COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

Claims

1. A compound of Formula (I): ##STR01071## or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1; a1, a2, a3, a4, and a5 are each independently 0 or 1, provided that a1+a2+a3+a4+a5≥1, and each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—; provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c provided the C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; and heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c, provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; Q.sup.1 is —R.sup.g; Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2; X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1; X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5; each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl; further provided that L.sup.A cannot include a cyclic group directly attached to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g; each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g; R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g; W is selected from the group consisting of: H; C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom; each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano; each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; —NR′C(═O)(C.sub.1-4 alkyl) and —SF.sub.5; each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; and C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; each occurrence of R.sup.h is independently selected from the group consisting of: C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.; and C.sub.6-10 aryl optionally substituted with 1-4 R.sup.i; each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo; each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a; each occurrence of bg is independently 1, 2, or 3; and each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

2. The compound of claim 1, wherein a2 is 1.

3. The compound of claim 1, wherein L.sup.2 is straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b, optionally wherein L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b; optionally wherein L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

4. The compound of claim 1, wherein L.sup.2 is selected from the group consisting of: C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c; and heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c.

5. The compound of claim 1, wherein a1 is 1.

6. The compound of claim 1, wherein L.sup.1 is selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, and —S—, optionally wherein L.sup.1 is —O—.

7. The compound of claim 1, wherein a1 is 0.

8. The compound of claim 1, wherein a3 is 1.

9. The compound of claim 1, wherein L.sup.3 is selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, and —S—, optionally wherein L.sup.3 is —O—.

10. The compound of claim 1, wherein a3 is 0.

11. The compound of claim 1, wherein a4 is 1.

12. The compound of claim 1, wherein: a1 and a2 are each 1; optionally, wherein: a1 and a2 are each 1; L.sup.1 is —O—, —N(H)—, or —N(R.sup.d)—; and L.sup.2 is selected from the group consisting of: straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b; C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c; optionally wherein: a1 and a2 are each 1; L.sup.1 is —O—; and L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b; optionally wherein: a1 and a2 are each 1; L.sup.1 is —O—; and L.sup.2 is C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; optionally wherein L.sup.2 is: ##STR01072## which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0, 1, or 2; Q.sup.2 is CH, CR.sup.c, or N; and the asterisk represents the point of attachment to -(L.sup.3).sub.a3-; optionally wherein n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH; optionally wherein n1 and n2 are 0 and Q.sup.2 is CH; optionally wherein L.sup.2 is cyclobutane-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is cyclobutane-1,3-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is unsubstituted cyclobutane-diyl; optionally wherein L.sup.2 is unsubstituted cyclobutane-1,3-diyl.

13. The compound of claim 12, wherein a3, a4, and a5 are each 0, optionally wherein L.sup.A is —O—CH.sub.2CH.sub.2—*, or ##STR01073## (such as or ##STR01074## wherein * represents the point of attachment to Q.sup.1.

14. The compound of claim 1, wherein a1 is 0; a2 is 1; optionally wherein L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b, optionally wherein L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

15. The compound of claim 14, wherein a3 is 1; optionally, wherein L.sup.3 is selected from the group consisting of: is —O—, —N(H)—, and —N(R.sup.d)—, optionally wherein L.sup.3 is —O—.

16. The compound of claim 14, wherein a4 is 0; and a5 is 0.

17. The compound of claim 1, wherein Q.sup.1 is selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and phenyl optionally substituted with 1-3 R.sup.c.

18. The compound of claim 1, wherein Q.sup.1 is heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; optionally wherein Q.sup.1 is ##STR01075## wherein m1 and m2 are each independently 0, 1, or 2; and wherein Q.sup.1 is optionally substituted with 1-2 R.sup.c; and optionally wherein each R.sup.d present in Q.sup.1 is independently selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a.

19. The compound of claim 1, wherein Y.sup.1 is CR.sup.1; Y.sup.2 is CR.sup.1; and/or Y.sup.3 is CR.sup.1.

20. The compound of claim 1, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each CH.

21. The compound of claim 1, wherein X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5; optionally wherein X.sup.1 is NH; and X.sup.2 is CH.

22. The compound of claim 1, wherein R.sup.6 is H.

23. The compound of claim 1, wherein W is: (i) C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; optionally C.sub.1-10 alkyl, which is optionally substituted with 1-6 R.sup.a2; optionally C.sub.1-4 alkyl, which is optionally substituted with 1-6 R.sup.a2.

24. The compound of claim 1, wherein W is: (i) monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; optionally monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

25. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

27. A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.

28. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.

29. A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and/or symptoms and/or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.

30. A combination comprising a compounds defined in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

31-32. (canceled)

Description

DETAILED DESCRIPTION

[0075] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

[0076] Formula I Compounds

[0077] In one aspect, the disclosure features a compound of Formula (I):

##STR00007##

[0078] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0079] L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1;

[0080] a1, a2, a3, a4, and a5 are each independently 0 or 1,

[0081] provided that a1+a2+a3+a4+a5≥1, and

[0082] each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—;

[0083] provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and

[0084] each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: [0085] straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; [0086] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c, provided the C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; and [0087] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c, provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0088] Q.sup.1 is —R.sup.g;

[0089] Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2;

[0090] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1;

[0091] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;

[0092] each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl;

[0093] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0094] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0095] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g;

[0096] W is selected from the group consisting of: [0097] H; [0098] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2; [0099] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0100] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[0101] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom;

[0102] each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano;

[0103] each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5;

[0104] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0105] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0106] each occurrence of R.sup.g is independently selected from the group consisting of: [0107] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; [0108] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; [0109] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.c; and [0110] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.c,

[0111] each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a;

[0112] each occurrence of bg is independently 1, 2, or 3; and

[0113] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

In another aspect, this disclosure features a compound of Formula (I):

##STR00008##

[0114] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0115] L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1;

[0116] a1, a2, a3, a4, and a5 are each independently 0 or 1,

[0117] provided that a1+a2+a3+a4+a5≥1, and

[0118] each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—;

[0119] provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and

[0120] each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: [0121] straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; [0122] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.e provided the C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; and [0123] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c, provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0124] Q.sup.1 is —R.sup.g;

[0125] Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2;

[0126] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1;

[0127] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;

[0128] each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl;

[0129] further provided that L.sup.A cannot include a cyclic group directly attached to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0130] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0131] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0132] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g;

[0133] W is selected from the group consisting of: [0134] H; [0135] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [0136] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0137] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[0138] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom;

[0139] each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano;

[0140] each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5;

[0141] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; [0142] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0143] each occurrence of R.sup.g is independently selected from the group consisting of: [0144] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; [0145] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; [0146] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.c; and [0147] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.c;

[0148] each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a;

[0149] each occurrence of bg is independently 1, 2, or 3; and

[0150] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

In another aspect, this disclosure features a compound of Formula (I):

##STR00009##

[0151] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0152] L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1;

[0153] a1, a2, a3, a4, and a5 are each independently 0 or 1,

[0154] provided that a1+a2+a3+a4+a5≥1, and

[0155] each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—;

[0156] provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and

[0157] each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: [0158] straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; [0159] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c provided the C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; and [0160] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c, provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0161] Q.sup.1 is —R.sup.g;

[0162] Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2;

[0163] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1;

[0164] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;

[0165] each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl;

[0166] further provided that L.sup.A cannot include a cyclic group directly attached to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0167] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0168] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0169] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g;

[0170] W is selected from the group consisting of: [0171] H; [0172] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [0173] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0174] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[0175] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom;

[0176] each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano;

[0177] each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5;

[0178] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0179] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0180] each occurrence of R.sup.g is independently selected from the group consisting of: [0181] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0182] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0183] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; and [0184] C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h;

[0185] each occurrence of R.sup.h is independently selected from the group consisting of: [0186] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; [0187] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; [0188] heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and [0189] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.i; [0190] each occurrence of R.sup.1 is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo;

[0191] each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a;

[0192] each occurrence of bg is independently 1, 2, or 3; and

[0193] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

[0194] In still another aspect, this disclosure features A compound of Formula (I):

##STR00010##

[0195] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0196] L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1;

[0197] a1, a2, a3, a4, and a5 are each independently 0 or 1,

[0198] provided that a1+a2+a3+a4+a5≥1, and

[0199] each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—;

[0200] provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and

[0201] each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: [0202] straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; [0203] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c provided the C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3; and [0204] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c, provided the heterocyclylene or heterocycloalkenylene is not directly connected to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0205] Q.sup.1 is —R.sup.g;

[0206] Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2;

[0207] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1;

[0208] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;

[0209] each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl;

[0210] further provided that L.sup.A cannot include a cyclic group directly attached to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[0211] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0212] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[0213] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g;

[0214] W is selected from the group consisting of: [0215] H; [0216] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [0217] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0218] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[0219] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom;

[0220] each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano;

[0221] each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; —NR′C(═O)(C.sub.1-4 alkyl) and —SF.sub.5;

[0222] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0223] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[0224] each occurrence of R.sup.g is independently selected from the group consisting of: [0225] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0226] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0227] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; and [0228] C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0229] each occurrence of R.sup.h is independently selected from the group consisting of: [0230] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; [0231] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; [0232] heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and [0233] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.;

[0234] each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo;

[0235] each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a;

[0236] each occurrence of bg is independently 1, 2, or 3; and

[0237] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

[0238] Variable L.sup.A (-(L).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, Wherein * Represents the Point of Attachment to Q.sup.1)

[0239] In some embodiments, L.sup.A is a divalent moiety having a 1-6 (e.g., 2-6 (e.g., 2, 3, or 4)) linear array of substituted or unsubstituted carbon and/or heteroatoms. In some embodiments, L.sup.A is a divalent moiety having a combination of a cyclic moiety and a 1-6 (e.g., 2-6 (e.g., 2, 3, or 4)) linear array of substituted or unsubstituted carbon and/or heteroatoms. For example, one cyclic moiety (e.g., C3-6, e.g., C4 cycloalkylene), and an acyclic moiety (e.g., O).

[0240] In some embodiments, provided that when a3 is 0; and a4 is 1, then L.sup.4 is other than straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b.

[0241] In some embodiments, a2 is 1. In some embodiments, a2 is 0.

[0242] In certain embodiments (when a2 is 1), L.sup.2 is straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b.

[0243] In certain of the foregoing embodiments, L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b.

[0244] In certain of the foregoing embodiments, L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[0245] In certain embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b— and —C(R.sup.b).sub.2—. For example, L.sup.2 can be —CH.sub.2—.

[0246] In certain embodiments (when L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b), L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[0247] In certain of these embodiments, L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of the foregoing embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0248] In certain embodiments, L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b. For example, L.sup.2 can be selected from the group consisting of:

##STR00011##

wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[0249] In certain embodiments (when a2 is 1), L.sup.2 is straight-chain C.sub.2-6 alkenylene, which is optionally substituted with 1-6 R.sup.b. In certain of these embodiments, L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b. For example, L.sup.2 can be selected from the group consisting of:

##STR00012##

wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[0250] In certain embodiments (when a2 is 1), L.sup.2 is selected from the group consisting of: [0251] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c; and [0252] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c.

[0253] In certain of these embodiments, L.sup.2 is selected from the group consisting of: [0254] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0255] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0256] In certain of the foregoing embodiments, L.sup.2 is:

##STR00013##

which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0, 1, or 2; Q.sup.2 is CH, CR.sup.c, or N; and the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[0257] In certain of these embodiments, Q.sup.2 is CH.

[0258] In certain embodiments (when L.sup.2 is:

##STR00014##

as defined supra), n1 and n2 are each 0.

[0259] As a non-limiting example (when L.sup.2 is:

##STR00015##

as defined supra), L.sup.2 can be

##STR00016##

wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3- or -(L.sup.1).sub.a1, e.g., -(L.sup.1).sub.a1, in which at is 1. For example, L.sup.2 can be

##STR00017##

wherein the asterisk represents the point of attachment to -(L.sup.1).sub.a1. In certain of these embodiments, -(L.sup.1).sub.a1 is O. In certain of the foregoing embodiments, each of a3, a4, and a5 is 0.

[0260] In some embodiments, at is 1. In some embodiments, a1 is 0.

[0261] In certain embodiments (when at is 1), L.sup.1 is selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, and —S—. In certain of these embodiments, L.sup.1 is —O—.

[0262] In some embodiments, a3 is 1. In some embodiments, a3 is 0.

[0263] In certain embodiments (when a3 is 1), L.sup.3 is selected from the group consisting of —O—, —N(H)—, —N(R.sup.d)—, and —S—. In certain of these embodiments, L.sup.3 is —O—. In certain other embodiments, L.sup.3 is —N(H)— or —N(R.sup.d)— (e.g., —N(H)—).

[0264] In some embodiments, a4 is 1. In some embodiments, a4 is 0.

[0265] In certain embodiments (when a4 is 1), L.sup.4 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.4 is —CH.sub.2—.

[0266] In certain embodiments (when a4 is 1), L.sup.4 is selected from the group consisting of: [0267] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0268] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0269] In certain of these embodiments, L.sup.4 is:

##STR00018##

[0270] In certain embodiments (when L.sup.4 is:

##STR00019##

n3 and n4 are each 1. In certain embodiments (when L.sup.4 is:

##STR00020##

Q.SUP.3 .is N.

[0271] As a non-limiting example of the foregoing embodiments, L.sup.4 can be

##STR00021##

wherein the asterisk represents the point of attachment to -(L.sup.5).sub.a5-.

[0272] In some embodiments, a5 is 0.

[0273] Non-Limiting Combinations of -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*

[0274] In some embodiments, -(L.sup.1).sub.a1(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L).sub.a5-* has a length of from 1 atom to 8 atoms (as used here and for counting purposes only, moieties such as CH.sub.2, C(O), CF.sub.2 and the like, whether present in acyclic or cyclic moieties, count as 1 atom); e.g., from 1 atom to 6 atoms, or from 1 atom to 5 atoms, or from 1 atom to 4 atoms; or from 1 atom to 3 atoms; or from 2 atoms to 6 atoms; or from 2 atoms to 4 atoms.

[0275] In certain embodiments, one of at, a3, and a5 is 1, and the other two of at, a3, and a5 are 0. In certain embodiments, at is 1, e.g., when L.sup.2 is a cyclic group (e.g., cycloalkylene).

[0276] In certain embodiments, one of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0277] In certain of the foregoing embodiments,

[0278] one of at, a3, and a5 is 1, and the other two of at, a3, and a5 are 0; and

[0279] one of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0280] In certain embodiments, 1≤a1+a2+a3+a4+a5≤4. In certain of these embodiments, 1≤a1+a2+a3+a4+a5≤3.

[0281] In certain embodiments, at and a2 are each 1.

[0282] [AA1] In certain embodiments,

[0283] at and a2 are each 1;

[0284] L is —O—, —N(H)—, or —N(R.sup.d)—;

[0285] L.sup.2 is selected from the group consisting of: [0286] straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b; [0287] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0288] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0289] [AA2] In certain embodiments,

[0290] a1 and a2 are each 1;

[0291] L.sup.1 is —O—; and

[0292] L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[0293] [AA3] In certain embodiments,

[0294] a1 and a2 are each 1;

[0295] L.sup.1 is —O—; and

[0296] L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—.

