.1, 8.6 Hz, 1H), 7.19-7.07 (m, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.81-6.70 (m, 1H), 4.66-4.53 (m, 1H), 4.42-4.36 (m, 1H), 4.27-4.18 (m, 2H), 4.07-3.97 (m, 1H), 3.86 (br dd, J=6.3, 9.5 Hz, 1H), 2.84 (d, J=4.9 Hz, 3H), 2.66 (s, 3H), 2.42-2.26 (m, 2H), 1.95 (s, 3H), 1.43 (br s, 2H), 1.30 (br s, 2H), 1.22-1.25 (m, 1H).

Example 600: (S)-2-Methyl-N-(1-(2-methyl-7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 820)

##STR01452##

[2314] Compound 820 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=496.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.41 (d, J=8.8 Hz, 1H), 9.32-9.15 (m, 1H), 8.49 (s, 1H), 8.22 (d, J=0.9 Hz, 1H), 8.13 (d, J=4.6 Hz, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.02-6.87 (m, 1H), 6.80-6.68 (m, 1H), 4.67-4.56 (m, 1H), 4.23 (d, J=5.3 Hz, 2H), 4.04 (dt, J=4.8, 9.5 Hz, 1H), 3.95 (s, 3H), 3.91-3.84 (m, 1H), 2.85 (d, J=10.6 Hz, 6H), 2.41-2.30 (m, 2H), 1.97 (s, 3H), 1.48-1.31 (m, 4H).

Example 601: (S)N-(1-(7-(Benzo[d]oxazol-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 718)

##STR01453##

[2315] Compound 718 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=519.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.49-9.24 (m, 2H), 9.16 (d, J=3.4 Hz, 1H), 8.82 (s, 1H), 8.74 (s, 1H), 7.98-7.82 (m, 3H), 7.60-7.36 (m, 2H), 7.16-7.00 (m, 1H), 6.92 (dd, J=2.7, 8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.35-4.17 (m, 2H), 4.00 (td, J=4.8, 9.5 Hz, 1H), 3.85 (q, J=9.5 Hz, 1H), 2.86-2.68 (m, 3H), 2.42-2.21 (m, 2H), 1.97 (s, 3H), 1.48 (br s, 2H), 1.35 (br s, 2H).

Example 602: (S)N-(1-(7-(Imidazo[1,5-a]pyridin-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 736)

##STR01454##

[2316] Compound 736 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=518.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.93-9.80 (m, 1H), 9.34-9.26 (m, 1H), 9.26-9.21 (m, 1H), 9.05 (br d, J=4.5 Hz, 1H), 8.66 (s, 2H), 8.52 (d, J=7.0 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.78-7.69 (m, 1H), 7.19-7.07 (m, 2H), 6.97-6.84 (m, 2H), 6.76 (d, J=2.8 Hz, 1H), 4.61 (br d, J=4.3 Hz, 1H), 4.24-4.21 (m, 2H), 4.05-4.01 (m, 1H), 3.87 (br dd, J=6.4, 9.4 Hz, 1H), 2.84 (d, J=4.9 Hz, 3H), 2.38-2.28 (m, 2H), 1.99 (s, 3H), 1.45 (br s, 2H), 1.34 (br s, 2H).

Example 603: (S)N-(1-(7-(Cyclohex-1-en-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 663)

##STR01455##

[2317] Compound 663 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=482.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.77-10.37 (m, 1H), 9.53-9.38 (m, 1H), 9.25 (br s, 1H), 9.16-9.04 (m, 1H), 8.20 (br s, 1H), 8.03 (br s, 1H), 7.92-7.80 (m, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.63 (br s, 1H), 4.66-4.55 (m, 1H), 4.38-4.28 (m, 1H), 4.21 (dd, J=3.1, 11.2 Hz, 1H), 4.03-3.94 (m, 1H), 3.91-3.75 (m, 2H), 2.81 (d, J=4.9 Hz, 3H), 2.70-2.65 (m, 1H), 2.37-2.28 (m, 4H), 1.96 (s, 3H), 1.86-1.78 (m, 2H), 1.72-1.64 (m, 2H), 1.41 (br s, 2H), 1.31 (br s, 2H).

Example 604: (S)N-(1-(7-(4-Fluorophenyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 678)

##STR01456##

[2318] Compound 678 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=496.1 (LCMS); .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.94 (br s, 1H), 9.23-9.13 (m, 2H), 9.01 (dd, J=1.5, 4.4 Hz, 1H), 8.21 (s, 2H), 7.99-7.89 (m, 2H), 7.68 (dd, J=4.3, 8.6 Hz, 1H), 7.46-7.36 (m, 2H), 7.13-7.07 (m, 1H), 6.97-6.88 (m, 1H), 6.77-6.70 (m, 1H), 4.60 (br d, J=4.6 Hz, 1H), 4.22 (d, J=5.5 Hz, 2H), 4.01 (dt, J=5.0, 9.6 Hz, 1H), 3.91-3.85 (m, 1H), 2.87-2.69 (m, 3H), 2.41-2.29 (m, 2H), 1.97 (s, 3H), 1.39 (br d, J=14.3 Hz, 4H).

Example 605: (S)N-(1-(7-(3-Chloro-4-fluorophenyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 687)

##STR01457##

[2319] Compound 687 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=530.3/532.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.88-9.80 (m, 1H), 9.20-9.16 (m, 1H), 9.11 (d, J=8.9 Hz, 1H), 8.98 (dd, J=1.5, 4.1 Hz, 1H), 8.25 (d, J=1.4 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.13 (dd, J=2.3, 7.1 Hz, 1H), 7.95-7.88 (m, 1H), 7.68-7.57 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.65-4.53 (m, 1H), 4.25-4.17 (m, 2H), 4.07-3.94 (m, 1H), 3.90-3.77 (m, 1H), 2.83 (d, J=4.9 Hz, 3H), 2.29 (s, 2H), 1.97 (s, 3H), 1.39 (s, 4H).

Example 606: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(6-oxo-1,6-dihydropyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 672)

##STR01458##

[2320] Compound 672 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=495.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.95-9.77 (m, 1H), 9.24-9.05 (m, 2H), 9.01-8.90 (m, 1H), 8.19-7.93 (m, 4H), 7.62 (dd, J=4.3, 8.8 Hz, 1H), 7.19-7.04 (m, 1H), 7.00-6.87 (m, 1H), 6.77-6.65 (m, 1H), 6.53 (d, J=9.7 Hz, 1H), 4.66-4.52 (m, 1H), 4.25-4.15 (m, 2H), 4.08-3.99 (m, 1H), 3.86 (br dd, J=6.3, 9.7 Hz, 1H), 2.83 (d, J=5.0 Hz, 3H), 2.44-2.30 (m, 2H), 1.97 (s, 3H), 1.37 (br s, 4H).

Example 607: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(pyrimidin-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 681)

##STR01459##

[2321] Compound 681 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=480.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.97-9.82 (m, 1H), 9.26-9.13 (m, 2H), 9.07-9.00 (m, 3H), 8.99-8.92 (m, 2H), 7.70 (dd, J=4.1, 8.5 Hz, 1H), 7.56 (t, J=4.9 Hz, 1H), 7.15-7.06 (m, 1H), 6.99-6.87 (m, 1H), 6.79-6.68 (m, 1H), 4.61 (br dd, J=3.3, 6.1 Hz, 1H), 4.29-4.16 (m, 2H), 4.08-3.96 (m, 1H), 3.86 (br dd, J=6.1, 9.5 Hz, 1H), 2.88-2.65 (m, 3H), 2.42-2.26 (m, 2H), 1.97 (s, 3H), 1.44 (br s, 2H), 1.29 (br s, 2H).

Example 608: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(2-(piperidin-1-yl)pyrimidin-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 701)

##STR01460##

[2322] Compound 701 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=563.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.32-11.16 (m, 1H), 9.89-9.76 (m, 1H), 9.52-9.44 (m, 1H), 9.30 (d, J=4.4 Hz, 1H), 8.94 (s, 2H), 8.50 (s, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.11 (dd, J=5.3, 8.6 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.91 (dd, J=2.7, 8.4 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 4.69-4.59 (m, 1H), 4.45 (dd, J=8.4, 11.3 Hz, 1H), 4.21 (dd, J=3.0, 11.1 Hz, 1H), 4.03-3.92 (m, 1H), 3.90-3.86 (m, 4H), 3.85-3.78 (m, 1H), 2.79 (d, J=5.0 Hz, 3H), 2.41-2.21 (m, 2H), 2.01-1.97 (m, 3H), 1.71-1.64 (m, 2H), 1.62-1.53 (m, 4H), 1.53-1.41 (m, 4H).