[0297] [AA4] In certain embodiments,

[0298] a1 and a2 are each 1;

[0299] L.sup.1 is —O—; and

[0300] L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[0301] In certain embodiments of [AA4], L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b. As non-limiting examples of the foregoing embodiments, L.sup.2 can be selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0302] [AA5] In certain embodiments,

[0303] a1 and a2 are each 1;

[0304] L.sup.1 is —O—;

[0305] L.sup.2 is selected from the group consisting of: [0306] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0307] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0308] In certain embodiments of [AA5], L.sup.2 is:

##STR00022##

which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0, 1, or 2; Q.sup.2 is CH, CR.sup.C, or N; and the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[0309] In certain of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH. For example, n1 and n2 can both be 0; and Q.sup.2 can be CH, e.g., L.sup.2 can be optionally substituted cyclobutane-diyl, e.g, optionally substituted cyclobutane-1,3-diyl.

[0310] In certain embodiments when at and a2 are each 1, a3, a4, and a5 are each 0.

[0311] In certain embodiments of [AA1], a3, a4, and a5 are each 0. In certain embodiments of [AA2], a3, a4, and a5 are each 0. In certain embodiments of [AA3], a3, a4, and a5 are each 0. In certain embodiments of [AA4], a3, a4, and a5 are each 0. In certain embodiments of [AA5], a3, a4, and a5 are each 0.

[0312] In certain embodiments when at and a2 are each 1, a3 and a5 are 0; and a4 is 1.

[0313] In certain embodiments of [AA1], a3 and a5 are 0; and a4 is 1. In certain embodiments of [AA2], a3 and a5 are 0; and a4 is 1. In certain embodiments of [AA3], a3 and a5 are 0; and a4 is 1. In certain embodiments of [AA4], a3 and a5 are 0; and a4 is 1. In certain embodiments of [AA5], a3 and a5 are 0; and a4 is 1.

[0314] In certain embodiments (when at and a2 are each 1, a3 and a5 are 0; and a4 is 1), L.sup.4 is selected from the group consisting of: [0315] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0316] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0317] In certain of these embodiments, L.sup.4 is:

##STR00023##

which is optionally substituted with 1-2 R.sup.c, wherein n3 and n4 are independently 0, 1, or 2; Q.sup.3 is CH, CR.sup.c, or N; and the asterisk represents the point of attachment to -(L.sup.5).sub.a5-. In certain of the foregoing embodiments, n3 and n4 are independently 0 or 1; and Q.sup.3 is N.

[0318] In certain embodiments, at is 0; and a2 is 1.

[0319] [BB1] In certain embodiments, at is 0; a2 is 1; and L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b.

[0320] In certain embodiments of [BB1], L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b. In certain of the foregoing embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—. For example, L.sup.2 can be —CH.sub.2—.

[0321] In certain embodiments of [BB1], L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of the foregoing embodiments, L.sup.2 is straight-chain C.sub.2 alkylene, which is optionally substituted with 1-3 R.sup.b. As non-limiting examples, L.sup.2 can be selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0322] In certain embodiments of [BB1], L.sup.2 is straight-chain C.sub.3 alkylene, which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.2 is selected from the group consisting of:

##STR00024##

wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[0323] In certain embodiments (when a1 is 0; and a2 is 1), a3 is 0; and a4 is 0.

[0324] In certain embodiments of [BB1], a3 is 0; and a4 is 0.

[0325] In certain embodiments (when at is 0; and a2 is 1), a3 is 1. In certain embodiments of [BB1], a3 is 1.

[0326] In certain embodiments (when a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a3 is 1; and L.sup.3 is selected from the group consisting of: is —O—, —N(H)—, and —N(R.sup.d)—. In certain of these embodiments, a3 is 1; and L.sup.3 is —O—. In certain other embodiments, a3 is 1; and L.sup.3 is —N(H)— or —N(R.sup.d)—, optionally —N(H)—.

[0327] In certain embodiments (when a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a4 is 1; and L.sup.4 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, a4 is 1; and L.sup.4 is —CH.sub.2—.

[0328] In certain embodiments (when a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a4 is 0.

[0329] [CC1] In certain embodiments, a1 is 0; a2 is 1; L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b.

[0330] In certain embodiments of [CC1], L.sup.2 is selected from the group consisting of:

##STR00025##

wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[0331] In certain embodiments of [CC1], a3 is 0; and a4 is 0.

[0332] For the avoidance of doubt when any one or more of a1, a2, a3, a4, and a5 are 0, this means that the corresponding variable (L.sup.1-L.sup.5) is absent from L.sup.A. For example, when each of a3, a4, and a5 are 0, this means that L.sup.A has the formula -L.sup.1-L.sup.2-.

[0333] In certain embodiments, L.sup.A is -L.sup.1-L.sup.2-.

[0334] In certain embodiments, L.sup.A is -L.sup.2-L.sup.3-.

[0335] In certain embodiments, L.sup.A is -L.sup.2-L.sup.3-L.sup.4-.

[0336] In certain embodiments, L.sup.A can be —CH.sub.2CH.sub.2—O—*, wherein * represents the point of attachment to Q.sup.1.

[0337] In certain embodiments, L.sup.A can be —O—CH.sub.2CH.sub.2—*, wherein * represents the point of attachment to Q.sup.1.

[0338] In certain embodiments, L.sup.A can be —CH.sub.2—O—CH.sub.2—.

[0339] In certain embodiments, L.sup.A can be

##STR00026##

(such as

##STR00027##

wherein * represents the point of attachment to Q.sup.1.

[0340] Variable Q.sup.1

[0341] In some embodiments, Q.sup.1 is selected from the group consisting of: [0342] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.e; and [0343] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.c.

[0344] In certain of these embodiments, Q.sup.1 is selected from the group consisting of: [0345] heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [0346] phenyl optionally substituted with 1-3 R.sup.c.

[0347] In certain of the foregoing embodiments, Q.sup.1 is selected from the group consisting of: [0348] heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [0349] phenyl optionally substituted with 1-3 R.sup.c.

[0350] In certain embodiments, Q.sup.1 is phenyl optionally substituted with 1-3 R.sup.c. In certain of these embodiments, Q.sup.1 is selected from the group consisting of:

##STR00028##

[0351] In certain embodiments, Q.sup.1 is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.cIn certain of these embodiments, Q.sup.1 is pyridyl, which is optionally substituted with 1-3 R.sup.cIn certain of the foregoing embodiments Q.sup.1 is selected from the group consisting of.

##STR00029##

[0352] In certain embodiments, Q.sup.1 is heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0353] In certain of these embodiments, Q.sup.1 is heterocyclyl of 4-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0354] In certain of the foregoing embodiments, Q.sup.1 is heterocyclyl of 4-8 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, provided that one ring atom is N(R.sup.d),

[0355] and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0356] As non-limiting examples of the foregoing embodiments, Q.sup.1 can be

##STR00030##

wherein m1 and m2 are each independently 0, 1, or 2; and wherein Q.sup.1 is optionally substituted with 1-2 R.sup.c. For example, Q.sup.1 can be

##STR00031##

As another non-limiting example, Q.sup.1 can be

##STR00032##

[0357] In certain embodiments, each R.sup.d present in Q.sup.1 is independently selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a.

[0358] In certain of the foregoing embodiments, each R.sup.d present in Q.sup.1 is C.sub.1-6 alkyl optionally substituted with 1-3 independently selected halo.

[0359] In certain of the foregoing embodiments, each R.sup.d present in Q.sup.1 is C.sub.1-4 alkyl substituted with 1-3 —F. In certain embodiments, each R.sup.d present in Q.sup.1 is C.sub.2-3 alkyl substituted with 1-3 —F. For example, each R.sup.d present in Q.sup.1 can be —CH.sub.2CF.sub.3.

[0360] In certain embodiments, each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.

[0361] In certain embodiments, each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and C.sub.1-6 alkyl which is optionally substituted with 1-6 independently selected halo.

[0362] In certain of the foregoing embodiments, each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo and C.sub.1-3 alkyl which is optionally substituted with 1-6 independently selected halo.

[0363] In certain embodiments, each R.sup.c present in Q.sup.1 is C.sub.1-3 alkyl which is optionally substituted with 1-6 —F. For example, each R.sup.c present in Q.sup.1 can be CF.sub.3.

[0364] In certain embodiments, each R.sup.c present in Q.sup.1 is an independently selected halo (e.g., —F or —Cl).

[0365] Variables Y.sup.1, Y.sup.2, Y.sup.3, X.sup.1, and X.sup.2

[0366] In some embodiments, Y.sup.1 is CR.sup.1.

[0367] In some embodiments, Y.sup.2 is CR.sup.1.

[0368] In some embodiments, Y.sup.3 is CR.sup.1.

[0369] In certain embodiments, each occurrence of R.sup.1 is independently H or R.sup.e. In certain of these embodiments, each occurrence of R.sup.1 is H.

[0370] In certain other embodiments, 1-2 occurrence of R.sup.1 is R.sup.c; and each remaining occurrence of R.sup.1 is H. For example, one occurrence of R.sup.1 can be halo (e.g., —F or —Cl); and each remaining occurrence of R.sup.1 can be H.

[0371] In certain embodiments, Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected CR.sup.1.

[0372] In certain embodiments, Y.sup.1, Y.sup.2, and Y.sup.3 are each CH.

[0373] In certain embodiments, one of Y.sup.1, Y.sup.2, and Y.sup.3 is CR.sup.C, optionally C-halo; and each of the remaining two Y.sup.1, Y.sup.2, and Y.sup.3 is CH.

[0374] In some embodiments, X.sup.1 is NR.sup.2. In certain of these embodiments, X.sup.1 is NH.

[0375] In some embodiments, X.sup.2 is CR.sup.5. In certain of these embodiments, X.sup.2 is CH.

[0376] In certain embodiments, X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5. In certain of the foregoing embodiments, X.sup.1 is NH; and X.sup.2 is CH.

[0377] In certain embodiments, Y.sup.1, Y.sup.2, and Y.sup.3 are each an independently selected CR.sup.1; X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5. In certain of the foregoing embodiments, Y.sup.1, Y.sup.2, and Y.sup.3 are each CH; X.sup.1 is NH; and X.sup.2 is CH.

[0378] Variables R.sup.6 and W

[0379] In some embodiments, R.sup.6 is H.

[0380] In some embodiments, W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with 1-6 R.sup.a2.

[0381] In certain of these embodiments, W is C.sub.1-10 alkyl, which is optionally substituted with 1-6 R.sup.a2. In certain of the foregoing embodiments, W is C.sub.1-6 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[0382] In certain embodiments, W is C.sub.1-4 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[0383] In certain of the foregoing embodiments, W is unsubstituted C.sub.1-4 alkyl. As non-limiting examples of the foregoing embodiments, W can be selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, and isobutyl. For example, W can be methyl or ethyl.

[0384] In some embodiments, W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group is replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon;

[0385] In certain embodiments, W is C.sub.1-4 alkyl, which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group is replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon;

[0386] In certain embodiments, W is C.sub.1-4 alkyl, which is optionally substituted with one R.sup.a2, wherein one or more of the internal methylene group is replaced by O.

[0387] In certain embodiments, W is —CH.sub.2—O—(CH.sub.2).sub.2—OCH.sub.3.

[0388] In certain embodiments, W is C.sub.1-4 alkyl, which is substituted with 1-6 R.sup.a2.

[0389] In certain of these embodiments, each R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano. For example, each R.sup.a2 can be independently selected from the group consisting of halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy.

[0390] In certain embodiments, W is C.sub.1-4 alkyl which is substituted with 1-3 substituents each independently selected from the group consisting of: halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy. As non-limiting examples, W can be

##STR00033##

[0391] As another non-limiting example of the foregoing embodiments, W can be

##STR00034##

[0392] In some embodiments, W is selected from the group consisting of: [0393] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0394] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0395] In certain of the foregoing embodiments, W is monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0396] In certain of these embodiments, W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0397] In certain embodiments, W is unsubstituted C.sub.3-8 cycloalkyl. As non-limiting examples of the foregoing embodiments, W can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, W can be cyclobutyl.

[0398] In some embodiments, W is H.

[0399] Non-Limiting Combinations

[0400] In certain embodiments, the compound is a compound of Formula (I-a):

##STR00035##

[0401] or a pharmaceutically acceptable salt thereof, wherein:

[0402] L.sup.1 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—;

[0403] L.sup.2 is selected from the group consisting of: [0404] straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b; [0405] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [0406] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[0407] In certain embodiments of Formula (I-a), L.sup.1 is —O—.

[0408] In certain embodiments of Formula (I-a), L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[0409] In certain embodiments of Formula (I-a), L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—, optionally wherein L.sup.2 is —CH.sub.2—.

[0410] In certain embodiments of Formula (I-a), L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0411] In certain embodiments of Formula (I-a), L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b.

[0412] In certain embodiments of Formula (I-a), L.sup.2 is:

##STR00036##

which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0, 1, or 2; Q.sup.2 is CH, CR.sup.C, or N; and the asterisk represents the point of attachment to Q.sup.1.

[0413] In certain of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH. For example, n1 and n2 can both be 0; and Q.sup.2 can be CH, e.g., L.sup.2 can be optionally substituted optionally substituted cyclobutane-diyl, e.g, optionally substituted cyclobutane-1,3-diyl.

[0414] In certain embodiments of Formula (I-a), L.sup.1 is —O—; and L.sup.2 is:

##STR00037##

which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH. For example, n1 and n2 can both be 0; and Q.sup.2 can be CH, e.g., L.sup.2 can be optionally substituted cyclobutane-diyl, e.g, optionally substituted 1,3-cyclobutane-1,3-diyl, e.g., unsubstituted cyclobutane-diyl, e.g, unsubstituted cyclobutane-1,3-diy.

[0415] In certain embodiments of Formula (I-a), L.sup.1 is —O—; and L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[0416] In certain of the foregoing embodiments of Formula (I-a), L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[0417] In certain of the foregoing embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0418] In certain embodiments of Formula (I-a), L.sup.1 is —O—; and L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2. For example, L.sup.2 can be —CH.sub.2—.

[0419] In certain embodiments, the compound is a compound of Formula (I-b):

##STR00038##

[0420] or a pharmaceutically acceptable salt thereof, wherein:

[0421] L.sup.2 is straight-chain C.sub.1-6 alkylene or straight-chain C.sub.2-6 alkenylene, each of which is optionally substituted with 1-6 R.sup.b.

[0422] In certain embodiments of Formula (I-b), L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[0423] In certain embodiments of Formula (I-b), L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0424] In certain embodiments of Formula (I-b), L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.2 is selected from the group consisting of:

##STR00039##

wherein the asterisk represents point of attachment to -Q.sup.1. For example, L.sup.2 can be

##STR00040##

[0425] In certain embodiments of Formula (I-b), L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b.

[0426] In certain of these embodiments, L.sup.2 is selected from the group consisting of:

##STR00041##

wherein the asterisk represents the point of attachment to -Q.sup.1.

[0427] In certain embodiments, the compound is a compound of Formula (I-c):

##STR00042##

[0428] or a pharmaceutically acceptable salt thereof, wherein:

[0429] L.sup.2 and L.sup.4 are independently selected straight-chain C.sub.1-3 alkylene which is optionally substituted with 1-6 R.sup.b; and

[0430] L.sup.3 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—.

[0431] In certain embodiments of Formula (I-c), L.sup.2 and L.sup.4 are independently selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2. In certain of these embodiments, L.sup.2 and L.sup.4 are each —CH.sub.2—.

[0432] In certain embodiments of Formula (I-c), L.sup.3 is —O—.

[0433] In certain embodiments of Formula (I-c), L.sup.3 is —N(H)— or —N(R.sup.d)—. For example, L.sup.3 can be —N(H)—.

[0434] In certain embodiments, the compound is a compound of Formula (I-d):

##STR00043##

[0435] or a pharmaceutically acceptable salt thereof, wherein:

[0436] L.sup.2 is straight-chain C.sub.1-3 alkylene which is optionally substituted with 1-6 R.sup.b; and

[0437] L.sup.3 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—.

[0438] In certain embodiments of Formula (I-d), L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2.

[0439] In certain embodiments of Formula (I-d), L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b. In certain of these embodiments, L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -L.sup.3. For example, L.sup.2 can be —CH.sub.2CH.sub.2—.

[0440] In certain embodiments of Formula (I-d), L.sup.3 is —O—.

[0441] In certain embodiments of Formula (I-d), L.sup.3 is —N(H)— or —N(R.sup.d)—. For example, L.sup.3 can be —N(H)—.

[0442] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is selected from the group consisting of: [0443] heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [0444] phenyl optionally substituted with 1-3 R.sup.c.

[0445] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is selected from the group consisting of: [0446] heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [0447] phenyl optionally substituted with 1-3 R.sup.c.

[0448] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is phenyl or pyridyl, each optionally substituted with 1-3 R.sup.c.

[0449] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is

##STR00044##

[0450] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is phenyl or pyridyl, each optionally substituted with 1-3 R.sup.c,

[0451] wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo and C.sub.1-3 alkyl which is optionally substituted with 1-6 independently selected halo.

[0452] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is

##STR00045##

and each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: —F, —Cl, and —CF.sub.3.

[0453] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is heterocyclyl of 4-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0454] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is:

##STR00046##

wherein m1 and m2 are each independently 0, 1, or 2.

[0455] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is

##STR00047##

[0456] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is:

##STR00048##

and

[0457] the R.sup.d present in Q.sup.1 is selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; or

[0458] wherein the R.sup.d present in Q.sup.1 is C.sub.2-3 alkyl substituted with 1-3 —F.

[0459] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), Q.sup.1 is:

##STR00049##

and

[0460] the R.sup.d present in Q.sup.1 is selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; or

[0461] wherein the R.sup.d present in Q.sup.1 is C.sub.2-3 alkyl substituted with 1-3 —F.

[0462] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), each R.sup.1 is H.

[0463] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), one occurrence of R.sup.1 is R.sup.c; and each remaining R.sup.1 is H.

[0464] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), R.sup.2 is H; and R.sup.5 is H.

[0465] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is C.sub.1-6 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[0466] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is C.sub.1-6 alkyl, which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group is replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon;

[0467] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is unsubstituted C.sub.1-4 alkyl. For example, W can be methyl or ethyl.

[0468] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is C.sub.1-4 alkyl, which is substituted with 1-6 R.sup.a2.

[0469] In certain of these embodiments, W is: C.sub.1-4 alkyl which is substituted with 1-3 substituents each independently selected from the group consisting of: halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy.

[0470] As non-limiting examples of the foregoing embodiments, W can be

##STR00050##

[0471] As another non-limiting example of the foregoing embodiments, W can be

##STR00051##

[0472] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is selected from the group consisting of: [0473] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0474] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[0475] In certain embodiments of Formula (I-a), (I-b), (I-c) or (I-d), W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. In certain of these embodiments, W is unsubstituted C.sub.3-8 cycloalkyl. For example, W can be cyclobutyl.

[0476] Non-Limiting Exemplary Compounds

[0477] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.