Example 609: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 699)

##STR01461##

[2323] Compound 699 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=564.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.09-9.89 (m, 1H), 9.28-9.19 (m, 1H), 9.15 (d, J=8.5 Hz, 1H), 9.02 (dd, J=1.4, 4.1 Hz, 1H), 8.66 (s, 1H), 8.48 (br d, J=2.0 Hz, 1H), 8.43 (s, 1H), 8.22 (d, J=1.7 Hz, 1H), 8.14-8.06 (m, 1H), 7.69 (dd, J=4.2, 8.6 Hz, 1H), 7.14-7.06 (m, 1H), 6.96-6.88 (m, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.65-4.57 (m, 1H), 4.25-4.19 (m, 2H), 4.07-3.99 (m, 1H), 3.93-3.85 (m, 1H), 3.84-3.79 (m, 4H), 3.51-3.40 (m, 4H), 2.85 (br d, J=4.4 Hz, 3H), 2.39-2.27 (m, 2H), 1.96 (s, 3H), 1.42 (br s, 4H).

Example 610: (S)N-(1-(7-(Imidazo[1,2-a]pyridin-6-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 702)

##STR01462##

[2324] Compound 702 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=518.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.84-10.70 (m, 1H), 9.59 (s, 1H), 9.37-9.33 (m, 1H), 9.26 (br d, J=8.8 Hz, 1H), 9.11-9.07 (m, 1H), 8.56-8.51 (m, 1H), 8.44 (dd, J=1.4, 9.5 Hz, 2H), 8.33-8.27 (m, 2H), 8.15 (d, J=9.2 Hz, 1H), 7.83-7.74 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.92 (dd, J=2.6, 8.3 Hz, 1H), 6.73 (d, J=2.9 Hz, 1H), 4.69-4.57 (m, 1H), 4.37 (dd, J=8.1, 11.4 Hz, 1H), 4.21 (dd, J=3.2, 11.3 Hz, 1H), 4.03-3.95 (m, 1H), 3.81 (s, 1H), 2.80 (d, J=5.0 Hz, 3H), 2.34-2.27 (m, 2H), 1.96 (s, 3H), 1.45-1.40 (m, 4H).

Example 611: (S)N-(1-(7-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 700)

##STR01463##

[2325] Compound 700 was synthesized according to an analogous procedure to the one described for compound 653. M+H.sup.+=519.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.19-10.91 (m, 1H), 9.85-9.63 (m, 2H), 9.54-9.39 (m, 1H), 9.35-9.24 (m, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.26-8.21 (m, 1H), 8.14-8.06 (m, 2H), 7.12-7.07 (m, 1H), 6.94-6.89 (m, 1H), 6.77 (d, J=2.8 Hz, 1H), 4.65-4.61 (m, 1H), 4.42 (dd, J=8.3, 11.4 Hz, 1H), 4.21 (dd, J=3.2, 11.1 Hz, 1H), 4.02-3.93 (m, 1H), 3.89-3.76 (m, 1H), 2.79 (d, J=4.8 Hz, 3H), 2.39-2.21 (m, 2H), 2.01-1.96 (m, 3H), 1.57-1.50 (m, 2H), 1.47 (br s, 2H).

Example 612: (S)-2-Methyl-5-(2-(methylamino)propoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 661)

##STR01464##

[2326] Compound 661 was synthesized according to an analogous procedure to the one described for compound 660. M+H.sup.+=416.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.54 (br d, J=6.1 Hz, 1H), 9.32 (s, 1H), 9.23-9.05 (m, 2H), 9.03-8.89 (m, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.96 (br d, J=5.5 Hz, 1H), 7.14-7.01 (m, 2H), 6.91 (dd, J=2.7, 8.3 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.64 (d, J=10.9 Hz, 1H), 4.16-4.11 (m, 1H), 4.04 (br dd, J=6.2, 10.7 Hz, 1H), 3.51 (br d, J=4.1 Hz, 1H), 2.56-2.52 (m, 3H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.34 (br s, 2H), 1.28 (d, J=6.8 Hz, 3H).

Example 613: (S)-5-(2-Aminopropoxy)-2-methyl-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 735)

##STR01465##

[2327] Compound 735 was synthesized according to an analogous procedure to the one described for compound 660. M+H.sup.+=402.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.57 (br d, J=8.4 Hz, 1H), 9.33 (s, 1H), 9.18 (d, J=4.0 Hz, 1H), 8.28-8.10 (m, 5H), 7.97 (dd, J=5.0, 8.5 Hz, 1H), 7.15-7.00 (m, 2H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 6.22 (d, J=17.6 Hz, 1H), 5.65 (d, J=10.9 Hz, 1H), 4.07-4.02 (m, 1H), 3.95-3.89 (m, 1H), 3.60-3.46 (m, 2H), 1.98 (s, 3H), 1.51-1.30 (m, 4H), 1.26 (d, J=6.7 Hz, 3H).

Example 614: (S)-5-(2-Aminopropoxy)-2-methyl-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 734)

##STR01466##

[2328] Compound 734 was synthesized according to an analogous procedure to the one described for compound 660. M+H.sup.+=432.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.59 (br d, J=8.4 Hz, 1H), 9.32 (s, 1H), 9.20 (d, J=4.1 Hz, 1H), 8.32-8.19 (m, 6H), 7.98 (dd, J=5.0, 8.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 5.91-5.73 (m, 1H), 5.49 (s, 1H), 4.07-4.03 (m, 1H), 3.95-3.91 (m, 1H), 3.57-3.44 (m, 2H), 2.27 (s, 3H), 1.97 (s, 4H), 1.45-1.39 (m, 2H), 1.34 (br s, 2H), 1.25 (d, J=6.8 Hz, 4H).

Example 615: N-(1-(7-(5-((((1S,3R)-3-Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (Compound 751)

##STR01467##

[2329] Compound 751 was synthesized according to an analogous procedure to the one described for compound 669. M+H.sup.+=597.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.49-10.38 (m, 1H), 9.26 (s, 1H), 9.21-9.12 (m, 3H), 9.00 (d, J=4.0 Hz, 1H), 8.25-8.17 (m, 2H), 7.78 (d, J=3.5 Hz, 1H), 7.69 (dd, J=4.3, 8.3 Hz, 1H), 7.43 (d, J=3.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.97-6.87 (m, 1H), 6.76-6.68 (m, 1H), 4.67-4.56 (m, 1H), 4.44 (br t, J=5.0 Hz, 2H), 4.36-4.27 (m, 1H), 4.24-4.18 (m, 1H), 4.12 (quin, J=5.1 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.80 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 2.73-2.64 (m, 1H), 2.36-2.27 (m, 2H), 2.23-2.18 (m, 1H), 2.25-2.16 (m, 1H), 2.26-2.16 (m, 1H), 1.74-1.63 (m, 1H), 1.77-1.61 (m, 3H), 1.43-1.39 (m, 1H), 1.41 (br s, 1H), 1.32 (br s, 2H).

Example 616: (S)N-(1-(7-(5-((Dimethylamino)methyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 756)

##STR01468##

[2330] Compound 756 was synthesized according to an analogous procedure to the one described for compound 669. M+H.sup.+=541.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.96-10.58 (m, 1H), 9.47-9.26 (m, 2H), 9.10 (br s, 1H), 8.45-8.18 (m, 2H), 7.99-7.75 (m, 2H), 7.50 (br s, 1H), 7.17-7.03 (m, 1H), 6.99-6.87 (m, 1H), 6.75 (s, 1H), 4.60 (br d, J=5.1 Hz, 2H), 4.42-4.34 (m, 1H), 4.21 (br dd, J=2.9, 11.3 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.79 (m, 2H), 2.84-2.72 (m, 9H), 2.36-2.27 (m, 2H), 1.96 (s, 3H), 1.50-1.30 (m, 3H).

Example 617: (S)N-(1-(7-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 805)

##STR01469##

[2331] Compound 805 was synthesized according to an analogous procedure to the one described for compound 669. M+H.sup.+=603.5 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.14 (s, 1H), 9.03 (d, J=8.3 Hz, 1H), 8.93-8.88 (m, 1H), 8.11 (s, 2H), 7.63 (d, J=3.5 Hz, 1H), 7.55 (sxt, J=4.2 Hz, 1H), 7.09 (d, J=3.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (dd, J=2.6, 8.4 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.90 (s, 2H), 3.86 (d, J=5.4 Hz, 2H), 3.26-3.16 (m, 2H), 2.98 (t, J=13.3 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.75-2.64 (m, 2H), 2.34-2.27 (m, 2H), 2.20 (s, 3H), 1.95 (s, 3H), 1.90-1.79 (m, 1H), 1.42-1.36 (m, 2H), 1.32-1.26 (m, 2H).