TABLE-US-00001 TABLE C1 Compound LC- No. Structure MS 101 [00052] embedded image 361.0 N-(5-(((3,4-dichlorobenzyl)oxy)methyl)-1H-indol- 3-yl)acetamide 102 [00053] 387.2 N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 103 [00054] 389.3 N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 104 [00055] 446.2 N-(5-(2-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yl)ethoxy)-1H-indol-3-yl)acetamide 105 [00056] embedded image 402.2 N-(5-(2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin- 4-yl)ethoxy)-1H-indol-3-yl)acetamide 106 [00057] 361.2 N-(5-(((3-(trifluoromethyl)benzyl)oxy)methyl)- 1H-indol-3-yl)acetamide 107 [00058] 393.3 2-methoxy-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)acetamide 108 [00059] embedded image 412.4 N-(5-(2-methyl-2-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)propoxy)-1H-indol-3- yl)acetamide 109 [00060] 401.2 N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)- 1H-indol-3-yl)cyclobutanecarboxamide 110 [00061] 382.2 N-(5-(2-((1R,5S,6s)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)ethoxy)-1H-indol-3- yl)acetamide 111 [00062] embedded image 363.1 N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)- 1H-indol-3-yl)acetamide 112 [00063] 388.3 N-(5-(3-(4,4-difluoropiperidin-1-yl)-2,2- difluoropropoxy)-1H-indol-3-yl)acetamide 113 [00064] 364.1 N-(5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethoxy)- 1H-indol-3-yl)acetamide 114 [00065] 368.1 N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)ethyl)-1H-indol-3-yl)acetamide 115 [00066] embedded image 347.15 N-(5-((4-(trifluoromethyl)phenoxy)methyl)-1H- indol-3-yl)acetamide 116 [00067] 336.05 N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H- indol-3-yl)acetamide 117 [00068] 414.1 2-methoxy-N-(5-(2-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3- yl)acetamide 118 [00069] 442.3 3-hydroxy-3-methyl-N-(5-(2-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3- yl)butanamide 119 [00070] embedded image 370.3 N-(5-((1-(2,2,2-trifluoroethy|)piperidin-4- yl)methoxy)-1H-indol-3-yl)acetamide 120 [00071] 368.3 N-(5-(((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)methoxy)-1H-indol- 3-yl)acetamide 121 [00072] 442.2 4-methoxy-N-(5-(2-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3- yl)butanamide 122 [00073] embedded image 384.1 N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)ethoxy)-1H-indol-3-yl)acetamide 123 [00074] 336.0 N-(5-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1H- indol-3-yl)acetamide 124 [00075] 335.2 N-(5-(4-(trifluoromethyl)phenoxy)-1H-indol-3- yl)acetamide 125 [00076] 349.0 N-(5-(((6-(trifluoromethyl)pyridin-3- yl)amino)methyl)-1H-indol-3-yl)acetamide 126 [00077] embedded image 363.1 N-(5-(2-((6-(trifluoromethyl)pyridin-3- yl)amino)ethyl)-1H-indol-3-yl)acetamide 127 [00078] 363.1 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 128 [00079] 333.1 N-(5-(4-(trifluoromethyl)benzyl)-1H-indol-3- yl)acetamide 129 [00080] 424.1 N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)ethoxy)-1H-indol-3-yl)cyclobutanecarboxamide 130 [00081] embedded image 361.1 N-(5-((4-(trifluoromethyl)phenoxy)methyl)-1H- indol-3-yl)propionamide 131 [00082] 415.2 N-(5-(4-(4-(trifluoromethyl)phenyl)butan-2-yl)- 1H-indol-3-yl)cyclobutanecarboxamide 132 [00083] 359.1 N-(5-(3-(4-(trifluoromethyl)phenyl)propyl)-1H- indol-3-yl)acetamide 133 [00084] 431.2 N-(5-(3-methoxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclobutanecarboxamide 134 [00085] embedded image 403.2 N-(5-(2-((5-(trifluoromethyl)pyridin-2- yl)amino)ethyl)-1H-indol-3- yl)cyclobutanecarboxamide 135 [00086] 399.2 (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en- 1-yl)-1H-indol-3-yl)cyclobutanecarboxamide 136 [00087] 363.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)acetamide 137 [00088] embedded image 415.1 N-(5-(2-methyl-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclobutanecarboxamide 138 [00089] 363.1 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)propionamide 139 [00090] 401.2 N-(5-(3-(4-(trifluoromethyl)phenyl)propyl)-1H- indol-3-yl)cyclobutanecarboxamide 140 [00091] embedded image 440.2 tert-butyl 4-(2-((3-(cyclobutanecarboxamido)-1H- indol-5-yl)oxy)ethyl)piperidine-1-carboxylate 141 [00092] 385.2 N-(5-(4-(trifluoromethyl)phenethyl)-1H-indol-3- yl)cyclobutanecarboxamide 142 [00093] 404.1 N-(5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethoxy)- 1H-indol-3-yl)cyclobutanecarboxamide 143 [00094] embedded image 285.2 (E)-N-(5-(2-ethoxyvinyl)-1H-indol-3- yl)cyclobutanecarboxamide 144 [00095] 385.2 (E)-N-(5-(4-(trifluoromethyl)styryl)-1H-indol-3- yl)cyclobutanecarboxamide 145 [00096] 403.1 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)cyclobutanecarboxamide 146 [00097] 377.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)propionamide 147 [00098] embedded image 415.1 trans-N-(5-(-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropanecarboxamide 148 [00099] 445.3 3-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)oxetane-3-carboxamide 149 [00100] 466.1 1-(2,2-difluoroethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)azetidine-3-carboxamide 150 [00101] embedded image 464.4 (1s,3S)-3-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 151 [00102] 482.1 3-fluoro-3-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 152 [00103] embedded image 480.1 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)tetrahydro-2H-pyran-4- carboxamide 153 [00104] 419.3 3-(hydroxymethyl)-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 154 [00105] 419.3 3-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)tetrahydrofuran-3-carboxamide 155 [00106] embedded image 403.3 2,2-dimethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 156 [00107] 419.3 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 157 [00108] 445.4 3,3-dimethyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)butanamide 158 [00109] embedded image 459.3 3-(hydroxymethyl)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 159 [00110] 459.3 3-methoxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 160 [00111] 480.3 2-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)tetrahydrofuran-2- carboxamide 161 [00112] embedded image 494.4 4-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)tetrahydro-2H-pyran-4- carboxamide 162 [00113] 417.3 cis-3-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 163 [00114] 405.2 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)oxetane-3-carboxamide 164 [00115] embedded image 403.05 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)oxetane-3-carboxamide 165 [00116] 417.1 3-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)oxetane-3-carboxamide 166 [00117] 405.1 3-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)oxetane-3-carboxamide 167 [00118] embedded image 390.1 N-(5-(2-((6-(trifluoromethyl)pyridin-3- yl)oxy)ethyl)-1H-indol-3- yl)cyclopropanecarboxamide 168 [00119] 323.15 N-(5-(2-(p-tolyloxy)ethyl)-1H-indol-3- yl)propionamide 169 [00120] 419.05 N-(5-(4-(pentafluoro-16-sulfaneyl)phenethoxy)- 1H-indol-3-yl)acetamide 170 [00121] 460.25 N-(5-(2-(4-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)phenoxy)ethyl)-1H-indol-3-yl)acetamide 171 [00122] embedded image 396.3 N-(5-(2-(2-(2,2,2-trifluoroethyl)-2- azaspiro[3.3]heptan-6-yl)ethoxy)-1H-indol-3- yl)acetamide 172 [00123] 417.1 N-(5-(1-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)-1- methylcyclopropane-1-carboxamide 173 [00124] 440.95 N-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)acetamide 174 [00125] embedded image 417.05 N-(5-(2-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)-1- methylcyclopropane-1-carboxamide 175 [00126] 441.1 2-chloro-2-fluoro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 176 [00127] 433.2 1-(methoxymethyl)-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 177 [00128] embedded image 437.2 3-chloro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 178 [00129] 433.3 3-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)tetrahydrofuran-3-carboxamide 179 [00130] 419.2 cis-3-hydroxy-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 180 [00131] embedded image 419.2 3-hydroxy-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 181 [00132] 425.2 2,2-difluoro-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 182 [00133] 436.15 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3- yl)cyclopropanecarboxamide 183 [00134] embedded image 459.2 N-(5-(2-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)ethoxy)-1H-indol-3- yl)cyclopropanecarboxamide 184 [00135] 364.32 N-(5-(2-((2-(trifluoromethyl)pyrimidin-5- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 185 [00136] 457.1 1-(trifluoromethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 186 [00137] embedded image 405.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)pivalamide 187 [00138] 428.1 2-cyano-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 188 [00139] 414.2 (1S,2R)-2-cyano-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 189 [00140] embedded image 433.2 3-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)tetrahydrofuran-3-carboxamide 190 [00141] 419.1 cis-3-hydroxy-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 191 [00142] 433.2 2-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)tetrahydrofuran-2-carboxamide 192 [00143] embedded image 417.1 2,2-dimethyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 193 [00144] 414.2 1-cyano-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 194 [00145] 434.0 trans-3-methoxy-N-(5-(2-(6- (trifluoromethyl)pyridin-3-yl)ethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 195 [00146] embedded image 487.15 1-(2,2,2-trifluoroethyl)-N-(5-(2-(6- (trifluoromethyl)pyridin-3-yl)ethoxy)-1H-indol-3- yl)azetidine-3-carboxamide 196 [00147] 351.1 N-(5-(2-(3-(trifluoromethyl)-1H-pyrazol-1- yl)ethoxy)-1H-indol-3-yl)acetamide 197 [00148] 353.05 N-(5-(2-(4-(trifluoromethyl)-1H-pyrazol-1- yl)ethoxy)-1H-indol-3-yl)acetamide 198 [00149] embedded image 474.2 N-(5-(2-(4-(4-methyl-1-(2,2,2- trifluoroethyl)piperidin-4-yl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 199 [00150] 363.05 N-(5-(2-((5-(trifluoromethyl)pyridin-2- yl)amino)ethyl)-1H-indol-3-yl)acetamide 200 [00151] 401.1 (R)-N-(5-(2-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclopropanecarboxamide 201 [00152] embedded image 401.15 (S)-N-(5-(2-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclopropanecarboxamide 202 [00153] 419.2 3,3-dimethyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)butanamide 203 [00154] 414.2 (1S,2S)-2-cyano-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 204 [00155] embedded image 433.2 1-(methoxymethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 205 [00156] 417.3 trans-3-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 206 [00157] 403.2 (1S,2S)-2-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 207 [00158] embedded image 421.2 3-fluoro-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 208 [00159] 474.25 N-(5-(2-(2-(4-methyl-1-(2,2,2- trifluoroethyl)piperidin-4-yl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 209 [00160] 401.1 N-(5-(1-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclopropanecarboxamide 210 [00161] embedded image 484.0 1-(2,2,2-trifluoroethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)azetidine-3-carboxamide 211 [00162] 431.1 trans-3-methoxy-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 212 [00163] 350.95 N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1- yl)propyl)-1H-indol-3-yl)acetamide 213 [00164] embedded image 379.0 N-(4-fluoro-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 214 [00165] 363.05 N-(5-(2-(3,4-dichlorophenoxy)ethyl)-1H-indol-3- yl)acetamide 215 [00166] 364.1 N-(5-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 216 [00167] 441.1 2-chloro-2-fluoro-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 217 [00168] embedded image 437.1 3-chloro-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 218 [00169] 407.2 1-fluoro-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 219 [00170] 486.1 1-(2,2,2-trifluoroethyl)-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)azetidine-3-carboxamide 220 [00171] embedded image 431.1 trans-3-methoxy-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 221 [00172] 431.15 cis-3-methoxy-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 222 [00173] 431.1 cis-3-methoxy-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 223 [00174] embedded image 379.1 N-(6-fluoro-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 224 [00175] 411.15 N-(5-(2-(4-(4,4- difluorocyclohexyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 225 [00176] N-(5-(2-(4-(3,3- difluorocyclobutyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 226 [00177] 377.0 N-(5-(2-(4-(tetrahydro-2H-pyran-4- yl)phenoxy)ethyl)-1H-indol-3-yl)acetamide 227 [00178] embedded image 524.15 N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)-1-(3,3,3-trifluoropropyl)azetidine-3- carboxamide 228 [00179] 307.1 N-(5-(2-(p-tolyloxy)ethyl)-1H-indol-3- yl)acetamide 229 [00180] 327.05 N-(5-(2-(4-chlorophenoxy)ethyl)-1H-indol-3- yl)acetamide 230 [00181] embedded image 347.15 N-(5-(2-(4-cyclobutylphenoxy)ethyl)-1H-indol-3- yl)acetamide 231 [00182] 361.1 N-(5-(2-(3-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 232 [00183] 364.1 N-(5-(2-((6-(trifluoromethyl)pyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 233 [00184] 390.1 N-(5-((1-(4-(trifluoromethyl)phenyl)azetidin-3- yl)oxy)-1H-indol-3-yl)acetamide 234 [00185] embedded image 433.2 3-methoxy-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 235 [00186] 417.2 1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3 -yl)cyclobutane-1-carboxamide 236 [00187] 431.2 3,3-dimethyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 237 [00188] embedded image 447.2 4-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)tetrahydro-2H-pyran-4-carboxamide 238 [00189] 419.2 3-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)oxetane-3-carboxamide 239 [00190] 433.2 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 240 [00191] embedded image 401.1 N-(5-(2-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)cyclopropanecarboxamide 241 [00192] 433.05 3-methoxy-N-(5-((1r,3r)-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)propanamide 242 [00193] 459.3 trans-3-methoxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 243 [00194] embedded image 510.15 1-(2,2,2-trifluoroethyl)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 244 [00195] 510.15 1-(2,2,2-trifluoroethyl)-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 245 [00196] 459.2 cis-3-methoxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 246 [00197] embedded image 459.2 cis-3-methoxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 247 [00198] 349.0 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)acetamide 248 [00199] 364.05 N-(5-(4-(trifluoromethyl)phenethoxy)-1H- pyrrolo[3,2-b]pyridin-3-yl)acetamide 249 [00200] embedded image 437.15 3,3-difluoro-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 250 [00201] 376.1 N-(7-methyl-5-(4-(trifluoromethyl)phenethoxy)- 1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide 251 [00202] 403.3 1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 252 [00203] embedded image 387.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclopropanecarboxamide 253 [00204] 480.3 N-(5-(2-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)ethoxy)- 1H-indol-3-yl)acetamide 254 [00205] 433.2 N-(5-(2-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)ethoxy)-1H-indol-3- yl)acetamide 255 [00206] embedded image 364.2 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- pyrrolo[3,2-b]pyridin-3-yl)acetamide 256 [00207] 377.1 N-(5-(2-((4-(trifluoromethyl)phenyl)thio)ethyl)- 1H-indol-3-yl)acetamide 257 [00208] 447.4 N-(5-(2-(1-(5-(trifluoromethyl)pyridin-2- yl)piperidin-4-yl)ethoxy)-1H-indol-3-yl)acetamide 258 [00209] embedded image 419.1 2-methoxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 259 [00210] 378.3 N-(7-methyl-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-pyrrolo[3,2- b]pyridin-3-yl)acetamide 260 [00211] 419.2 2-methoxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 261 [00212] embedded image 429.0 1-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 262 [00213] 359.2 N-(5-(2-(3-phenylbicyclo[1.1.1]pentan-1- yl)ethoxy)-1H-indol-3-yl)acetamide 263 [00214] 429.15 1-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 264 [00215] embedded image 375.15 N-(7-methyl-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 265 [00216] 412.1 N-(5-(((4- (trifluoromethyl)phenyl)sulfonamido)methyl)-1H- indol-3-yl)acetamide 266 [00217] 415.1 N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropanecarboxamide 267 [00218] embedded image 364.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H- pyrrolo[2,3-b]pyridin-3-yl)acetamide 268 [00219] 382.2 N-(5-(((1-(2,2,2-trifluoroethyl)piperidin-4- yl)methoxy)methyl)-1H-indol-3-yl)acetamide 270 [00220] 379.1 N-(7-fluoro-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 271 [00221] embedded image 364.05 N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide 272 [00222] 375.15 N-(7-methyl-5-(((4- (trifluoromethyl)benzyl)oxy)methyl)-1H-indol-3- yl)acetamide 273 [00223] 378.15 2-methoxy-N-(5-((4- (trifluoromethyl)phenoxy)methyl)-1H-indol-3- yl)acetamide 274 [00224] embedded image 381.05 N-(5-((((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)methoxy)methyl)-1H- indol-3-yl)acetamide 275 [00225] 410.4 N-(5-(3-methyl-3-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)butyl)-1H-indol-3- yl)acetamide 276 [00226] 379.15 N-(7-fluoro-5-(((4- (trifluoromethyl)benzyl)oxy)methyl)-1H-indol-3- yl)acetamide 277 [00227] embedded image 402.3 N-(7-fluoro-5-(2-(1-(2,2,2-trifluoroethyl)piperidin- 4-yl)ethoxy)-1H-indol-3-yl)acetamide 278 [00228] 353.15 N-(5-(2-(4,4-difluoro-1- hydroxycyclohexyl)ethoxy)-1H-indol-3- yl)acetamide 279 [00229] 384.25 (R)-N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3- yl)ethoxy)-1H-indol-3-yl)acetamide 280 [00230] embedded image 384.2 (S)-N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3- yl)ethoxy)-1H-indol-3-yl)acetamide 281 [00231] 398.3 N-(7-methyl-5-(2-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3- yl)acetamide 282 [00232] 375.1 N-(5-(1-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)acetamide 283 [00233] embedded image 410.2 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)acetamide 284 [00234] 375.1 N-(5-(2-hydroxy-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)acetamide 285 [00235] 377.15 (S)-N-(5-((1-(4-(trifluoromethyl)phenyl)propan-2- yl)oxy)-1H-indol-3-yl)acetamide 286 [00236] embedded image 377.15 (R)-N-(5-((1-(4-(trifluoromethyl)phenyl)propan-2- yl)oxy)-1H-indol-3-yl)acetamide 287 [00237] 375.0 N-(5-(2-(4-(trifluoromethyl)phenoxy)propyl)-1H- indol-3-yl)acetamide 288 [00238] 384.35 N-(5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 289 [00239] embedded image 389.15 N-(5-((1-(4- (trifluoromethyl)phenyl)cyclopropyl)methoxy)- 1H-indol-3-yl)acetamide 290 [00240] 308.0 N-(5-(2-hydroxy-5-methylbenzyl)-1H-indol-3- yl)propionamide 291 [00241] 308.0 N-(5-((p-tolyloxy)methyl)-1H-indol-3- yl)propionamide 292 [00242] 342.15 N-(5-(2-((3aR,5r,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl)ethoxy)- 1H-indol-3-yl)acetamide 293 [00243] embedded image 410.2 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 294 [00244] 403.3 1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 295 [00245] 459.4 trans-3-methoxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 296 [00246] embedded image 480.4 trans-3-methoxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 297 [00247] 433.2 3-methoxy-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 298 [00248] 462.3 1-(2-methoxyethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)azetidine-3-carboxamide 299 [00249] embedded image 500.1 N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3- yl)-1-(3,3,3-trifluoropropyl)azetidine-3- carboxamide 300 [00250] 419.3 trans-3-methoxy-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 301 [00251] 389.3 1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 302 [00252] embedded image 433.3 1-fluoro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 303 [00253] 465.4 1-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)azetidine-3-carboxamide 304 [00254] 475.4 2-cyano-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 305 [00255] embedded image 480.4 1-(methoxymethyl)-N-(5-(2-((3aR,5r,6aS)-2- (2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 306 [00256] 480.4 3-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)tetrahydrofuran-3- carboxamide 307 [00257] embedded image 472.3 2,2-difluoro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 308 [00258] 433.3 3-(hydroxymethyl)-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 309 [00259] 417.3 1-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 310 [00260] embedded image 419.0 3-hydroxy-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 311 [00261] 418.0 1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)azetidine-3-carboxamide 312 [00262] 433.3 3-(hydroxymethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 313 [00263] embedded image 392.25 N-(5-(2-((3aR,5r,6aS)-2-(2,2- difluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)acetamide 314 [00264] 300.15 3,3-dimethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)butanamide 315 [00265] 423.3 1-(trifluoromethyl)-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 316 [00266] embedded image 405.0 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)pivalamide 317 [00267] 443.0 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropanecarboxamide 318 [00268] 391.0 2-chloro-2-fluoro-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 319 [00269] embedded image 375.0 1-(methoxymethyl)-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 320 [00270] 427.2 trans-3-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 321 [00271] 419.0 cis-3-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 322 [00272] embedded image 403.3 3-chloro-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 323 [00273] 403.3 3-fluoro-3-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 324 [00274] 423.2 cis-3-hydroxy-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 325 [00275] embedded image 421.3 2-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)tetrahydrofuran-2-carboxamide 326 [00276] 405.3 3-fluoro-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 327 [00277] 419.0 3,3-dimethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 328 [00278] embedded image 407.0 4-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)tetrahydro-2H-pyran-4-carboxamide 329 [00279] 417.3 3-hydroxy-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 330 [00280] 433.0 2,2-difluoro-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 331 [00281] embedded image 405.3 1-fluoro-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 332 [00282] 411.2 cis-2-cyano-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 333 [00283] 393.0 1-(methoxymethyl)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 334 [00284] embedded image 440.3 trans-3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 335 [00285] 459.1 cis-3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 336 [00286] 443.3 3-chloro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 337 [00287] embedded image 443.3 cis-3-hydroxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 338 [00288] 463.1 3-hydroxy-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 339 [00289] 445.3 3,3-dimethyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 340 [00290] embedded image 445.2 (1S,2S)-2-cyano-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 341 [00291] 466.4 (1r,3R)-3-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 342 [00292] embedded image 461.4 3-chloro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 343 [00293] 464.4 3-(hydroxymethyl)-N-(5-(2-((3aR,5r,6aS)-2- (2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 344 [00294] embedded image 484.0 cis-3-hydroxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 345 [00295] 480.3 3-methoxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 346 [00296] embedded image 466.4 3,3-dimethyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 347 [00297] 480.1 3-hydroxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 348 [00298] embedded image 478.1 3,3-dimethyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 349 [00299] 466.1 N-(5-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 3-yl)ethoxy)-1H-indol-3-yl)acetamide 350 [00300] 431.3 N-(4-bromo-5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)acetamide 351 [00301] embedded image 339.1 2-cyano-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 352 [00302] 441.0 3-methoxy-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclobutane-1-carboxamide 353 [00303] 414.3 1-(trifluoromethyl)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 354 [00304] embedded image 419.3 N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)pivalamide 355 [00305] 483.3 2-cyano-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 356 [00306] 431.4 3-fluoro-3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 357 [00307] embedded image 454.3 3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydrofuran-3-carboxamide 358 [00308] 461.3 2-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydrofuran-2-carboxamide 359 [00309] 459.3 2,2-dimethyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 360 [00310] embedded image 459.3 1-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 361 [00311] 443.4 3,3-dimethyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 362 [00312] 443.3 1-cyano-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 363 [00313] embedded image 457.3 4-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 364 [00314] 440.3 2,2-difluoro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 365 [00315] 473.3 N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 366 [00316] embedded image 451.3 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)-1- (trifluoromethyl)cyclopropane-1-carboxamide 367 [00317] 459.3 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)pivalamide 368 [00318] embedded image 484.4 2,2-dimethyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 369 [00319] 504.4 1-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 370 [00320] embedded image 452.4 1-cyano-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 371 [00321] 464.4 1-fluoro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 372 [00322] embedded image 464.4 3-methyl-N-(5-(2-(6-(trifluoromethyl)pyridin-3- yl)ethoxy)-1H-indol-3-yl)oxetane-3-carboxamide 373 [00323] 461.4 N-(5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethoxy)- 1H-indol-3-yl)oxetane-3-carboxamide 374 [00324] 454.4 N-(5-(2-(methyl(5-(trifluoromethyl)pyridin-2- yl)amino)ethyl)-1H-indol-3-yl)acetamide 375 [00325] embedded image 420.05 N-(4,6-difluoro-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 376 [00326] 406.15 1-methyl-N-(5-(3-(6-(trifluoromethyl)pyridin-3- yl)cyclobutoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 377 [00327] 377.15 N-(5-(2-((1-(2,2,2-trifluoroethyl)azetidin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 378 [00328] embedded image 396.9 3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)oxetane-3-carboxamide 379 [00329] 430.05 1-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 380 [00330] 356.05 3-fluoro-3-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 381 [00331] embedded image 463.3 N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)oxetane-3-carboxamide 382 [00332] 445.2 3-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)oxetane-3-carboxamide 383 [00333] 450.4 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)oxetane-3-carboxamide 384 [00334] embedded image 435.2 N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1- yl)propyl)-1H-indol-3- yl)cyclopropanecarboxamide 385 [00335] 391.05 N-(5-(2-(1-(difluoromethyl)-1H-pyrazol-4- yl)ethoxy)-1H-indol-3-yl)acetamide 386 [00336] 466.2 N-(5-(2-((4-benzyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]thiazin-6-yl)oxy)ethyl)-1H-indol-3- yl)acetamide 387 [00337] embedded image 452.15 1-(trifluoromethyl)-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 388 [00338] 377.15 3,3-difluoro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 389 [00339] 333.05 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)pivalamide 390 [00340] embedded image 470.1 2-cyano-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 391 [00341] 437.3 (1S,2S)-2-cyano-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 392 [00342] 457.2 trans-3-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 393 [00343] embedded image 439.2 cis-3-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 394 [00344] 405.3 (1S,2S)-2-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 395 [00345] 428.2 3-fluoro-3-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 396 [00346] embedded image 414.2 2-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)tetrahydrofuran-2-carboxamide 397 [00347] 417.2 2,2-dimethyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 398 [00348] 417.3 1-cyano-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 399 [00349] embedded image 403.2 1-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 400 [00350] 435.3 1-fluoro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 401 [00351] 431.2 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)tetrahydro-2H-pyran-4-carboxamide 402 [00352] embedded image 417.3 N-(2-bromo-5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)acetamide 404 [00353] 403.2 2-(2-methoxyethoxy)-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)acetamide 405 [00354] 407.2 2-(2-methoxyethoxy)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 406 [00355] embedded image 433.3 2-(2-methoxyethoxy)-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 407 [00356] 2-(2-methoxyethoxy)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)acetamide 408 [00357] 440.8 2-(2-methoxyethoxy)-N-(5-(2-((3aR,5r,6aS)-2- (2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)acetamide 409 [00358] embedded image 419.15 2,2-dimethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)oxetane-3-carboxamide 410 [00359] 399.2 N-(5-(2-(3,5-difluoro-4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 411 [00360] 397.1 N-(5-(2-(2-chloro-4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 412 [00361] embedded image 500.2 cis-3-acetamido-1-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 413 [00362] 500.2 trans-3-acetamido-1-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 414 [00363] 419.15 cis-3-hydroxy-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 415 [00364] embedded image 419.15 trans-3-hydroxy-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 416 [00365] 433.15 trans-3-(hydroxymethyl)-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 417 [00366] 433.25 cis-3-(hydroxymethyl)-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 418 [00367] embedded image 447.2 trans-4-hydroxy-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclohexane-1-carboxamide 419 [00368] 447.25 trans-4-hydroxy-1-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclohexane-1-carboxamide 420 [00369] 459.15 1-(hydroxymethyl)-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 421 [00370] embedded image 468.1 1-(2,2-difluoroethyl)-3-methyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)azetidine-3-carboxamide 422 [00371] 502.2 1-(2-methoxyethyl)-3-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 423 [00372] 445.1 (2S,3R)-2-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)oxetane-3-carboxamide 424 [00373] embedded image 445.25 (2R,3R)-2-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)oxetane-3-carboxamide 425 [00374] 487.2 4-hydroxy-1-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclohexane-1-carboxamide 426 [00375] 487.3 cis-4-hydroxy-1-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclohexane-1-carboxamide 427 [00376] embedded image 494.2 (1r,3R)-3-methoxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 428 [00377] 419.15 2,4-dimethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)oxetane-3-carboxamide 429 [00378] 433.25 (R)-2-hydroxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)butanamide 430 [00379] embedded image 407.15 (S)-2-hydroxy-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)butanamide 431 [00380] 407.2 (R)-2-hydroxy-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)butanamide 432 [00381] 417.2 N-(5-((1R,3R)-2,2-dimethyl-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 433 [00382] embedded image 508.2 4,4,4-trifluoro-3-hydroxy-N-(5-(2-((3aR,5r,6aS)- 2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 434 [00383] 508.2 2-(2,2,2-trifluoroethoxy)-N-(5-(2-((3aR,5r,6aS)-2- (2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)acetamide 435 [00384] embedded image 403.15 N-(5-(trans-3-(2-methyl-4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 436 [00385] 389.05 N-(5-((6-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)oxy)-1H-indol-3- yl)acetamide 437 [00386] 401.1 N-(5-((7-(trifluoromethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)methoxy)-1H-indol-3- yl)acetamide 438 [00387] embedded image 397.3 N-(5-(2-(3-fluoro-4- (trifluoromethoxy)phenoxy)ethyl)-1H-indol-3- yl)acetamide 439 [00388] 346.2 N-(5-(2-((5-(difluoromethyl)pyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 440 [00389] 388.2 N-(5-(2-(2-cyano-4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 441 [00390] embedded image 421.2 N-(5-(2-(3-(2,2,2-trifluoroethyl)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 442 [00391] 421.1 N-(5-(2-(4-(2,2,2-trifluoroethyl)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 443 [00392] 401.1 N-(5-((1R,2R,3R)-2-methyl-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 444 [00393] embedded image 393.35 N-(5-((1-(2,2,2-trifluoroethyl)-1,4,5,6- tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)- 1H-indol-3-yl)acetamide 445 [00394] 433.15 (cis)-3-hydroxy-1-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 446 [00395] 433.1 trans-3-hydroxy-1-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 447 [00396] embedded image 393.1 N-(5-((2-(2,2,2-trifluoroethyl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)- 1H-indol-3-yl)acetamide 448 [00397] 401.1 N-(5-((1R,2S,3R)-2-methyl-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 449 [00398] 346.2 N-(5-(2-(isoquinolin-7-yloxy)ethyl)-1H-indol-3- yl)acetamide 450 [00399] embedded image 397.2 N-(5-(2-(4-chloro-2- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 451 [00400] 372.2 N-(5-(2-(4-(pyridin-4-yl)phenoxy)ethyl)-1H-indol- 3-yl)acetamide 452 [00401] 393.2 N-(5-(2-(4-(2,2,2-trifluoroethoxy)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 453 [00402] 334.3 N-(5-(2-(3-(cyanomethyl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 454 [00403] embedded image 369.35 N-(5-(2-(cis-4- (trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3- yl)acetamide 455 [00404] 390.1 N-(5-(cis-3-(6-(trifluoromethyl)pyridin-3- yl)cyclobutoxy)-1H-indol-3-yl)acetamide 456 [00405] 369.35 N-(5-(2-(trans-4- (trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3- yl)acetamide 457 [00406] embedded image 394.15 N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethyl)-1H-indol-3-yl)acetamide 458 [00407] 285.15 N-(5-(2-(bicyclo[1.1.1]pentan-1-yl)ethoxy)-1H- indol-3-yl)acetamide 459 [00408] 430.3 N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 460 [00409] embedded image 472.3 4-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)piperidine-4-carboxamide 461 [00410] 353.3 N-(5-(2-(4-(2-methoxyethyl)phenoxy)ethyl)-1H- indol-3-yl)acetamide 462 [00411] 320.2 N-(5-(2-(4-cyanophenoxy)ethyl)-1H-indol-3- yl)acetamide 463 [00412] 336.3 N-(5-(2-((2-cyclopropylpyridin-4-yl)oxy)ethyl)- 1H-indol-3-yl)acetamide 464 [00413] embedded image 402.1 1-methyl-N-(5-(3-(5-(trifluoromethyl)pyridin-2- yl)propyl)-1H-indol-3-yl)cyclopropane-1- carboxamide 465 [00414] 518.1 4-(trifluoromethyl)-N-(5-(trans-3-(6- (trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H- indol-3-yl)benzamide 466 [00415] 529.3 tert-butyl 3-((5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)carbamoyl)azetidine-1-carboxylate 467 [00416] embedded image 454.3 2-cyano-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 468 [00417] 459.3 1-(methoxymethyl)-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 469 [00418] 461.3 3-fluoro-3-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 470 [00419] embedded image 381.2 N-(5-(2-(4-fluoro-3- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 471 [00420] 380.2 N-(5-(2-((6-(trifluoromethoxy)pyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 472 [00421] 355.25 N-(5-((4-(trifluoromethyl)cyclohexyl)methoxy)- 1H-indol-3-yl)acetamide 473 [00422] 375.25 N-(5-((5-(trifluoromethyl)-2,3-dihydro-1H-inden- 2-yl)oxy)-1H-indol-3-yl)acetamide 474 [00423] embedded image 353.15 N-(5-(2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan- 1-yl)ethoxy)-1H-indol-3-yl)acetamide 475 [00424] 392.2 N-(5-(2-(4-(2-methylthiazol-4-yl)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 476 [00425] 354.2 N-(5-(2-(3-chloro-5-cyanophenoxy)ethyl)-1H- indol-3-yl)acetamide 477 [00426] 430.3 N-(5-(2-((8-(trifluoromethoxy)quinolin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 478 [00427] embedded image 396.1 N-(5-(2-(5-(2,2,2-trifluoroethyl)-5- azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3- yl)acetamide 479 [00428] 452.15 3-methyl-N-(5-(((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)methoxy)-1H-indol-3-yl)oxetane-3- carboxamide 480 [00429] 430.3 N-(5-(2-((6-(trifluoromethoxy)quinolin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 481 [00430] embedded image 364.2 N-(5-(2-((5-(trifluoromethyl)pyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 482 [00431] 401.1 N-(5-((trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H- indol-3-yl)acetamide 483 [00432] 508.2 1-(2,2-difluoroethyl)-3-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 484 [00433] embedded image 382.05 N-(5-(2-(4-methyl-2-(trifluoromethyl)thiazol-5- yl)ethoxy)-1H-indol-3-yl)acetamide 485 [00434] 452.1 3-methyl-N-(5-(((1R,3s,5S)-8-(2,2,2- trifluoroethyl)-8-azabicyclo[3.2.1]octan-3- yl)methoxy)-1H-indol-3-yl)oxetane-3- carboxamide 486 [00435] 463.3 2-(2-methoxyethoxy)-N-(5-((trans)-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)acetamide 487 [00436] embedded image 459.3 2-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydrofuran-2-carboxamide 488 [00437] 473.4 4-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 489 [00438] 433.2 1-fluoro-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 490 [00439] embedded image 349.3 N-(5-(2-((5,6,7,8-tetrahydronaphthalen-2- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 491 [00440] 362.2 N-(5-(2-((2-(difluoromethoxy)pyridin-4- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 492 [00441] 382.05 N-(5-(((2-(2,2,2-trifluoroethyl)-2- azabicyclo[2.1.1]hexan-1-yl)methoxy)methyl)-1H- indol-3-yl)acetamide 493 [00442] embedded image 459.3 N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 494 [00443] 404.05 N-(5-((1-(4-(trifluoromethyl)phenyl)pyrrolidin-3- yl)oxy)-1H-indol-3-yl)acetamide 495 [00444] 341.05 N-(5-((4-(trifluoromethyl)phenyl)ethynyl)-1H- indol-3-yl)acetamide 496 [00445] embedded image 445.1 2,2,4,4-tetramethyl-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)oxetane-3-carboxamide 497 [00446] 361.05 N-(5-(1-(4-(trifluoromethyl)phenyl)ethoxy)-1H- indol-3-yl)acetamide 498 [00447] 410.15 N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3- yl)ethoxy)-1H-indol-3- yl)cyclopropanecarboxamide 499 [00448] embedded image 412.2 N-(5-(2-((2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3- yl)propan-2-yl)oxy)ethyl)-1H-indol-3- yl)acetamide 500 [00449] 401.1 N-(5-((cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H- indol-3-yl)acetamide 501 [00450] 385.05 N-(5-(2-(trans-4-hydroxy-4- (trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3- yl)acetamide 504 [00451] embedded image 508.2 (1r,4R)-4-hydroxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclohexane-1- carboxamide 505 [00452] 508.2 (1s,4S)-4-hydroxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclohexane-1- carboxamide 506 [00453] embedded image 390.15 N-(5-(2-(methylamino)-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)acetamide 507 [00454] 403.05 N-(5-((3-(4- (trifluoromethyl)phenyl)tetrahydrofuran-3- yl)methyl)-1H-indol-3-yl)acetamide 508 [00455] 403.05 N-(5-(2-(3-(4-(trifluoromethyl)phenyl)oxetan-3- yl)ethyl)-1H-indol-3-yl)acetamide 509 [00456] embedded image 466.2 (2S,3R)-2-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)oxetane-3-carboxamide 510 [00457] 466.2 (2R,3R)-2-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)oxetane-3-carboxamide 511 [00458] embedded image 494.2 (1s,3S)-3-(hydroxymethyl)-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 512 [00459] 494.2 (1r,3R)-3-(hydroxymethyl)-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 513 [00460] embedded image 480.2 (1s,3S)-3-hydroxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 514 [00461] 480.2 (1r,3R)-3-hydroxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-l- carboxamide 515 [00462] embedded image 494.2 (1s,3S)-3-methoxy-1-methyl-N-(5-(2- ((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 516 [00463] 418.15 N-(1-(3-acetamido-1H-indol-5-yl)-3-(4- (trifluoromethyl)phenyl)propan-2-yl)acetamide 517 [00464] 376.1 N-(5-(2-amino-3-(4- (trifluoromethyl)phenyl)propyl)-1H-indol-3- yl)acetamide 518 [00465] embedded image 431.1 N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)oxetane-3-carboxamide 519 [00466] 421.15 3-hydroxy-3-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)butanamide 520 [00467] 468.25 4-methoxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 521 [00468] embedded image 454.2 (S)-2-hydroxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 522 [00469] 454.2 (R)-2-hydroxy-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 523 [00470] embedded image 468.15 3-hydroxy-3-methyl-N-(5-(2-((3aR,5r,6aS)-2- (2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)butanamide 525 [00471] 433.1 2,4-dimethyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)oxetane-3-carboxamide 526 [00472] 346.2 N-(5-(2-(quinolin-6-yloxy)ethyl)-1H-indol-3- yl)acetamide 527 [00473] embedded image 419.3 methyl 3-(3-acetamido-1H-indol-5-yl)-2-(4- (trifluoromethyl)benzyl)propanoate 528 [00474] 432.4 4-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)piperidine-4-carboxamide 529 [00475] 472.3 4-methyl-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)piperidine-4-carboxamide 530 [00476] embedded image 447.2 trans-3-(hydroxymethyl)-1-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 531 [00477] 447.15 cis-3-(hydroxymethyl)-1-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 532 [00478] 403.0 3-(3-acetamido-1H-indol-5-yl)-2-(4- (trifluoromethyl)benzyl)propanoic acid 533 [00479] embedded image 433.1 cis-3-(hydroxymethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 534 [00480] 433.15 trans-3-(hydroxymethyl)-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 536 [00481] 366.3 N-(5-(2-(3-(1- (dimethylamino)ethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 537 [00482] embedded image 430.3 N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 538 [00483] 408.2 N-(5-(1-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)propan-2-yl)-1H-indol-3-yl)acetamide 539 [00484] 408.2 N-(5-(3-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)propyl)-1H-indol-3-yl)acetamide 540 [00485] embedded image 418.2 N-(5-(2-hydroxy-3-(5-(trifluoromethyl)pyridin-2- yl)propyl)-1H-indol-3-yl)-1-methylcyclopropane- 1-carboxamide 541 [00486] 364.3 N-(5-(2-((2-(trifluoromethyl)pyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 542 [00487] 452.15 3-methyl-N-(5-(((3aR,5s,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)methoxy)-1H-indol-3-yl)oxetane-3- carboxamide 543 [00488] embedded image 439.0 N-(5-(2-(3-bromo-4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 544 [00489] 438.95 N-(5-(2-(2-bromo-4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 545 [00490] 365.0 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)acetamide-2-13C-2,2,2-d3 546 [00491] embedded image 441.05 N-(4-bromo-5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)acetamide 547 [00492] 393.3 N-(5-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 548 [00493] 335.3 N-(5-(2-(2-allylphenoxy)ethyl)-1H-indol-3- yl)acetamide 549 [00494] 365.3 N-(5-(2-(4-(3-oxobutyl)phenoxy)ethyl)-1H-indol- 3-yl)acetamide 550 [00495] embedded image 460.1 cis-3-(hydroxymethyl)-N-(5-(cis-3-(6- (trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H- indol-3-yl)cyclobutane-1-carboxamide 551 [00496] 460.1 trans-3-(hydroxymethyl)-N-(5-(cis-3-(6- (trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H- indol-3-yl)cyclobutane-1-carboxamide 552 [00497] 458.1 cis-3-(hydroxymethyl)-N-(5-(trans-3-(6- (trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H- indol-3-yl)cyclobutane-1-carboxamide 553 [00498] embedded image 458.1 trans-3-(hydroxymethyl)-N-(5-(trans-3-(6- (trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H- indol-3-yl)cyclobutane-1-carboxamide 554 [00499] 463.2 3-chloro-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 555 [00500] 414.3 N-(5-(2-((8-(trifluoromethyl)quinolin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 556 [00501] embedded image 344.2 N-(5-(2-((6-chloro-2-methylpyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 557 [00502] 344.2 N-(5-(2-((6-chloro-5-methylpyridin-3- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 558 [00503] 295.2 N-(5-(2-phenoxyethyl)-1H-indol-3-yl)acetamide 559 [00504] 398.2 N-(5-(2-((2-chloro-6-(trifluoromethyl)pyridin-4- yl)oxy)ethyl)-1H-indol-3-yl)acetamide 560 [00505] embedded image 380.2 N-(5-(2-((5-chloroquinolin-3-yl)oxy)ethyl)-1H- indol-3-yl)acetamide 561 [00506] 480.15 1-(2,2-difluoroethyl)-3-methyl-N-(5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)azetidine-3-carboxamide 562 [00507] 440.2 (1s,2s)-2-cyano-N-(5-((trans)-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 563 [00508] embedded image 443.3 2,2-dimethyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 564 [00509] 443.3 1-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 565 [00510] 440.3 1-cyano-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 567 [00511] embedded image 444.25 3-methyl-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)azetidine-3-carboxamide 568 [00512] 542.15 tert-butyl 3-methyl-3-((5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)carbamoyl)azetidine-1-carboxylate 569 [00513] 418.15 3-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)- 1H-indol-3-yl)azetidine-3-carboxamide 570 [00514] embedded image 516.15 tert-butyl 3-methyl-3-((5-(4- (trifluoromethyl)phenethoxy)-1H-indol-3- yl)carbamoyl)azetidine-1-carboxylate 571 [00515] 467.2 2-chloro-2-fluoro-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 572 [00516] 459.2 3-methoxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 573 [00517] embedded image 445.2 3-hydroxy-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 574 [00518] 451.2 2,2-difluoro-N-(5-(trans-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 575 [00519] 467.3 2-chloro-2-fluoro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 576 [00520] embedded image 447.2 3-fluoro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 577 [00521] 488.3 2-chloro-2-fluoro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 578 [00522] embedded image 440.8 N-(7-bromo-5-(2-(4-(trifluoromethyl)phenoxy)ethyl)- 1H-indol-3-yl)acetamide 579 [00523] 430.15 1-methyl-N-(5-(cis-3-(6-(trifluoromethyl)pyridin- 3-yl)cyclobutoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 580 [00524] 430.15 1-methyl-N-(5-(cis-3-(6-(trifluoromethyl)pyridin- 3-yl)cyclobutoxy)-1H-indol-3-yl)cyclopropane-1- carboxamide 581 [00525] embedded image 296.2 N-(5-(2-(pyridin-3-yloxy)ethyl)-1H-indol-3- yl)acetamide 582 [00526] 412.1 (1S,2R)-2-cyano-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 584 [00527] 425.3 3,3-difluoro-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 585 [00528] embedded image 400.3 (1S,2S)-2-cyano-N-(5-((4- (trifluoromethyl)benzyl)oxy)-1H-indol-3- yl)cyclopropane-1-carboxamide 586 [00529] 400.3 1-cyano-N-(5-((4-(trifluoromethyl)benzyl)oxy)- 1H-indol-3-yl)cyclopropane-1-carboxamide 587 [00530] 465.3 3,3-difluoro-N-(5-(cis-3-(4- (trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3- yl)cyclobutane-1-carboxamide 588 [00531] embedded image 486.4 3,3-difluoro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 589 [00532] 468.3 3-fluoro-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5- yl)ethoxy)-1H-indol-3-yl)cyclobutane-1- carboxamide 590 [00533] embedded image 418.3 1-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)azetidine-3-carboxamide 591 [00534] 419.3 3,3-dimethyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)butanamide 592 [00535] 389.2 N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H- indol-3-yl)cyclopropanecarboxamide 593 [00536] embedded image 421.2 3-fluoro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclobutane-1-carboxamide 594 [00537] 447.3 4-methyl-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)tetrahydro-2H-pyran-4-carboxamide 595 [00538] 425.2 2,2-difluoro-N-(5-(2-(4- (trifluoromethyl)phenoxy)ethyl)-1H-indol-3- yl)cyclopropane-1-carboxamide 596 [00539] embedded image 401.1