Example 618: (S)N-(1-(7-(5-((Cyclopentylamino)methyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 752)

##STR01470##

[2332] Compound 752 was synthesized according to an analogous procedure to the one described for compound 669. M+H.sup.+=581.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.74-10.50 (m, 1H), 9.43-9.27 (m, 3H), 9.23 (br s, 1H), 9.04 (br s, 1H), 8.25 (br d, J=9.1 Hz, 2H), 7.80 (d, J=3.5 Hz, 1H), 7.74 (br d, J=4.5 Hz, 1H), 7.46 (d, J=3.0 Hz, 1H), 7.16-7.04 (m, 1H), 6.97-6.86 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.72-4.57 (m, 1H), 4.50-4.40 (m, 2H), 4.40-4.29 (m, 1H), 4.22 (dd, J=3.1, 11.3 Hz, 1H), 4.08-3.94 (m, 1H), 3.91-3.81 (m, 1H), 2.85-2.79 (m, 1H), 2.82 (d, J=5.0 Hz, 2H), 2.44-2.23 (m, 2H), 2.02-1.94 (m, 4H), 1.80-1.67 (m, 4H), 1.65-1.50 (m, 2H), 1.43 (br s, 2H), 1.34 (br s, 2H).

Example 619: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(5-(morpholinomethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 793)

##STR01471##

[2333] Compound 793 was synthesized according to an analogous procedure to the one described for compound 669. M+H.sup.+=583.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.92-11.64 (m, 1H), 11.31-10.99 (m, 1H), 9.56 (br s, 1H), 9.40 (br s, 1H), 9.20 (br s, 1H), 8.44 (br s, 1H), 8.34 (br s, 1H), 8.02-7.86 (m, 2H), 7.56 (d, J=3.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 4.6-4.61 (m, 3H), 4.42 (br dd, J=8.6, 10.8 Hz, 1H), 4.21 (br dd, J=3.1, 11.3 Hz, 1H), 3.99-3.94 (m, 4H), 3.84 (br dd, J=6.3, 9.6 Hz, 4H), 3.35 (br d, J=11.9 Hz, 2H), 2.79 (d, J=5.0 Hz, 3H), 2.36-2.23 (m, 2H), 1.98-1.93 (m, 3H), 1.46 (br s, 2H), 1.38 (br s, 2H).

Example 620: (S)-2-Methyl-N-(1-(7-(methyl(2,2,2-trifluoroethyl)amino)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 781)

##STR01472##

[2334] Compound 781 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=513.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.23 (br s, 1H), 9.66-9.56 (m, 1H), 9.41-9.31 (m, 1H), 9.00 (d, J=5.5 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.76 (dd, J=5.6, 8.3 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.15-7.05 (m, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.77 (d, J=2.6 Hz, 1H), 4.65 (q, J=9.1 Hz, 3H), 4.49-4.39 (m, 1H), 4.23 (dd, J=3.1, 11.2 Hz, 1H), 4.04-3.92 (m, 1H), 3.91-3.80 (m, 1H), 3.37 (br s, 2H), 3.27 (s, 3H), 2.80 (d, J=4.8 Hz, 3H), 2.40-2.26 (m, 2H), 2.02-1.96 (m, 3H), 1.48-1.31 (m, 4H).

Example 621: (S)-2-Methyl-N-(1-(2-methyl-7-((2,2,2-trifluoroethyl)amino)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 807)

##STR01473##

[2335] Compound 807 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=527.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.20-10.89 (m, 1H), 9.42 (br d, J=8.4 Hz, 1H), 9.28 (s, 1H), 7.80 (br s, 1H), 7.63 (br d, J=8.4 Hz, 1H), 7.32 (br s, 1H), 7.10 (br d, J=8.3 Hz, 1H), 6.95-6.90 (m, 1H), 6.75 (br s, 1H), 4.69-4.54 (m, 3H), 4.48-4.38 (m, 1H), 4.27-4.19 (m, 1H), 4.05-3.93 (m, 1H), 3.90-3.80 (m, 1H), 3.25 (s, 3H), 2.92-2.76 (m, 6H), 2.40-2.26 (m, 2H), 1.99 (s, 3H), 1.47-1.27 (m, 4H).

Example 622: (S)N-(1-(7-(Dipropylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 771)

##STR01474##

[2336] Compound 771 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=501.5 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.05-9.93 (m, 1H), 9.30 (br d, J=7.5 Hz, 1H), 9.16 (s, 1H), 8.84 (d, J=4.6 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.54 (dd, J=5.8, 8.1 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.97-6.89 (m, 2H), 6.76 (d, J=2.5 Hz, 1H), 4.67-4.57 (m, 1H), 4.24 (d, J=5.3 Hz, 2H), 4.03 (br d, J=4.4 Hz, 1H), 3.93-3.83 (m, 1H), 3.53-3.48 (m, 4H), 2.85 (br s, 3H), 2.43-2.28 (m, 2H), 1.97 (s, 3H), 1.74-1.63 (m, 4H), 1.38 (br s, 2H), 1.28 (br s, 2H), 0.97 (t, J=7.3 Hz, 6H).

Example 623: (S)N-(1-(7-(Azetidin-1-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 722)

##STR01475##

[2337] Compound 722 was synthesized according to an analogous procedure to the one described for compound 683. 1H NMR (400 MHZ, DMSO-d.sub.6) =9.37-9.27 (m, 1H), 9.16 (s, 1H), 9.00-8.80 (m, 3H), 7.58-7.52 (m, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.15-7.09 (m, 1H), 6.95-6.90 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 6.57-6.51 (m, 1H), 4.72-4.59 (m, 1H), 4.29-4.21 (m, 1H), 4.21-4.12 (m, 5H), 4.02-3.91 (m, 1H), 3.87-3.77 (m, 1H), 2.48-2.29 (m, 4H), 1.98 (s, 3H), 1.40-1.24 (m, 3H).

Example 624: (S)N-(1-(7-(Azetidin-1-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 723)

##STR01476##

[2338] Compound 723 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=457.4. (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.01-10.13 (m, 1H), 9.10 (s, 1H), 8.85 (br d, J=7.9 Hz, 1H), 8.68 (dd, J=1.4, 4.3 Hz, 1H), 7.22 (dd, J=4.3, 8.4 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.91 (dd, J=2.6, 8.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.66-6.62 (m, 1H), 4.64-4.47 (m, 1H), 4.31 (br dd, J=9.1, 10.1 Hz, 1H), 4.24-4.13 (m, 1H), 3.99 (br t, J=7.3 Hz, 4H), 3.95-3.87 (m, 1H), 3.86-3.72 (m, 1H), 2.76 (br s, 3H), 2.44-2.23 (m, 4H), 1.99 (s, 3H), 1.32 (br s, 2H), 1.18 (br s, 2H).

Example 625: (S)N-(1-(7-(3-Methoxyazetidin-1-yl)-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 811)

##STR01477##

[2339] Compound 811 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=501.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 15.81 (br d, J=2.1 Hz, 1H), 11.43-11.03 (m, 1H), 9.38-9.32 (m, 1H), 9.30-9.26 (m, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.14-7.07 (m, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.83-6.73 (m, 2H), 4.70-4.58 (m, 1H), 4.49-4.41 (m, 2H), 4.39-4.32 (m, 2H), 4.22 (dd, J=3.1, 11.2 Hz, 1H), 4.03-3.94 (m, 3H), 3.85 (br dd, J=6.8, 9.3 Hz, 1H), 3.31 (s, 3H), 2.82 (s, 3H), 2.80 (d, J=4.9 Hz, 3H), 2.38-2.26 (m, 1H), 2.40-2.26 (m, 1H), 2.00 (s, 3H), 1.37 (br s, 2H), 1.27 (br s, 2H).

Example 626: (S)-2-Methyl-N-(1-(2-methyl-7-(3-(trifluoromethyl)azetidin-1-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 810)

##STR01478##

[2340] Compound 810 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=539.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 15.90-15.51 (m, 1H), 11.29-10.82 (m, 1H), 9.43-9.33 (m, 1H), 9.30-9.22 (m, 1H), 7.59-7.53 (m, 1H), 7.33-7.25 (m, 1H), 7.13-7.06 (m, 1H), 6.95-6.89 (m, 1H), 6.83-6.72 (m, 2H), 4.75-4.55 (m, 1H), 4.49-4.36 (m, 3H), 4.27-4.16 (m, 3H), 4.06-3.96 (m, 1H), 3.93-3.82 (m, 2H), 2.88-2.65 (m, 6H), 2.43-2.20 (m, 2H), 2.06-1.93 (m, 3H), 1.43-1.24 (m, 4H).