[0478] Pharmaceutical Compositions and Administration

[0479] General

[0480] In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0481] In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22.sup.nd Edition (Pharmaceutical Press, London, U K. 2012).

[0482] Routes of Administration and Composition Components

[0483] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0484] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0485] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0486] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0487] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0488] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

[0489] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0490] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0491] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0492] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0493] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0494] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0495] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

[0496] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0497] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0498] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0499] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0500] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[0501] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0502] Dosages

[0503] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0504] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg).

[0505] Regimens

[0506] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0507] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0508] Methods of Treatment

[0509] In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessive)STING activity (e.g., e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided.

[0510] Indications

[0511] In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostatic neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplasia disorders, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermal tumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

[0512] In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of neurological disorders include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other “tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome.

[0513] In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

[0514] In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, lower or upper respiratory tract infection (e.g., respiratory syncytial virus), Ebola, Zika, and SARS-CoV-2 (COVID19)).

[0515] In some embodiments, the condition, disease or disorder is hepatits B (see, e.g., WO 2015/061294).

[0516] In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).

[0517] In some embodiments, the condition, disease or disorder is age-related macular degeneration.

[0518] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitits, which can occur as a result of chemotherapy or radiation therapy, either alone or in combination as well as damage caused by exposure to radiation outside of the context of radiation therapy.

[0519] In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

[0520] In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.

[0521] In some embodiments, the condition, disease or disorder is selected from the group consisting of Familial Chilblain Lupus, RVCL (autosomal dominant retinal vasculopathy with cerebral leukodystrophy), lupus nephritis (LN), Sjogren's Syndrome (SS), lung inflammation, acute lung inflammation, idiopathic pulmonary fibrosis, liver and renal fibrosis, nonalcoholic steatohepatitis (NASH), cirrhosis, endomyocardial fibrosis, acute and chronic kidney injury, APOL1-associated podocytopathy, acute pancreatitis, chronic obstructive pulmonary disease (COPD), senescence, and aging.

[0522] Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.

[0523] Combination Therapy

[0524] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0525] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.

[0526] In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.

[0527] The one or more additional cancer therapies can include, without limitation, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well as combinations thereof. Immunotherapy, including, without limitation, adoptive cell therapy, the derivation of stem cells and/or dendritic cells, blood transfusions, lavages, and/or other treatments, including, without limitation, freezing a tumor.

[0528] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

[0529] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.

[0530] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A, and MGA271.

[0531] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to cancer cells. In a further embodiment, an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents can function by impairing cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules or they can work by modifying a cell's DNA. In a further embodiment an alkylating agent is a synthetic, semisynthetic or derivative.

[0532] In certain embodiments, the additional chemotherapeutic agent is an anti-metabolite. Anti-metabolites masquerade as purines or pyrimidines, the building-blocks of DNA and in general, prevent these substances from becoming incorporated in to DNA during the “S” phase (of the cell cycle), stopping normal development and division. Anti-metabolites can also affect RNA synthesis. In an embodiment, an antimetabolite includes, but is not limited to azathioprine and/or mercaptopurine. In a further embodiment an anti-metabolite is a synthetic, semisynthetic or derivative.

[0533] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel. In a further embodiment a plant alkaloid or terpernoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and/or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and/or ortataxel. [021] In an embodiment, a cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).

[0534] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In a further embodiment, a stilbenoid includes, but is not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In a further embodiment a stilbenoid is a synthetic, semisynthetic or derivative.

[0535] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, an antracenedione is, without limitation, mitoxantrone and/or pixantrone. In a further embodiment, an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin. In a further embodiment a cytotoxic antibiotic is a synthetic, semisynthetic or derivative.

[0536] In certain embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-β), vasculostatin, vasostatin (calreticulin fragment) and the like.

[0537] In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0538] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus.

[0539] In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[0540] In some embodiments, the additional therapeutic agent and/or regimen are those that can be used for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.

[0541] Non-limiting examples of additional therapeutic agents and/or regimens for treating rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®)), and biologics (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobarilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®)).

[0542] Non-limiting examples of additional therapeutic agents and/or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDIO700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and/or neonatal lupus can also be administered.

[0543] Non-limiting examples of additional therapeutic agents and/or regimens for treating STING-associated vasculopathy with onset in infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0544] Non-limiting examples of additional therapeutic agents and/or regimens for treating Aicardi-Goutières Syndrome (AGS) include physiotherapy, treatment for respiratory complications, anticonvulsant therapies for seizures, tube-feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine/tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0545] Non-limiting examples of additional therapeutic agents and/or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[0546] Non-limiting examples of additional therapeutic agents and/or regimens for treating irritable bowel syndrome include alosetron, bile acid sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonist (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.

[0547] Non-limiting examples of additional therapeutic agents and/or regimens for treating scleroderma include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).

[0548] Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn's Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0549] Non-limiting examples of additional therapeutic agents and/or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SH1P647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0550] Non-limiting examples of additional therapeutic agents and/or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

[0551] Non-limiting examples of additional therapeutic agents and/or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

[0552] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by one or more chemotherapeutics agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

[0553] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

[0554] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), sulfasalazine, and eicopentaenoic acid.

[0555] Non-limiting examples of additional therapeutic agents and/or regimens for treating radaiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0556] Non-limiting examples of additional therapeutic agents and/or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0557] Non-limiting examples of additional therapeutic agents and/or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0558] Non-limiting examples of additional therapeutic agents and/or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0559] Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alphal-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0560] Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[0561] Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alphal-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0562] Non-limiting examples of additional therapeutic agents and/or regimens for treating acute graft-vs-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0563] Non-limiting examples of additional therapeutic agents and/or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0564] Non-limiting examples of additional therapeutic agents and/or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

[0565] Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

[0566] Non-limiting examples of additional therapeutic agents and/or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total skin body electron beam therapy), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate (Folotyn®) biologics (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).

[0567] Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel@), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implant (e.g., fluocinolone insert), and vitrectomy.

[0568] on-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).

[0569] In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[0570] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

[0571] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

[0572] Patient Selection

[0573] In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying a subject can include assaying the patient's tumor microenvironment for the absence of T-cells and/or presence of exhausted T-cells, e.g., patients having one or more cold tumors. Such patients can include those that are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T-cells into the tumor, and in some cases, further treated with one or more checkpoint inhibitors, e.g., once the T-cells become exhausted.

[0574] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells).

[0575] Compound Preparation

[0576] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0577] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, .sup.1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.

[0578] To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

EXAMPLES

Abbreviation of Chemical Terms

[0579] Ac=acetyl [0580] ADDP=1,1′-(azodicarbonyl)-dipiperidine [0581] ACN=acetonitrile [0582] Boc.sub.2O=di-tert-butyl pyrocarbornate [0583] Bu=butyl [0584] BOP=Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluoro-phosphate [0585] Bn=benzyl [0586] Bz=benzoyl [0587] CataCxium A=Bis(adamant-1-yl)(butyl)phosphine [0588] CMPB=(Cyanomethylene)tri-n-butylphosphorane [0589] DAST=Diethylaminosulphur trifluoride [0590] DBAD=di-tert-butyl azodiformate [0591] DCE=dichloroethane [0592] DCM=dichloromethane [0593] DEAD=diethyl azodiformate [0594] DIBAL-H=Diisobutylaluminum hydride [0595] DIAD=diisopropyl azodicarboxylate [0596] DIEA=N,N-diisopropylethylamine [0597] DMA=Dimethylacetamide [0598] DMAP=4-dimethylaminopyridine [0599] DMF=N,N-dimethylformamide [0600] DMF-DMA=N,N-dimethylformamide dimethyl acetal [0601] DMSO=dimethyl sulfoxide [0602] DPPA=diphenyl azidophosphate [0603] Dppf=bis(diphenylphosphino)ferrocene [0604] DtBPF=1,1′-Bis[bis(1,1-dimethylethyl)phosphino]ferrocene [0605] Grubbs 1.sup.st=Grubbs Catalyst 1st Generation [0606] FA=Formic acid [0607] HATU=2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphateHMDS=1,1,1,3,3,3-Hexamethyldisilazane [0608] H.sub.2O=Water [0609] HPLC=high performance liquid chromatography [0610] IBX=2-iodoxybenzoic acid [0611] LAH=Lithium aluminum hydride [0612] LC-MS=liquid chromatography-mass spectrometry [0613] Me=methyl [0614] NMI=1-methylimidazole [0615] NMR=nuclear magnetic resonance [0616] POT=tris(2-methylphenyl)phosphine [0617] Pr=propyl [0618] Py=pyridine [0619] RT=retention time [0620] TBDPS=t-butyl-diphenylsilyl [0621] TBS=tert-Butyldimethylsilyl [0622] TBUP=Tri-n-butylphosphine [0623] TCFH=N,N,N′,N′-tetramethylchloroformamidinium-hexafluorophosphate [0624] TEA=trimethylamine [0625] Tf=trifluoromethanesulfonyl [0626] TFA=trifluoroacetic acid [0627] Tf.sub.2O=trifluoromethanesulfonic anhydride [0628] THE=tetrahydrofuran [0629] TMS=Trimethylsilyl [0630] Tol=methylbenzene [0631] T.sub.3P=2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane [0632] Ts=Tosyl [0633] t-AmOH=2-methylbutan-2-ol [0634] XPhos=(2-(2,4,6-triisopropylphenethyl)phenyl)dicyclohexylphosphine [0635] Na.sub.2SO.sub.4=Sodium sulfate [0636] Speedvac=Savant SC250EXP SpeedVac Concentrator [0637] DMSO=Dimethyl Sulfoxide [0638] Cs2CO3=Cesium carbonate [0639] TCFH=N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphateN— [0640] HPLC-1=high-performance liquid chromatography

Materials and Methods

[0641] For schemes 1-51 and examples 1-195 and, the LC-MS methods and prep-HPLC methods are one of the following methods.
LCMS Method A: Kinetex EVO C18 100A, 30*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.
LCMS Method B: Xselect CSH C18, 50*3 mm, 1.0 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.
LCMS Method C: XBridge Shield RP18, 50*4.6 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH.sub.3.H.sub.2O and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min.
LCMS Method D: kinetex 2.6 μm EVO, 50*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.
LCMS Method E: HALOC18, 30*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.
LCMS Method F: Shim-pack Scepter C18-120, 33*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 50% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.
LCMS Method G: Poroshell HPH C18, 50 *3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3+5 mM NH.sub.4OH and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

Method A

[0642] Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge C18, 50*2.1 mm*5 m or equivalent
Mobile Phase: A: H.sub.2O (0.04% TFA); B: CH.sub.3CN (0.02% TFA)
Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.
Flow Rate: 0.6 mL/min or 0.8 mL/min

Column Temp: 40° C. or 50° C.

UV: 220 nm

Method B

[0643] Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 m or equivalent
Mobile Phase:A: H.sub.2O (0.05% NH.sub.3.H.sub.2O) or 10 mM ammonia bicarbonate; B: CH.sub.3CN
Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound.
Flow Rate: 0.6 mL/min or 0.8 mL/min

Column Temp: 40° C.

UV: 220 nm

[0644] Prep. HPLC condition

Instrument:

1. GILSON 281 and Shimadzu LCMS 2010A

2. GILSON 215 and Shimadzu LC-20AP

3. GILSON 215

Mobile Phase:

[0645] A: NH.sub.4OH/H.sub.2O=0.05% v/v; B: ACN
A: FA/H.sub.2O=0.225% v/v; B: ACN

Column

[0646] Xtimate C18 150*25 mm*5 μm
Flow rate: 25 mL/min or 30 mL/min
Monitor wavelength: 220&254 nm
Gradient: actual method would depend on clog P of compound

Detector: MS Trigger or UV

[0647] NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.
For scheme 52-75 and examples 196-289, the LC-MS, NMR, Prep-HPLC are conducted using one of the following methods.
LCMS Method A: Kinetex EVO C18 100A, 30*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.
LCMS Method B: Xselect CSH C18, 50*3 mm, 1.0 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.
LCMS Method C: XBridge Shield RP18, 50*4.6 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH.sub.3.H.sub.2O and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min.
LCMS Method D: kinetex 2.6 μm EVO, 50*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.
LCMS Method E: HALOC18, 30*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.
LCMS Method F: Shin-pack Scepter C18-120, 33*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 50% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

[0648] Method A

[0649] Instrument: Agilent LCMS system equipped with DAD and ELSD detector

[0650] Ion mode: Positive

[0651] Column: Waters X-Bridge C18, 50*2.1 mm*5 m or equivalent

[0652] Mobile Phase: A: H.sub.2O (0.04% TFA); B: CH.sub.3CN (0.02% TFA)

[0653] Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.

[0654] Flow Rate: 0.6 mL/min or 0.8 mL/min

[0655] Column Temp: 40° C. or 50° C.

[0656] UV: 220 nm

[0657] Method B

[0658] Instrument: Agilent LCMS system equipped with DAD and ELSD detector

[0659] Ion mode: Positive

[0660] Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 m or equivalent

[0661] Mobile Phase:A: H.sub.2O (0.05% NH.sub.3.H.sub.2O) or 10 mM ammonia bicarbonate; B: CH.sub.3CN

[0662] Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound.

[0663] Flow Rate: 0.6 mL/min or 0.8 mL/min

[0664] Column Temp: 40° C.