Example 627: (S)N-(1-(7-(3-Fluoroazetidin-1-yl)-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 816)

##STR01479##

[2341] Compound 816 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=489.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.32 (br d, J=8.5 Hz, 1H), 9.25-9.21 (m, 1H), 9.23 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.02-6.91 (m, 1H), 6.84-6.72 (m, 1H), 6.67 (s, 1H), 5.79-5.46 (m, 1H), 4.68-4.58 (m, 1H), 4.57-4.43 (m, 2H), 4.37-4.20 (m, 4H), 4.03 (dt, J=4.6, 9.5 Hz, 1H), 3.87 (q, J=9.3 Hz, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.41-2.28 (m, 2H), 1.98 (s, 3H), 1.37 (br s, 2H), 1.29 (br s, 2H).

Example 628: (S)-2-Methyl-N-(1-(2-methyl-7-((2,2,2-trifluoroethyl)amino)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 826)

##STR01480##

[2342] Compound 826 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=513.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 15.89 (br s, 1H), 11.25 (br d, J=4.1 Hz, 1H), 9.39-9.29 (m, 2H), 8.12 (br t, J=6.6 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.21 (d, J=1.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.7, 8.4 Hz, 1H), 6.77 (d, J=2.6 Hz, 1H), 4.72-4.59 (m, 1H), 4.46 (dd, J=8.4, 11.2 Hz, 1H), 4.24 (br d, J=3.3 Hz, 1H), 4.02-3.77 (m, 4H), 2.84 (s, 3H), 2.80 (d, J=5.0 Hz, 3H), 2.38-2.23 (m, 2H), 2.02-1.96 (m, 3H), 1.38 (br s, 2H), 1.22 (br s, 2H).

Example 629: (S)-5-(Azetidin-2-ylmethoxy)-2-methyl-N-(1-(7-morpholinoquinolin-5-yl)cyclopropyl)benzamide (Compound 712)

##STR01481##

[2343] Compound 712 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=473.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.29 (br d, J=7.8 Hz, 1H), 9.16 (s, 1H), 8.94-8.89 (m, 2H), 8.88-8.80 (m, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.62 (dd, J=5.3, 8.3 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.7, 8.5 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.70-4.64 (m, 1H), 4.29-4.19 (m, 2H), 4.16-4.12 (m, 1H), 3.93 (br d, J=7.4 Hz, 1H), 3.89-3.74 (m, 8H), 2.40-2.27 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.32 (br s, 2H).

Example 630: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-morpholinoquinolin-5-yl)cyclopropyl)benzamide (Compound 740)

##STR01482##

[2344] Compound 740 was synthesized according to an analogous procedure to the one described for compound 683. M+H.sup.+=487.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.78-10.66 (m, 1H), 9.49 (br d, J=7.9 Hz, 1H), 9.26 (s, 1H), 8.96 (d, J=4.6 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.73 (dd, J=5.6, 8.3 Hz, 1H), 7.31-7.25 (m, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.93 (dd, J=2.6, 8.4 Hz, 1H), 6.82-6.72 (m, 1H), 4.68-4.57 (m, 1H), 4.37 (dd, J=7.9, 11.4 Hz, 1H), 4.22 (dd, J=3.3, 11.4 Hz, 1H), 4.05-3.95 (m, 1H), 3.88-3.80 (m, 5H), 3.53-3.50 (m, 4H), 2.85-2.79 (m, 3H), 2.39-2.27 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.34 (br s, 2H).

Example 631: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(isoxazol-4-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 714)

##STR01483##

[2345] Compound 714 was synthesized according to an analogous procedure to the one described for compound 689. M+H.sup.+=455.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.76-9.67 (m, 1H), 9.46-9.35 (m, 1H), 9.27-9.19 (m, 1H), 9.16-9.10 (m, 1H), 9.04-8.95 (m, 1H), 8.32-8.27 (m, 1H), 8.22-8.15 (m, 1H), 7.71-7.62 (m, 1H), 7.13-7.05 (m, 1H), 6.96-6.86 (m, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.71-4.59 (m, 1H), 4.26-4.17 (m, 1H), 4.16-4.08 (m, 1H), 3.98-3.76 (m, 2H), 2.48-2.30 (m, 2H), 2.00-1.92 (m, 3H), 1.43-1.32 (m, 4H).

Example 632: (S)-5-(Azetidin-2-ylmethoxy)-N-(1-(7-(imidazo[1,5-a]pyridin-1-yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 733)

##STR01484##

[2346] Compound 733 was synthesized according to an analogous procedure to the one described for compound 689. M+H.sup.+=504.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.48-9.40 (m, 1H), 9.26 (s, 1H), 9.13 (br d, J=3.9 Hz, 1H), 8.91-8.76 (m, 2H), 8.73-8.67 (m, 2H), 8.54 (d, J=7.0 Hz, 1H), 8.48 (s, 1H), 8.17 (d, J=9.3 Hz, 1H), 7.89-7.80 (m, 1H), 7.23-7.15 (m, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.94-6.87 (m, 2H), 6.75 (d, J=2.5 Hz, 1H), 4.65 (br d, J=5.9 Hz, 1H), 4.27-4.21 (m, 1H), 4.14 (br dd, J=3.4, 11.1 Hz, 1H), 3.96-3.90 (m, 2H), 2.47-2.27 (m, 2H), 1.99 (s, 3H), 1.47 (br s, 2H), 1.35 (br s, 2H).

Example 633: (S)-2-Methyl-N-(1-(7-(prop-1-en-2-yl)quinolin-5-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)benzamide (Compound 715)

##STR01485##

[2347] Compound 715 was synthesized according to an analogous procedure to the one described for compound 713. M+H.sup.+=442.1 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.36-9.27 (m, 1H), 9.23-9.16 (m, 1H), 9.10-9.01 (m, 1H), 8.23-8.18 (m, 1H), 8.05-8.00 (m, 1H), 7.83-7.74 (m, 1H), 7.12-7.05 (m, 1H), 6.95-6.86 (m, 1H), 6.73-6.61 (m, 1H), 5.83-5.75 (m, 1H), 5.45-5.39 (m, 1H), 4.22-4.10 (m, 1H), 4.03-3.93 (m, 1H), 3.88-3.77 (m, 1H), 3.23-3.13 (m, 2H), 2.30-2.22 (m, 3H), 2.14-2.03 (m, 1H), 1.99-1.84 (m, 5H), 1.73-1.61 (m, 1H), 1.43-1.37 (m, 2H), 1.33-1.26 (m, 2H).

Example 634: (S)-2-Methyl-N-(1-(2-methyl-7-(prop-1-yn-1-yl)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 824)

##STR01486##

[2348] Compound 824 was synthesized according to an analogous procedure to the one described for compound 721. M+H.sup.+=454.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.35-9.96 (m, 1H), 9.17 (s, 1H), 9.11 (br d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=1.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.14-7.05 (m, 1H), 6.97-6.87 (m, 1H), 6.80-6.63 (m, 1H), 4.61 (br d, J=5.4 Hz, 1H), 4.31-4.19 (m, 2H), 4.03 (br dd, J=4.6, 8.9 Hz, 1H), 3.87 (br dd, J=6.1, 9.6 Hz, 1H), 2.84 (br d, J=4.4 Hz, 3H), 2.74 (s, 3H), 2.43-2.29 (m, 2H), 2.15 (s, 3H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.23 (br s, 2H).

Example 635: (S)-2-Methyl-N-(1-(7-(methylamino)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 763)

##STR01487##

[2349] Compound 763 was synthesized according to an analogous procedure to the one described for compound 729. M+H.sup.+=431.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.09-9.88 (m, 1H), 9.26 (br d, J=8.3 Hz, 1H), 9.15 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 7.78-7.65 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.52 (dd, J=5.6, 8.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.93 (dd, J=2.6, 8.6 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 6.66 (s, 1H), 4.68-4.55 (m, 1H), 4.24 (d, J=5.3 Hz, 2H), 4.09-3.99 (m, 1H), 3.88 (br d, J=9.9 Hz, 1H), 2.91-2.81 (m, 6H), 2.42-2.29 (m, 2H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.20 (br s, 2H).

Example 636: (S)-2-Methyl-4-(methylamino)-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 745)

##STR01488##

[2350] Compound 745 was synthesized according to an analogous procedure to the one described for compound 737. M+H.sup.+=457.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.81-10.58 (m, 1H), 9.76-9.61 (m, 1H), 9.17 (d, J=4.6 Hz, 1H), 9.00 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.96 (dd, J=5.0, 8.3 Hz, 1H), 7.15-6.99 (m, 1H), 6.87-6.73 (m, 1H), 6.41 (br s, 1H), 6.26-6.15 (m, 1H), 5.65 (d, J=11.0 Hz, 1H), 4.68-4.59 (m, 1H), 4.33 (br dd, J=5.7, 11.6 Hz, 1H), 4.19 (br dd, J=2.5, 12.0 Hz, 1H), 4.10-4.02 (m, 2H), 2.82 (s, 3H), 2.73 (s, 3H), 2.41-2.34 (m, 2H), 2.08 (s, 3H), 1.42 (br s, 2H), 1.37-1.30 (m, 2H).

Example 637: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-((2,2,2-trifluoroethyl)amino)quinolin-5-yl)cyclopropyl)benzamide (Compound 759)

##STR01489##

[2351] Compound 759 was synthesized according to an analogous procedure to the one described for compound 743. M+H.sup.+=499.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.05 (s, 1H), 8.85-8.73 (m, 1H), 8.66 (d, J=2.9 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.24-7.19 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.90-6.80 (m, 2H), 6.60 (d, J=2.5 Hz, 1H), 4.14-4.00 (m, 2H), 3.86 (d, J=5.4 Hz, 2H), 3.27-3.21 (m, 2H), 2.77-2.69 (m, 1H), 2.21 (s, 3H), 1.97 (s, 3H), 1.95-1.79 (m, 2H), 1.31 (br s, 2H), 1.16-1.10 (m, 2H).

Example 638: (S)N-(1-(7-(Benzylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 747)

##STR01490##

[2352] Compound 747 was synthesized according to an analogous procedure to the one described for compound 743. M+H.sup.+=507.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.02-10.84 (m, 1H), 9.43-9.35 (m, 1H), 9.31-9.21 (m, 1H), 8.80-8.73 (m, 1H), 8.49-8.32 (m, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.56 (dd, J=5.8, 8.2 Hz, 1H), 7.46-7.35 (m, 4H), 7.32-7.25 (m, 1H), 7.13-7.07 (m, 1H), 6.96-6.90 (m, 1H), 6.85-6.80 (m, 1H), 6.77 (d, J=2.8 Hz, 1H), 4.67-4.58 (m, 1H), 4.50-4.37 (m, 3H), 4.22 (dd, J=3.1, 11.1 Hz, 1H), 4.04-3.95 (m, 1H), 3.93-3.77 (m, 1H), 2.81 (d, J=4.6 Hz, 3H), 2.40-2.24 (m, 2H), 1.99 (s, 3H), 1.38 (br s, 2H), 1.21 (br s, 2H).

Example 639: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-4-(methylsulfonamido)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 760)

##STR01491##

[2353] Compound 760 was synthesized according to an analogous procedure to the one described for compound 746. M+H.sup.+=521.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.84 (br s, 1H), 9.62 (br d, J=8.5 Hz, 1H), 9.47-9.29 (m, 1H), 9.27-9.13 (m, 2H), 8.25 (d, J=1.3 Hz, 1H), 8.17 (s, 1H), 7.97 (dd, J=5.0, 8.5 Hz, 1H), 7.16-7.00 (m, 2H), 6.97-6.83 (m, 1H), 6.22 (d, J=17.6 Hz, 1H), 5.65 (d, J=11.0 Hz, 1H), 4.68 (br dd, J=3.4, 8.7 Hz, 1H), 4.39 (dd, J=5.8, 11.6 Hz, 1H), 4.24 (br dd, J=2.6, 11.6 Hz, 1H), 4.06-4.01 (m, 1H), 3.85 (br d, J=3.1 Hz, 1H), 2.99 (s, 3H), 2.83 (d, J=5.0 Hz, 3H), 2.40-2.33 (m, 2H), 1.98 (s, 3H), 1.44 (br s, 2H), 1.35 (br s, 2H).

Example 640: (S)-4-Hydroxy-2-methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 755)

##STR01492##

[2354] Compound 755 was synthesized according to an analogous procedure to the one described for compound 750. M+H.sup.+=444.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.11-9.03 (m, 1H), 8.93-8.84 (m, 2H), 8.06-8.00 (m, 1H), 7.94-7.89 (m, 1H), 7.59-7.50 (m, 1H), 7.05-6.92 (m, 1H), 6.77-6.71 (m, 1H), 6.55-6.51 (m, 1H), 6.12-6.03 (m, 1H), 5.51-5.44 (m, 1H), 3.97-3.66 (m, 3H), 2.90-2.82 (m, 1H), 2.25-2.22 (m, 3H), 2.18-1.92 (m, 6H), 1.39-1.32 (m, 2H), 1.27-1.20 (m, 2H).

Example 641: N-(1-(7-(5-(1-Hydroxyethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((S)-1-methylazetidin-2-yl)methoxy)benzamide (Compound 762)

##STR01493##

[2355] Compound 762 was synthesized according to an analogous procedure to the one described for compound 753. M+H.sup.+=528.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.35-10.20 (m, 1H), 9.30-9.20 (m, 2H), 9.03 (br d, J=3.6 Hz, 1H), 8.20 (br d, J=18.0 Hz, 2H), 7.77-7.69 (m, 1H), 7.66 (d, J=3.6 Hz, 1H), 7.12-7.08 (m, 1H), 7.05 (d, J=3.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 5.00 (q, J=6.0 Hz, 1H), 4.65-4.57 (m, 1H), 4.35-4.26 (m, 1H), 4.25-4.18 (m, 1H), 4.03-3.95 (m, 1H), 3.87-3.80 (m, 1H), 2.82 (d, J=5.0 Hz, 3H), 2.72-2.62 (m, 1H), 2.37-2.27 (m, 2H), 1.97 (s, 3H), 1.48 (d, J=6.4 Hz, 3H), 1.41 (br s, 2H), 1.37-1.31 (m, 2H).

Example 642: 2-Methyl-5-((R)-1-((S)-1-methylazetidin-2-yl) ethoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 758)

##STR01494##

[2356] Compound 758 was synthesized according to an analogous procedure to the one described for compound 757. M+H.sup.+=442.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.91-10.63 (m, 1H), 9.47 (br s, 1H), 9.27 (s, 1H), 9.12 (br d, J=2.3 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.94-7.83 (m, 1H), 7.11-7.01 (m, 2H), 6.96 (dd, J=2.6, 8.4 Hz, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.62 (d, J=10.9 Hz, 1H), 4.95-4.81 (m, 1H), 4.44-4.31 (m, 1H), 3.98-3.92 (m, 1H), 3.82 (br dd, J=6.8, 9.5 Hz, 1H), 2.78 (d, J=4.9 Hz, 3H), 2.39-2.32 (m, 1H), 2.28-2.20 (m, 1H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.33 (br s, 2H), 1.07 (d, J=6.1 Hz, 3H).

Example 643: (R)N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)benzamide (Compound 774)

##STR01495##

[2357] Compound 774 was synthesized according to an analogous procedure to the one described for compound 775. M+H.sup.+=472.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.10 (s, 1H), 8.95 (d, J=8.3 Hz, 1H), 8.81 (dd, J=1.4, 4.2 Hz, 1H), 7.48-7.38 (m, 2H), 7.31 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.84 (dd, J=2.7, 8.3 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 4.02-3.85 (m, 4H), 3.78 (dd, J=6.1, 9.6 Hz, 1H), 2.80-2.68 (m, 1H), 2.61 (s, 1H), 2.44 (d, J=8.8 Hz, 1H), 2.30 (s, 3H), 2.03-1.84 (m, 4H), 1.52 (dd, J=7.6, 12.6 Hz, 1H), 1.33 (br s, 2H), 1.19 (br s, 2H), 0.61-0.34 (m, 4H).

Example 644: (S)-2-Methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)-N-(1-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 788)

##STR01496##

[2358] Compound 788 was synthesized according to an analogous procedure to the one described for compound 782. M+H.sup.+=431.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.45-10.30 (m, 1H), 9.34-9.27 (m, 1H), 9.22 (s, 1H), 9.05 (br d, J=3.8 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.77 (br dd, J=4.8, 8.5 Hz, 1H), 7.13-6.99 (m, 2H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 6.15 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.67-4.56 (m, 1H), 4.38-4.18 (m, 2H), 4.05-3.95 (m, 1H), 3.90-3.81 (m, 1H), 2.41-2.26 (m, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.31 (br s, 2H).

Example 645: (S)N-(1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-(methyl-d.SUB.3.)azetidin-2-yl)methoxy)benzamide (Compound 798)

##STR01497##

[2359] Compound 798 was synthesized according to an analogous procedure to the one described for compound 782. M+H.sup.+=449.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.24-9.96 (m, 1H), 9.36-9.12 (m, 2H), 7.68 (br d, J=8.1 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.97-6.87 (m, 1H), 6.81-6.69 (m, 1H), 4.74-4.55 (m, 1H), 4.23 (d, J=5.3 Hz, 2H), 4.10-4.01 (m, 1H), 3.97 (s, 3H), 3.87 (br dd, J=6.1, 9.7 Hz, 1H), 2.81 (s, 3H), 2.44-2.27 (m, 2H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.26 (br s, 2H).