[0665] UV: 220 nm

[0666] Prep. HPLC-1 Condition-1

[0667] Instrument: [0668] 1. GILSON 281 and Shimadzu LCMS 2010A [0669] 2. GILSON 215 and Shimadzu LC-20AP [0670] 3. GILSON 215

[0671] Mobile Phase: [0672] A: NH.sub.4OH/H.sub.2O=0.05% v/v; B: ACN [0673] A: FA/H.sub.2O=0.225% v/v; B: ACN

[0674] Column [0675] Xtimate C18 150*25 mm*5 μm [0676] Flow rate: 25 mL/min or 30 mL/min [0677] Monitor wavelength: 220&254 nm [0678] Gradient: actual method would depend on clog P of compound [0679] Detector: MS Trigger or UV
NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.

Preparative Examples

[0680] Scheme for the preparation of Key Intermediates: Schemes below illustrate the preparation of key intermediates.

##STR00540##

Step 1: 5-bromo-1H-indole-3-carbonyl azide

[0681] 5-Bromo-1H-indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv.) was dissolved in THE (150 mL), then TEA (26.1 mL, 187.4 mmol, 1.5 equiv.) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 12 hours at ambient temperature, then quenched by the addition of water and stirred for an additional 10 min. The precipitated solid was collected by filtration and dried to give 5-bromo-1H-indole-3-carbonyl azide (33.6 g) as an off-white solid. LCMS Method B: [M−H].sup.−=263.

Step 2: tert-butyl (5-bromo-1H-indol-3-yl)carbamate

[0682] 5-Bromo-1H-indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv.) was dissolved in t-BuOH (300 mL). The reaction mixture was heated to 80° C. for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl (5-bromo-1H-indol-3-yl)carbamate (22.1 g) as a pale white solid. LCMS Method A: [M+H].sup.+=311.

Step 3: 5-bromo-1H-indol-3-amine hydrochloride

[0683] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A: [M+H].sup.+=211.

Step 4: N-(5-bromo-1H-indol-3-yl)acetamide

[0684] 5-Bromo-1H-indol-3-amine (18.7 g, 88.6 mmol, 1.0 equiv.) and TEA (37.1 mL, 265.8 mmol, 3.0 equiv.) were dissolved in DCM (200 mL) and the solution was cooled to 0° C. Then AcCl (6.9 mL, 97.4 mmol, 1.1 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give N-(5-bromo-1H-indol-3-yl)acetamide (15.0 g) as a brown solid. LCMS Method A: [M+H].sup.+=253.

Step 5: tert-butyl 5-bromo-3-acetamidoindole-1-carboxylate

[0685] N-(5-bromo-1H-indol-3-yl)acetamide (1.0 g, 4.0 mmol, 1.0 equiv.) was dissolved in THF (30 mL), then TEA (1.1 mL, 7.9 mmol, 2 equiv.), Boc.sub.2O (862.3 mg, 4.0 mmol, 1.0 equiv.) and DMAP (48.3 mg, 0.4 mmol, 0.1 equiv.) were added. The reaction mixture was stirred for 50 min at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl 5-bromo-3-acetamidoindole-1-carboxylate (800.0 mg) as a pale yellow solid. LCMS Method C: [M+H].sup.+=3M53.

The intermediates in the following table were prepared using the same method described for Intermediates 1 and 2.

TABLE-US-00002 Intermediate Structure LCMS data Intermediate 3 [00541] embedded image Method A: MS-ESI: 267 [M + H].sup.+ Intermediate 4 [00542] Method A: MS-ESI: 367 [M + H].sup.+ Intermediate 5 [00543] Method A: MS-ESI: 293 [M + H].sup.+ Intermediate 6 [00544] Method A: MS-ESI: 393 [M + H].sup.+

##STR00545##

Step 1: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide

[0686] N-(5-bromo-1H-indol-3-yl)acetamide (10.0 g, 39.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (20.1 g, 79.0 mmol, 2.0 equiv.), KOAc (7.7 g, 79.0 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (2.8 g, 3.9 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (20:1) to give N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (9.1 g) as a brown solid. LCMS Method A: [M+H].sup.+=301.

Step 2: N-(5-hydroxy-1H-indol-3-yl)acetamide

[0687] N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (6.5 g, 21.6 mmol, 1.0 equiv.) was dissolved in THE (50 mL) and water (50 mL), then NaOH (1.7 g, 42.5 mmol, 2.0 equiv.) was added. This was followed by the addition of H.sub.2O.sub.2 (30% wt. in water, 28.0 mL, 420.0 mmol, 20.0 equiv.) dropwise at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give N-(5-hydroxy-1H-indol-3-yl)acetamide (2.5 g) as a grey solid. LCMS Method A: [M+H].sup.+=191.

The intermediates in the following table were prepared using the same method described for Intermediate 7.

TABLE-US-00003 Intermediate Starting material Structure LCMS data Intermediate 8 [00546] embedded image [00547] Method A: MS-ESI: 205 [M + H].sup.+ Intermediate 9 [00548] [00549] Method A: MS-ESI: 231 [M + H].sup.+

##STR00550##

Step 1: tert-butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate

[0688] N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (1.0 g, 3.3 mmol, 1.0 equiv.) and Boc.sub.2O (872.5 mg, 4.0 mmol, 1.2 equiv.) were dissolved in THF, then TEA (0.9 mL, 6.7 mmol, 2.0 equiv.) and DMAP (40.7 mg, 0.3 mmol, 0.1 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:7) to give tert-butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (907.5 mg) as a yellow solid. LCMS Method B: [M+H].sup.+=401.

Step 2: tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate

[0689] tert-Butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (1.0 g, 2.5 mmol, 1.0 equiv.) was dissolved in THE (10 mL), then aqueous NaOH (2% wt., 10 mL, 5.0 mmol, 2.0 equiv.) and H.sub.2O.sub.2 (30% wt., 2.6 mL, 25.0 mmol, 10.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was adjusted to pH 6 with saturated aqueous NH.sub.4HCO.sub.3, then extracted with ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (20:1) to give tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate (690.0 mg) as a grey solid. LCMS Method B: [M+H].sup.+=291.

##STR00551##

Step 1: tert-butyl 3-acetamido-5-ethenylindole-1-carboxylate

[0690] tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (660.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (4 mL) and water (1 mL), then 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (575.6 mg, 3.7 mmol, 2.0 equiv.), Cs.sub.2CO.sub.3 (1.2 g, 3.7 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (273.4 mg, 0.4 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 85° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl 3-acetamido-5-ethenylindole-1-carboxylate (400.0 mg %) as a pale yellow solid. LCMS Method C: [M+H].sup.+=301.

Step 2: tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate

[0691] tert-Butyl 3-acetamido-5-ethenylindole-1-carboxylate (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then BH.sub.3-THF (1 M, 2.5 mL, 2.5 mmol, 1.5 equiv.) was added dropwise. The reaction mixture was stirred for 40 min at ambient temperature. Then a solution of aqueous NaOH (1 M, 3.3 mL, 3.3 mmol, 2.0 equiv.) was added and the reaction mixture was cooled to 0° C. This was followed by the dropwise addition of H.sub.2O.sub.2 (30% wt. in water, 1.3 mL, 3.3 mmol, 2.0 equiv.), maintaining the reaction mixture at 0° C. The reaction mixture was stirred for additional 30 min at 0° C., then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (12:1) to give tert-butyl 3-acetamido-5-(2-hydroxyethyl) indole-1-carboxylate (300.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=319.

The intermediate in the following table was prepared using the same method described for Intermediate 11.

TABLE-US-00004 Intermediate Starting material Structure LCMS data Intermediate 12 [00552] embedded image [00553] Method A: MS-ESI: 359 [M + H].sup.+

##STR00554##

[0692] tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL), then (tributylstannyl)methanol (909.1 mg, 2.8 mmol, 2.0 equiv.) and Pd(PPh.sub.3).sub.4 (327.2 mg, 0.3 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 85° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl 3-acetamido-5-(hydroxymethyl)indole-1-carboxylate (262.5 mg) as a pale yellow solid. LCMS Method C: [M+H].sup.+=305.

The intermediate in the following table was prepared using the same method described for Intermediate 13.

TABLE-US-00005 Intermediate Starting material Structure LCMS data Intermediate 14 [00555] embedded image [00556] Method C: MS-ESI: 319 [M + H].sup.+

##STR00557##

[0693] tert-Butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (320.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in DCM (25 mL), then IBX (562.9 mg, 2.0 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 50° C. for 3 hours, the cooled to ambient temperature and the solids were removed by filtration. The filtrate was concentrated under vacuum to give tert-butyl 3-acetamido-5-(2-oxoethyl)indole-1-carboxylate (311.2 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=317.

[0694] The intermediate in the following table was prepared using the same method described for Intermediate 15.

TABLE-US-00006 Intermediate Starting material Structure LCMS data Intermediate 16 [00558] embedded image [00559] Method A: MS-ESI: 357 [M + H].sup.+

##STR00560##

[0695] tert-Butyl 3-acetamido-5-ethenylindole-1-carboxylate (400.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and water (15 mL), then K.sub.2O.sub.sO.sub.4.2H.sub.2O (98.1 mg, 0.3 mmol, 0.2 equiv.) and NaIO.sub.4 (1.1 g, 5.3 mmol, 4.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and then diluted with water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give tert-butyl 3-acetamido-5-formylindole-1-carboxylate (350.0 mg) as a dark yellow solid. LCMS Method B: [M+H].sup.+=303.

##STR00561##

Step 1: benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate

[0696] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.6 g, 6.4 mmol, 1.5 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then NaH (60% wt., 342.9 mg, 8.6 mmol, 2.0 equiv.) was added, maintaining the reaction mixture at 0° C. The reaction mixture was stirred for 30 min at ambient temperature. This was followed by the dropwise addition of benzyl 4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol, 1.0 equiv.) at 0° C. The resulting mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate (1.2 g) as a colorless oil. LCMS Method A: [M+H].sup.+=322.

Step 2: ethyl 2-fluoro-2-(piperidin-4-yl)acetate

[0697] Benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate (1.2 g, 3.7 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pd/C (120.0 mg, 10% wt.) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 2-fluoro-2-(piperidin-4-yl)acetate (650.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=190.

Step 3: ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate

[0698] Ethyl 2-fluoro-2-(piperidin-4-yl)acetate (1.0 g, 5.3 mmol, 1.0 equiv.) and TEA (1.5 mL, 10.6 mmol, 2.0 equiv.) were dissolved in ACN (20 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 g, 7.9 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate (820.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=272.

Step 4: 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethan-1-ol

[0699] Ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate (400.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and cooled to 0° C., then LiAlH.sub.4 (111.9 mg, 2.9 mmol, 2.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of Na.sub.2SO.sub.4.10H.sub.2O. The solid was removed by filtration, then the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethan-1-ol (310.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=230.

##STR00562##

[0700] 1-Fluoro-4-(trifluoromethyl)benzene (500.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then K.sub.2CO.sub.3 (842.1 mg, 6.0 mmol, 2.0 equiv.) and 4-piperidineethanol (393.6 mg, 3.0 mmol, 1.0 equiv.) were added. The reaction mixture was heated to 120° C. overnight, then cooled to ambient temperature and quenched by the addition of aqueous HCl (2N). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 2-[1-[4-(trifluoromethyl)phenyl]piperidin-4-yl]ethanol (280.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=274.

The intermediates in the following table were prepared using the same method described for Intermediate 19.

TABLE-US-00007 Starting Intermediate Starting material A material B Structure LCMS data Intermediate 20 [00563] embedded image [00564] [00565] Method A: MS-ESI: 212 [M + H].sup.+ Intermediate 21 [00566] [00567] [00568] Method A: MS-ESI: 198 [M + H].sup.+ Intermediate 22 [00569] [00570] [00571] Method A: MS-ESI: 196 [M + H].sup.+

##STR00572##

Step 1: ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate

[0701] Ethyl 2-methyl-2-(piperidin-4-yl)propanoate (500.0 mg, 2.5 mmol, 1.0 equiv.) and TEA (0.5 mL, 3.8 mmol, 1.5 equiv.) were dissolved in ACN (25 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (873.5 mg, 3.8 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 65° C. for 6 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (205.5 mg) as a yellow oil. LCMS Method C: [M+H].sup.+=282.

Step 2: 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol

[0702] Ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to 0° C. Then LiAlH.sub.4 (40.5 mg, 1.1 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol (21.3 mg) as a yellow oil. LCMS Method C: [M+H].sup.+=240.

##STR00573##

Step 1: (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde

[0703] Oxalyl chloride (1.0 mL, 12.3 mmol, 2.5 equiv.) was dissolved in DCM (30 mL) and cooled to −78° C., then DMSO (1.7 mL, 24.6 mmol, 5.0 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at −78° C. under an atmosphere of nitrogen. This was followed by the dropwise addition of a solution of [(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]methanol (1.0 g, 4.9 mmol, 1.0 equiv.) in DCM (20 mL), maintaining the solution at −78° C. The reaction mixture was stirred for an additional 2 hours at −78° C., then TEA (6.9 mL, 49.2 mmol, 10.0 equiv.) was added dropwise and the resulting solution was stirred for another 4 hours at ambient temperature. The reaction was quenched by the addition of water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (980.0 mg) as a pale yellow liquid. LCMS Method A: [M+H].sup.+=202.

Step 2: (1R,5S,6S)-3-benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane

[0704] Methyltriphenylphosphonium bromide (2.0 g, 5.7 mmol, 1.5 equiv.) was dissolved in THF (20 mL) and cooled to −50° C., then n-BuLi (3M in THF, 1.9 mL, 5.7 mmol, 1.5 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at −50° C. After 30 min at −50° C., a solution of (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (760.0 mg, 3.8 mmol, 1.0 equiv.) in THE (5 mL) was added dropwise. The resulting mixture was stirred for additional 4 hours at ambient temperature and then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give (1R,5S,6S)-3-benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane (480.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=200.

Step 3: 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol

[0705] (1R,5S,6S)-3-benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane (480.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then BH.sub.3—SMe.sub.2 (0.80 mL, 2.4 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at 65° C., then cooled down to 0° C. Then a solution of NaOH (578.0 mg, 14.4 mmol, 6.0 equiv.) in H.sub.2O (2 mL) was added, followed by the dropwise addition of H.sub.2O.sub.2 (30% aqueous, 1.5 mL, 14.4 mmol, 6.0 equiv.). The resulting mixture was heated to 50° C. overnight, then cooled to ambient temperature and quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (510.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=218.

Step 4: 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol

[0706] 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (450.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pd/C (10% wt., 44.1 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 6 hours at 45° C. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (250.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=128.

Step 5: 2-[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol

[0707] 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (250.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in ACN (5 mL) and cooled to 0° C., then K.sub.2CO.sub.3 (543.3 mg, 3.9 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (684.3 mg, 2.9 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 80° C. for 50 min, the cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 2-[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (260.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=210.

##STR00574##

Step 1: 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one

[0708] DMA (1.3 mL, 13.9 mmol, 1.2 equiv.) was dissolved in DCE (30 mL) and cooled to 5° C., then Tf.sub.2O (2.7 mL, 16.3 mmol, 1.4 equiv.) was added dropwise, maintaining the solution at 5° C. The reaction mixture was stirred for 30 min at 5° C. This was followed by the addition of a solution of 1-ethenyl-4-(trifluoromethyl) benzene (840.0 mg, 4.9 mmol, 1.0 equiv.) and 2,4,6-collidine (2.0 g, 16.3 mmol, 1.4 equiv.) in DCE (10 mL) dropwise at 5° C. The resulting mixture was heated to 80° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:7) to give 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one (450.0 mg) as a pale yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 3.79-3.75 (m, 1H), 3.63-3.50 (m, 2H), 3.34-3.23 (m, 2H).