Example 646: (S)-2-Methyl-5-((1-methylazetidin-2-yl)methoxy)-N-(1-(7-(N-methylmethylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (Compound 818)

##STR01498##

[2360] Compound 818 was synthesized according to an analogous procedure to the one described for compound 786. M+H.sup.+=509.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.99-9.75 (m, 1H), 9.22-9.16 (m, 1H), 9.09 (d, J=8.4 Hz, 1H), 8.97 (dd, J=1.4, 4.2 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.65 (dd, J=4.3, 8.5 Hz, 1H), 7.13-7.06 (m, 1H), 6.92 (dd, J=2.8, 8.4 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.66-4.55 (m, 1H), 4.24-4.18 (m, 2H), 4.06-4.00 (m, 1H), 3.89 (br s, 1H), 3.41 (s, 3H), 3.06 (s, 3H), 2.84 (d, J=5.0 Hz, 3H), 2.43-2.24 (m, 2H), 1.97 (s, 3H), 1.39 (br s, 2H), 1.30-1.15 (m, 2H).

Example 647: (S)-2-Methyl-N-(1-(2-methyl-7-(methylsulfonamido)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 825)

##STR01499##

[2361] Compound 825 was synthesized according to an analogous procedure to the one described for compound 786. M+H.sup.+=509.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.83-10.49 (m, 1H), 10.06-9.74 (m, 1H), 9.18 (s, 2H), 7.84 (s, 1H), 7.74 (br s, 1H), 7.69-7.58 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.93 (dd, J=2.8, 8.4 Hz, 1H), 6.80-6.69 (m, 1H), 4.67-4.58 (m, 1H), 4.23 (d, J=4.9 Hz, 2H), 4.12-3.97 (m, 1H), 3.92-3.84 (m, 1H), 3.20 (s, 3H), 2.85 (d, J=4.8 Hz, 3H), 2.78-2.70 (m, 3H), 2.42-2.29 (m, 2H), 1.96 (s, 3H), 1.39 (br s, 2H), 1.20 (br s, 2H).

Example 648: (S)-2-Methyl-N-(1-(2-methyl-7-(N-methylmethylsulfonamido)quinolin-5-yl)cyclopropyl)-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 819)

##STR01500##

[2362] Compound 819 was synthesized according to an analogous procedure to the one described for compound 786. M+H.sup.+=523.2 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.21-9.15 (m, 2H), 8.02 (d, J=2.3 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.13-7.07 (m, 1H), 6.92 (dd, J=2.6, 8.4 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 4.68-4.57 (m, 1H), 4.26-4.16 (m, 2H), 4.02 (dt, J=4.4, 9.7 Hz, 1H), 3.86 (q, J=9.7 Hz, 1H), 3.40 (s, 3H), 3.08 (s, 3H), 2.83 (s, 3H), 2.76 (s, 3H), 2.41-2.29 (m, 2H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.25 (br s, 2H).

Example 649: (S)N-(1-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl-2,2,3,3-d)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 804)

##STR01501##

[2363] Compound 804 was synthesized according to an analogous procedure to the one described for compound 794. M+H.sup.+=450.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.20-9.95 (m, 1H), 9.35 (br d, J=8.6 Hz, 1H), 9.18 (s, 1H), 7.75 (br d, J=8.4 Hz, 1H), 7.62 (br d, J=1.4 Hz, 1H), 7.42 (s, 1H), 7.11 (br d, J=8.5 Hz, 1H), 6.93 (dd, J=2.4, 8.2 Hz, 1H), 6.80-6.69 (m, 1H), 4.67-4.59 (m, 1H), 4.24 (br d, J=5.3 Hz, 2H), 4.08-3.97 (m, 4H), 3.94-3.84 (m, 1H), 2.92-2.80 (m, 6H), 2.44-2.28 (m, 2H), 1.96 (s, 3H).

Example 650: (S)N-(1-(7-(Fluoromethoxy)-2-methylquinolin-5-yl)cyclopropyl)-2-methyl-5-((1-methylazetidin-2-yl)methoxy)benzamide (Compound 823)

##STR01502##

[2364] Compound 823 was synthesized according to an analogous procedure to the one described for compound 795. M+H.sup.+=464.4 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 11.13-10.71 (m, 1H), 9.52 (br d, J=8.1 Hz, 1H), 9.35 (s, 1H), 7.96-7.83 (m, 2H), 7.78 (d, J=2.1 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.14-7.06 (m, 1H), 7.00-6.89 (m, 1H), 6.83-6.72 (m, 1H), 6.17 (s, 1H), 6.04 (s, 1H), 4.71-4.57 (m, 1H), 4.39 (dd, J=8.1, 11.3 Hz, 1H), 4.22 (dd, J=3.2, 11.2 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.81 (m, 1H), 2.92 (s, 3H), 2.83-2.65 (m, 3H), 2.42-2.27 (m, 2H), 1.98 (s, 3H), 1.42 (br s, 2H), 1.31 (br s, 2H).

Example 651: N-(1-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy)benzamide (Compound 801)

##STR01503##

[2365] Compound 801 was synthesized according to an analogous procedure to the one described for compound 799. M+H.sup.+=508.3 (LCMS); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 9.08 (s, 1H), 8.93 (d, J=8.3 Hz, 1H), 8.79 (dd, J=1.6, 4.3 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.35 (dd, J=4.3, 8.5 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.27-7.21 (m, 1H), 7.18-7.10 (m, 3H), 7.02 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.8, 8.4 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 4.16 (dd, J=5.8, 10.1 Hz, 1H), 3.97 (dd, J=4.6, 10.2 Hz, 1H), 3.92 (s, 3H), 3.80 (t, J=4.9 Hz, 1H), 3.06 (ddd, J=4.9, 7.1, 11.9 Hz, 1H), 2.85-2.75 (m, 1H), 2.74-2.66 (m, 1H), 2.63-2.56 (m, 1H), 2.44 (s, 3H), 1.94 (s, 3H), 1.40-1.29 (m, 2H), 1.22-1.14 (m, 2H).

Additional Biological Data

List of Abbreviations

TABLE-US-00003 BG Back Ground CPD Compound DMSO Dimethyl Sulfoxide HPE Hundred Percent Effect IC.sub.50 50% Inhibitory Concentration PLpro Papain-like Protease ZPE Zero Percent Effect

Example 652: Evaluation of In Vitro Inhibitory Activity of Compounds Against SARS-CoV-2 Papain-Like Protease

[2366] Test compounds were assayed at 10 concentrations from 10 M, in duplicate for the IC.sub.50 determination. The assay buffer contained 50 mM HEPES (pH 7.5), 0.01% Triton-X 100, 0.1 mg/ml BSA and 5 mM DTT. The final concentrations of the PLpro protein and substrate in the assay were 6.25 nM and 25 M, respectively.

[2367] Compounds were 3 folds serially diluted to 10 concentrations and added to an assay plate (384 w format) using ECHO, in duplicate wells. The final concentrations are 10 M, 3.33 M, 1.11 M, 0.37 M, 0.123 M, 0.041 M, 0.014 M, 0.0046 M, 0.0015 UM and 0.00051 M.

[2368] 20 L of 7.8 nM of PLpro protein were added to an assay plate containing compounds using a Multidrop. The compounds and PLpro protein were pre-incubated at room temperature for 30 min. Then 5 L of 125 M of substrate were added to an assay plate using a Multidrop. The final concentrations of PLpro and substrate were 6.25 nM and 25 M, respectively. For 100% inhibition control (HPE, hundred percent effect), high concentration of positive compound was added. For no inhibition control (ZPE, zero percent effect), no compound was added. The final DMSO concentration is 1%

[2369] After 60 min incubation at 25 C., the fluorescence signal (RFU) was detected using a microplate reader SpectraMax M2e (Molecular Devices) at Ex/Em=360 nm/460 nm.

[2370] The inhibitory activity (Inhibition %) was calculated using the formula below, IC.sub.50 values were calculated using the Inhibition % data.

[00001]$\mathrm{Inhibition}\%=\left[\left(\mathrm{Sample}-\mathrm{Average}\mathrm{ZPE}\right)/\left(\mathrm{Average}\mathrm{HPE}-\mathrm{Average}\mathrm{ZPE}\right)\right]*100{\%}^{\#}$

[2371] For more potent compounds, the following PLpro enzymatic assay was used: .sup.#HEP: Hundred percent effect controls. Containing substrate+assay buffer, no compound. ZPE: Zero percent effective controls. Containing enzyme+substrate, no compound. Sample: Compound activity testing wells. Containing compound+enzyme+substrate. [2372] PLpro enzyme: 20 L of 1.25 nM, 1 nM final concentration [2373] Substrate: 5 L of 125 M, 25 M final concentration [2374] Incubation time: 120 min [2375] Certain compounds having a relatively greater potency were not tested at a top concentration of 10 M.

[2376] IC.sub.50 values of compounds were calculated with the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. responseVariable slope (four parameters). IC.sub.50 values are provided in the table below, wherein A represents an IC.sub.50 value of <0.1 M; B represents an IC.sub.50 value of 0.1 to <1 M; C represents an IC.sub.50 value of 1 to <5 M; and D represents an IC.sub.50 value of 5 M.

TABLE-US-00004 PLpro Example IC.sub.50 Compd ID No. Structure (M.sup.1) 172 1 [01504] D 168 2 [01505] D 155 3 [01506] D 101 4 [01507] C 136 5 [01508] C 132 6 [01509] D .sup.1US provisional application No. 63/352,580, to which the present application claims priority, contained a typographical error in the corresponding column heading, where the IC.sub.50 data were incorrectly presented as millimolar (mM) concentrations instead of micromolar (M) concentrations. The column heading has been corrected in the current version of the table.

TABLE-US-00005 PLpro Example IC.sub.50 Compd ID No. Structure (M.sup.1) 158 7 [01510] C 159 8 [01511] B 160 9 [01512] B 152 10 [01513] C 141 11 [01514] B 164 12 [01515] C 162 13 [01516] B 100 14 [01517] D 121 15 [01518] C 107 16 [01519] D 115 17 [01520] C 119 18 [01521] C 165 19 [01522] D 153 20 [01523] C 189 21 [01524] D 148 22 [01525] B 156 23 [01526] C 192 24 [01527] B 206 25 [01528] C 125 26 [01529] D 102 27 [01530] C 128 28 [01531] B 131 29 [01532] C 124 30 [01533] D 142 31 [01534] B 150 32 [01535] C 167 33 [01536] D 145 34 [01537] C 163 35 [01538] D 195 36 [01539] D 200 37 [01540] C 185 38 [01541] C 183 39 [01542] C 191 40 [01543] B 281 41 [01544] D 241 42 [01545] D 147 43 [01546] B 219 44 [01547] D 177 45 [01548] B 313 46 [01549] B 378 47 [01550] A 257 48 [01551] B 312 49 [01552] B 398 50 [01553] A 399 51 [01554] A 373 52 [01555] A 215 53 [01556] A 211 54 [01557] D 316 55 [01558] B 233 56 [01559] A 386 57 [01560] A 214 58 [01561] A 351 59 [01562] A 247 60 [01563] B 362 61 [01564] A 361 62 [01565] A 315 63 [01566] C 360 64 [01567] A 359 65 [01568] A 358 66 [01569] A 300 67 [01570] A 254 68 [01571] A 284 69 [01572] B 209 70 [01573] B 324 71 [01574] A 343 72 [01575] A 400 73 [01576] A 367 74 [01577] A 322 75 [01578] A 352 76 [01579] A 256 77 [01580] A 274 78 [01581] A 310 79 [01582] A 309 80 [01583] A 387 81 [01584] A 349 82 [01585] B 314 83 [01586] A 396 84 [01587] C 331 85 [01588] D 330 86 [01589] A 323 87 [01590] A 332 88 [01591] A 348 89 [01592] A 341 90 [01593] A 394 91 [01594] A 393 92 [01595] B 285 93 [01596] B 171 94 [01597] B 265 95 [01598] B 263 96 [01599] A 283 97 [01600] A 268 98 [01601] B 289 99 [01602] B 339 100 [01603] A 288 101 [01604] B 293 101 [01605] B 286 102 [01606] A 302 103 [01607] B 376 105 [01608] A 303 106 [01609] D 269 107 [01610] B 337 108 [01611] D 353 109 [01612] D 311 110 [01613] B 216 111 [01614] B 369 112 [01615] A 366 113 [01616] B 350 114 [01617] C 275 115 [01618] C 199 116 [01619] B 240 117 [01620] B 180 118 [01621] B 170 119 [01622] A 248 120 [01623] C 246 121 [01624] D 244 122 [01625] D 232 123 [01626] C 221 124 [01627] A 173 125 [01628] B 273 126 [01629] A 260 127 [01630] B 202 128 [01631] B 222 129 [01632] B 213 130 [01633] C 229 131 [01634] A 204 132 [01635] B 205 133 [01636] B 225 134 [01637] B 226 135 [01638] D 234 136 [01639] B 201 137 [01640] B 296 138 [01641] B 218 139 [01642] A 290 140 [01643] A 239 141 [01644] A 295 142 [01645] B 203 143 [01646] B 212 144 [01647] B 292 145 [01648] B 207 146 [01649] B 210 147 [01650] B 249 148 [01651] B 243 149 [01652] C 262 150 [01653] B 190 151 [01654] A 231 152 [01655] A 176 153 [01656] B 304 154 [01657] A 305 154 [01658] B 197 155 [01659] A 198 156 [01660] B 220 157 [01661] A 235 158 [01662] B 236 158 [01663] B 230 159 [01664] B 224 160 [01665] B 397 161 [01666] B 223 162 [01667] B 280 163 [01668] B 245 164 [01669] A 238 165 [01670] B 237 166 [01671] C 297 167 [01672] B 227 168 [01673] B 334 169 [01674] C 194 170 [01675] C 272 171 [01676] D 252 172 [01677] D 259 173 [01678] D 251 174 [01679] B 261 175 [01680] C 258 176 [01681] D 326 177 [01682] C 282 178 [01683] C 255 179 [01684] D 253 180 [01685] D 321 181 [01686] B 364 182 [01687] B 344 183 [01688] B 267 184 [01689] D 294 185 [01690] D 271 186 [01691] D 298 187 [01692] C 270 188 [01693] D 279 189 [01694] C 327 190 [01695] C 308 191 [01696] D 307 192 [01697] D 291 193 [01698] B 264 194 [01699] C 276 195 [01700] D 338 196 [01701] C 266 197 [01702] D 355 198 [01703] B 325 199 [01704] B 169 200 [01705] B 187 201 [01706] C 186 202 [01707] B 196 203 [01708] B 318 204 [01709] C 335 205 [01710] B 317 206 [01711] B 336 207 [01712] B 340 208 [01713] B 329 209 [01714] B 370 210 [01715] B 357 211 [01716] B 368 212 [01717] B 356 213 [01718] A 403 214 [01719] B 346 215 [01720] B 354 216 [01721] B 395 217 [01722] A 301 218 [01723] A 374 219 [01724] A 385 220 [01725] A 381 221 [01726] A 383 222 [01727] A 391 223 [01728] A 390 224 [01729] A 380 225 [01730] A 379 226 [01731] A 371 227 [01732] A 382 228 [01733] A 299 229 [01734] A 375 230 [01735] A 402 231 [01736] A 333 232 [01737] B 388 233 [01738] A 363 234 [01739] A 320 235 [01740] A 345 236 [01741] A 347 237 [01742] A 384 238 [01743] A 401 239 [01744] A 319 240 [01745] A 392 241 [01746] A 377 242 [01747] A 389 243 [01748] A 365 244 [01749] A 120 245 [01750] D 126 246 [01751] C 134 247 [01752] B 137 248 [01753] C 140 249 [01754] C 146 250 [01755] B 151 251 [01756] B 154 252 [01757] C 143 253 [01758] D 144 254 [01759] D 149 255 [01760] D 135 256 [01761] C 139 257 [01762] D 404 258 [01763] A 406 259 [01764] A 416 260 [01765] A 414 261 [01766] A 412 262 [01767] A 421 263 [01768] A 413 264 [01769] A 407 265 [01770] A 410 266 [01771] A 418 267 [01772] A 411 268 [01773] A 405 269 [01774] A 409 270 [01775] A 415 271 [01776] B 417 272 [01777] A 408 273 [01778] A 419 274 [01779] A 420 275 [01780] A 459 276 [01781] D 448 277 [01782] C 453 278 [01783] D 499 279 [01784] D 451 280 [01785] A 450 281 [01786] A 425 282 [01787] B 424 283 [01788] B 439 284 [01789] A 440 285 [01790] A 438 286 [01791] A 437 287 [01792] A 442 288 [01793] A 441 289 [01794] A 491 290 [01795] B 492 290 [01796] B 534 291 [01797] A 533 292 [01798] A 487 293 [01799] A 435 294 [01800] B 447 295 [01801] B 449 296 [01802] A 455 297 [01803] A 431 298 [01804] B 452 299 [01805] B 472 300 [01806] A 463 301 [01807] B 505 302 [01808] A 426 303 [01809] B 432 304 [01810] B 457 305 [01811] B 445 306 [01812] A 490 307 [01813] A 489 308 [01814] A 433 309 [01815] A 474 310 [01816] A 461 311 [01817] A 541 312 [01818] A 443 313 [01819] A 484 314 [01820] A 482 315 [01821] A 496 316 [01822] A 495 317 [01823] A 520 318 [01824] A 481 319 [01825] A 501 320 [01826] A 508 321 [01827] A 521 322 [01828] A 423 323 [01829] A 471 324 [01830] B 486 325 [01831] A 539 326 [01832] A 468 327 [01833] A 470 328 [01834] A 475 329 [01835] A 477 330 [01836] A 465 331 [01837] C 483 332 [01838] A 434 333 [01839] A 530 334 [01840] A 526 335 [01841] A 560 336 [01842] A 575 337 [01843] A 511 338 [01844] A 527 339 [01845] A 462 340 [01846] A 528 341 [01847] A 550 342 [01848] A 561 343 [01849] B 584 344 [01850] B 597 345 [01851] A 587 346 [01852] A 598 347 [01853] A 563 348 [01854] A 497 349 [01855] A 581 350 [01856] A 600 351 [01857] A 568 352 [01858] A 551 353 [01859] A 588 354 [01860] A 436 355 [01861] A 529 356 [01862] A 547 357 [01863] A 545 358 [01864] A 544 359 [01865] A 548 360 [01866] A 555 361 [01867] A 467 362 [01868] A 565 363 [01869] A 542 364 [01870] A 586 365 [01871] A 538 366 [01872] A 509 367 [01873] B 549 368 [01874] D 522 369 [01875] D 524 370 [01876] B 106 371 [01877] D 178 372 [01878] D 184 373 [01879] D 208 374 [01880] D 179 375 [01881] D 577 376 [01882] D 580 377 [01883] D 111 378 [01884] D 116 379 [01885] D 161 380 [01886] D 166 381 [01887] D 108 382 [01888] D 118 383 [01889] D 105 384 [01890] D 109 385 [01891] D 242 386 [01892] D 138 387 [01893] D 217 388 [01894] D 624 389 [01895] A 729 390 [01896] A 627 391 [01897] A 611 392 [01898] A 743 393 [01899] A 744 394 [01900] A 786 395 [01901] A 757 396 [01902] A 713 397 [01903] A 748 398 [01904] A 749 399 [01905] A 800 400 [01906] A 726 401 [01907] A 746 402 [01908] A 785 403 [01909] A 796 404 [01910] A 660 405 [01911] A 638 406 [01912] A 676 407 [01913] A 697 408 [01914] A 620 409 [01915] A 696 410 [01916] A 803 411 [01917] A 738 412 [01918] A 677 413 [01919] A 692 414 [01920] A 761 415 [01921] B 626 416 [01922] A 797 417 [01923] A 732 418 [01924] A 775 419 [01925] A 776 419 [01926] A 789 420 [01927] A 790 420 [01928] A 783 421 [01929] A 784 421 [01930] A 799 422 [01931] A 794 423 [01932] A 750 424 [01933] A 737 425 [01934] A 625 426 [01935] A 791 427 [01936] B 817 428 [01937] A 809 429 [01938] A 795 430 [01939] A 815 431 [01940] A 648 432 [01941] A 683 433 [01942] A 630 434 [01943] A 608 435 [01944] A 753 436 [01945] A 780 437 [01946] A 669 438 [01947] A 767 439 [01948] D 812 440 [01949] A 814 441 [01950] A 782 442 [01951] A 806 443 [01952] A 619 444 [01953] A 653 445 [01954] 689 446 [01955] A 821 447 [01956] A 808 448 [01957] A 181 449 [01958] D 104 450 [01959] D 188 451 [01960] D 127 452 [01961] D 739 453 [01962] A 110 454 [01963] D 123 455 [01964] D 113 456 [01965] D 114 457 [01966] D 117 458 [01967] D 182 459 [01968] D 607 460 [01969] A 606 461 [01970] A 513 462 [01971] A 430 463 [01972] A 428 464 [01973] B 429 465 [01974] B 277 466 [01975] D 278 467 [01976] D 569 468 [01977] D 427 469 [01978] A 306 470 [01979] D 572 471 [01980] A 567 472 [01981] A 571 473 [01982] A 444 474 [01983] A 559 475 [01984] A 596 476 [01985] A 454 477 [01986] B 473 478 [01987] A 456 479 [01988] A 458 480 [01989] A 507 481 [01990] B 488 482 [01991] A 617 483 [01992] A 498 484 [01993] A 446 485 [01994] A 566 486 [01995] A 464 487 [01996] A 485 488 [01997] A 506 489 [01998] A 479 490 [01999] A 502 491 [02000] A 480 492 [02001] A 478 493 [02002] A 476 494 [02003] A 787 495 [02004] A 493 496 [02005] A 514 497 [02006] A 518 498 [02007] A 500 499 [02008] A 510 500 [02009] A 512 501 [02010] A 556 502 [02011] A 517 503 [02012] A 503 504 [02013] A 578 505 [02014] A 554 506 [02015] A 516 507 [02016] A 504 508 [02017] A 558 509 [02018] A 531 510 [02019] A 532 511 [02020] A 557 512 [02021] A 553 513 [02022] A 535 514 [02023] A 536 515 [02024] A 537 516 [02025] A 543 517 [02026] A 540 518 [02027] A 552 519 [02028] D 593 520 [02029] C 599 521 [02030] C 573 522 [02031] A 562 523 [02032] B 579 524 [02033] A 570 525 [02034] A 603 526 [02035] A 650 527 [02036] A 668 528 [02037] A 632 529 [02038] A 623 530 [02039] A 604 531 [02040] A 652 532 [02041] A 670 533 [02042] A 633 534 [02043] A 651 535 [02044] A 582 536 [02045] A 644 537 [02046] A 659 538 [02047] A 609 539 [02048] A 621 540 [02049] A 594 541 [02050] A 574 542 [02051] A 592 543 [02052] A 590 544 [02053] A 591 545 [02054] A 612 546 [02055] A 613 547 [02056] A 667 548 [02057] A 704 549 [02058] A 640 550 [02059] A 643 551 [02060] A 658 552 [02061] A 673 553 [02062] A 645 554 [02063] A 641 555 [02064] A 646 556 [02065] A 694 557 [02066] A 698 558 [02067] A 680 559 [02068] A 636 560 [02069] A 635 561 [02070] A 649 562 [02071] A 634 563 [02072] A 656 564 [02073] A 664 565 [02074] A 642 566 [02075] A 665 567 [02076] A 695 568 [02077] A 711 569 [02078] A 662 570 [02079] A 675 571 [02080] A 666 572 [02081] A 674 573 [02082] A 637 574 [02083] A 682 575 [02084] A 688 576 [02085] A 686 577 [02086] A 685 578 [02087] A 822 579 [02088] A 615 580 [02089] A 616 581 [02090] A 639 582 [02091] A 647 583 [02092] A 802 584 [02093] A 717 585 [02094] A 813 586 [02095] A 719 587 [02096] A 684 588 [02097] A 690 589 [02098] A 721 590 [02099] A 657 591 [02100] A 754 592 [02101] A 764 593 [02102] A 691 594 [02103] A 654 595 [02104] A 655 596 [02105] A 671 597 [02106] A 716 598 [02107] A 693 599 [02108] A 820 600 [02109] 718 601 [02110] A 736 602 [02111] A 663 603 [02112] A 678 604 [02113] A 687 605 [02114] A 672 606 [02115] A 681 607 [02116] A 701 608 [02117] A 699 609 [02118] A 702 610 [02119] A 700 611 [02120] A 661 612 [02121] A 735 613 [02122] A 734 614 [02123] A 751 615 [02124] A 756 616 [02125] A 805 617 [02126] A 752 618 [02127] A 793 619 [02128] A 781 620 [02129] A 807 621 [02130] A 771 622 [02131] A 722 623 [02132] A 723 624 [02133] A 811 625 [02134] A 810 626 [02135] A 816 627 [02136] A 826 628 [02137] A 712 629 [02138] A 740 630 [02139] A 714 631 [02140] A 733 632 [02141] A 715 633 [02142] A 824 634 [02143] A 763 635 [02144] A 745 636 [02145] A 759 637 [02146] A 747 638 [02147] A 760 639 [02148] A 755 640 [02149] A 762 641 [02150] A 758 642 [02151] A 774 643 [02152] A 788 644 [02153] A 798 645 [02154] A 818 646 [02155] A 825 647 [02156] A 819 648 [02157] A 804 649 [02158] A 823 650 [02159] A 801 651 [02160] A