Step 2: cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol

[0709] 3-[4-(Trifluoromethyl)phenyl]cyclobutan-1-one (300.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL) and cooled to −10° C., then NaBH.sub.4 (106.0 mg, 2.8 mmol, 2.0 equiv.) was added, maintaining the solution at −10° C. The reaction mixture was stirred for 50 min at −10° C. under an atmosphere of nitrogen and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (260.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=217.

Step 3: trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate

[0710] Cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (130.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in THE (2 mL), then p-nitrobenzoic acid (100.5 mg, 0.6 mmol, 1.0 equiv.), PPh.sub.3 (315.4 mg, 1.2 mmol, 2.0 equiv.) and DIAD (243.2 mg, 1.2 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:6) to give trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate (160.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=366.

Step 4: trans-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol

[0711] Trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (1 mL), then K.sub.2CO.sub.3 (227.0 mg, 1.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 65° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give trans-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (155.2 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=217.

##STR00575##

Step 1: 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one

[0712] DMA (12.1 g, 138.9 mmol, 1.2 equiv.) was dissolved in DCE (400 mL) and cooled to 0° C., then Tf.sub.2O (46.0 g, 163.0 mmol, 1.4 equiv.) was added dropwise at 0-5° C., over the course of 30 min. The resulting mixture was stirred for 1 hour at 5° C., then 2,4,6-collidine (19.7 g, 162.5 mmol, 1.4 equiv.) and 1-ethenyl-4-(trifluoromethyl)benzene (20.0 g, 116.2 mmol, 1.0 equiv.) were added at 5° C. The resulting solution heated to 80° C. for 48 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with 300 mL of water, extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (3:7) to give 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (8.0 g) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 3.79-3.75 (m, 1H), 3.63-3.50 (m, 2H), 3.34-3.23 (m, 2H).

Step 2: cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol

[0713] 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (7.9 g, 36.9 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL) and cooled to 0° C., then NaBH.sub.4 (2.1 g, 55.3 mmol, 1.5 equiv.) was added in portions, while maintaining the reaction mixture at 0° C. The resulting mixture was stirred for 1 hour at 0° C., then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (99:1) to afford cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (60.5 g) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.65 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 5.14 (d, J=7.2 Hz, 1H), 4.11-4.01 (m, 1H), 3.02-2.93 (m, 1H), 2.66-2.60 (m, 2H), 1.95-1.86 (m, 2H).

##STR00576##

Step 1: 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol

[0714] [6-(Trifluoromethyl)pyridin-3-yl]acetic acid (500.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0° C. Then BH.sub.3.THF (1 M, 4.9 mL, 4.9 mmol, 1.5 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred overnight at ambient temperature and the quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (330.0 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=192.

Step 2: 2-[6-(trifluoromethyl)pyridin-3-yl]ethyl 4-methylbenzenesulfonate

[0715] 2-[6-(Trifluoromethyl)pyridin-3-yl]ethanol (300.0 mg, 1.6 mmol, 1.0 equiv.) and TEA (1.1 mL, 7.8 mmol, 5.0 equiv.) were dissolved in DCM (3 mL), then TsCl (897.6 mg, 4.7 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 16 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with DCM, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 2-[6-(trifluoromethyl)pyridin-3-yl]ethyl 4-methylbenzenesulfonate (500.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=346.

##STR00577##

Step 1: 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol

[0716] 2,2-Difluoropropane-1,3-diol (2.0 g, 17.8 mmol, 1.0 equiv.) was dissolved in THE (20.0 mL) and cooled to 0° C., then NaH (60% wt., 1.0 g, 26.7 mmol, 1.5 equiv.) was added, maintaining the solution at 0° C. After 2 hours at 0° C., TBDPSCl (9.8 g, 35.6 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for an additional 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (5.1 g) as a yellow oil. LCMS Method C: [M+H].sup.+=351.

Step 2: 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate

[0717] 3-[(tert-Butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (4.9 g, 14.0 mmol, 1.0 equiv.) was dissolved in DCE (20 mL) and cooled to −70° C., then DIEA (9.7 mL, 55.9 mmol, 4.0 equiv.) and trifluoromethanesulfonic anhydride (4.7 mL, 27.9 mmol, 2.0 equiv.) were added dropwise at −70° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at −20° C. and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate (5.2 g) as a yellow oil. LCMS Method A: [M+H].sup.+=483.

Step 3: 1-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine

[0718] 3-[(tert-Butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate (5.0 g, 10.3 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), then 4,4-difluoropiperidine (1.5 g, 12.4 mmol, 1.2 equiv.) and DIEA (3.5 mL, 20.7 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 50° C., then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine (3.8 g) as a yellow oil. LCMS Method A: [M+H].sup.+=454.

Step 4: 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol

[0719] 1-[3-[(tert-Butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine (3.6 g, 7.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), then HF.Py (70% wt., 1.1 mL, 31.7 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 12 hours at ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol (1.0 g) as a yellow oil. LCMS Method A: [M+H].sup.+=216.

Step 5: 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropyl 4-methylbenzenesulfonate

[0720] 3-(4,4-Difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol (220.0 mg, 1.0 mmol, 1.0 equiv.) and TEA (0.3 mL, 2.0 mmol, 2.0 equiv.) were dissolved in DCM (10 mL), then TsCl (389.8 mg, 2.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 12 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropyl 4-methylbenzenesulfonate (320.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=370.

##STR00578##

Step 1: 2-methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene

[0721] 4-Fluoro-2-methyl-1-nitrobenzene (19.0 g, 122.5 mmol, 1.0 equiv.) was dissolved in DMF (100 mL), then K.sub.2CO.sub.3 (50.8 g, 367.4 mmol, 3.0 equiv.) and 4-(trifluoromethyl)phenol (23.8 g, 146.9 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:9) to give 2-methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (30.0 g) as a yellow solid.

Step 2: (E)-N,N-dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine

[0722] 2-Methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (20.0 g, 67.3, 1.0 equiv.) was dissolved in DMF (100 mL), then DMF-DMA (10.7 mL, 80.7 mmol, 1.2 equiv.) was added. The reaction mixture was heated to 140° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give (E)-N,N-dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine (24.0 g) as a red solid. LCMS Method A: [M+H].sup.+=353.

Step 3: 5-(4-(trifluoromethyl)phenoxy)-1H-indole

[0723] (E)-N,N-dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine (24.0 g, 68.1 mmol, 1.0 equiv.) was dissolved in ethyl acetate (250 mL), then Pd/C (10% wt., 2.5 g) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 36 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:6) to give 5-(4-(trifluoromethyl)phenoxy)-1H-indole (11.5 g) as a green solid. LCMS Method A: [M+H].sup.+=278.

Step 4: 3-nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole

[0724] A mixture of AgNO.sub.3 (3.6 g, 21.6 mmol, 1.2 equiv.) and ACN (50 mL) was cooled to 0° C., then benzoyl chloride (2.5 mL, 21.6 mmol, 1.2 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 10 min at 0° C., then a solution of 5-(4-(trifluoromethyl)phenoxy)-1H-indole (5.0 g, 18.0 mmol, 1.0 equiv.) in ACN (5 mL) was added dropwise. The resulting solution was stirred for 1 hour at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 3-nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole (3.1 g) as a black solid. LCMS Method B: [M−H].sup.−=321.

Step 5: tert-butyl (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate

[0725] 3-Nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole (3.1 g, 9.7 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL), then (Boc).sub.2O (4.2 g, 19.4 mmol, 2.0 equiv.) and Pd/C (10% wt., 0.4 g) were added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 10 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate (1.3 g) as a brown solid. LCMS Method A: [M+H].sup.+=393.

Step 6: 5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-amine hydrochloride

[0726] tert-Butyl (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate (1.3 g, 3.3 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 15 mL). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum to give 5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-amine hydrochloride (910.0 mg) as a green solid. LCMS Method A: [M+H].sup.+=293.

The intermediates in the following table were prepared using the same method described for Intermediate 29.

TABLE-US-00008 Starting Intermediate material A Starting material B Structure LCMS data Intermediate 30 [00579] embedded image [00580] [00581] Method A: MS-ESI: 294 [M + H].sup.+ Intermediate 31 [00582] [00583] [00584] Method A: MS-ESI: 294 [M + H].sup.+

##STR00585##

Step 1: tert-butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate

[0727] tert-Butyl N-(5-hydroxy-1H-indol-3-yl)carbamate (300.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled to 0° C., then 2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethanol (306.3 mg, 1.5 mmol, 1.2 equiv.) and P(n-Bu).sub.3 (733.4 mg, 3.6 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. This was followed by the dropwise addition of a solution of ADDP (609.8 mg, 2.4 mmol, 2.0 equiv.) in DCM (5 mL), maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate (285.0 mg) as a pale yellow solid. LCMS Method C: [M+H].sup.+=442.

Step 2: 5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride

[0728] tert-Butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate (1.0 g, 2.3 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 10 mL). The reaction mixture was stirred for 40 min at ambient temperature and then concentrated under vacuum to give 5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride (910.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=342.

[0729] The intermediate in the following table was prepared using the same method described for Intermediate 32.

TABLE-US-00009 Intermediate Starting material Structure LCMS data Intermediate 33 [00586] embedded image [00587] Method C: MS-ESI: 321 [M-H].sup.−

##STR00588##

[0730] 1-Allyl-4-(trifluoromethyl)benzene (1.0 g, 5.4 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), then 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.7 g, 10.7 mmol, 2.0 equiv.) and Grubbs 1st (224.8 mg, 0.3 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 50° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give (E)-4,4,5,5-tetramethyl-2-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1,3,2-dioxaborolane (640 mg) as a brown liquid. LCMS Method A: [M+H].sup.+=313.

##STR00589##

[0731] Bromo[4-(trifluoromethyl)phenyl]magnesium (8 mL, 0.5 mol/L, 4.0 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C. Then 3-chloro-2-methylpropene (0.4 g, 4.0 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at 0° C. and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether (100%) to give 1-(2-methylprop-2-en-1-yl)-4-(trifluoromethyl)benzene (410.0 mg) as a light yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=7.6 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.89-4.87 (m, 1H), 4.77-4.75 (m, 1H), 3.39 (s, 2H), 1.70 (s, 3H).

##STR00590##

Step 1: 1-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol

[0732] 4-(Trifluoromethyl)benzaldehyde (2.0 g, 11.5 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0° C., then bromo(ethenyl)magnesium (1M in THF, 13.8 mL, 13.8 mmol, 1.2 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 1-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol (1.0 g) as a pale yellow solid. LCMS Method A: [M+H].sup.+=203.

Step 2: 1-(1-methoxyprop-2-en-1-yl)-4-(trifluoromethyl)benzene

[0733] 1-[4-(Trifluoromethyl)phenyl]prop-2-en-1-ol (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then NaH (60% wt., 0.4 g, 9.9 mmol, 2.0 equiv.) was added. This was followed by the dropwise addition of CH.sub.3I (0.6 mL, 9.9 mmol, 2.0 equiv.) while maintaining the internal reaction temperature at 0° C. The reaction mixture was allowed to warm to ambient temperature and for 2 hours, then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 1-(1-methoxyprop-2-en-1-yl)-4-(trifluoromethyl)benzene (0.9 g) as a pale yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 5.97-5.82 (m, 1H), 5.37-5.23 (m, 2H), 4.70 (d, J=6.8 Hz, 1H), 3.38 (s, 3H). LCMS Method A: [M+H].sup.+=217.

##STR00591##

Step 1: 5-bromo-1H-indole-3-carbonyl azide

[0734] 5-Bromo-1H-indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv.) was dissolved in THE (150 mL), then TEA (26.1 mL, 187.4 mmol, 1.5 equiv.) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 12 hours at ambient temperature, then quenched by the addition of water and stirred for an additional 10 min. The precipitated solid was collected by filtration and dried to give 5-bromo-1H-indole-3-carbonyl azide (33.6 g) as an off-white solid. LCMS Method B: [M−H].sup.−=263.

Step 2: tert-butyl (5-bromo-1H-indol-3-yl)carbamate

[0735] 5-Bromo-1H-indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv.) was dissolved in t-BuOH (300 mL). The reaction mixture was heated to 80° C. for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl (5-bromo-1H-indol-3-yl)carbamate (22.1 g) as a pale white solid. LCMS Method A: [M+H].sup.+=311.

Step 3: 5-bromo-1H-indol-3-amine hydrochloride

[0736] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A: [M+H].sup.+=211.

Step 4: N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide

[0737] Cyclopropanecarboxylic acid (172.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in DCM (20 mL), then DIEA (1.0 mL, 6.0 mmol, 3.0 equiv.), HATU (1.1 g, 3.0 mmol, 1.5 equiv.) and 5-bromo-1H-indol-3-amine hydrogen chloride (500.0 mg, 2.0 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide (510.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=279.

The intermediates in the following Table were prepared using the same method described for Intermediate 37.

TABLE-US-00010 Intermediate Structure LCMS data Intermediate 38 [00592] embedded image Method A: MS-ESI: 293 [M + H].sup.+ Intermediate 39 [00593] Method A: MS-ESI: 254 [M + H]+ Intermediate 40 [00594] Method A: MS-ESI: 329 [M + H]+

##STR00595##

Step 1: 5-bromo-7-fluoro-3-nitro-1H-indole

[0738] 5-Bromo-7-fluoro-1H-indole (8.5 g, 39.7 mmol, 1.0 equiv.) was dissolved in in ACN (150 mL) and cooled to 0° C., then AgNO.sub.3 (10.1 g, 59.6 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 15 min, then benzoyl chloride (8.4 g, 59.6 mmol, 1.5 equiv.) was added batchwise, maintaining the reaction mixture at 0° C. The reaction mixture was stirred for 3 hours at 0° C., then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 5-bromo-7-fluoro-3-nitro-1H-indole (7.4 g) as a black solid. LCMS Method A: [M+H].sup.+=259.

Step 2: tert-butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate

[0739] 5-Bromo-7-fluoro-3-nitro-1H-indole (3.0 g, 11.6 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL) then (Boc).sub.2O (3.0 g, 13.8 mmol, 1.2 equiv.) was added. This was followed by the portionwise addition of SnCl.sub.2 (6.6 g, 34.7 mmol, 3.0 equiv.) and NaBH.sub.4 (1.3 g, 34.7 mmol, 3.0 equiv.), while maintain the reaction mixture at 0° C. The reaction mixture was stirred for 4 hours at 0° C., then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:9) to give tert-butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate (1.3 g) as a yellow solid. LCMS Method A: [M+H].sup.+=329.

Step 3: 5-bromo-7-fluoro-1H-indol-3-amine hydrochloride

[0740] tert-Butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate (1.3 g, 3.9 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 15 mL). The reaction mixture was stirred for 2 hours at ambient temperature then concentrated under vacuum to give 5-bromo-7-fluoro-1H-indol-3-amine hydrochloride (980.0 mg) as a grey solid. LCMS Method A: [M+H].sup.+=229.

Step 4: N-(5-bromo-7-fluoro-1H-indol-3-yl)acetamide

[0741] 5-Bromo-7-fluoro-1H-indol-3-amine (980.0 mg, 4.3 mmol, 1.0 equiv.) and TEA (2.3 mL, 17.1 mmol, 4.0 equiv.) were dissolved in DCM (10 mL), then acetyl chloride (0.4 mL, 5.1 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (20:1) to give N-(5-bromo-7-fluoro-1H-indol-3-yl)acetamide (800.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=271.

[0742] The intermediates in the following table were prepared using the same method described for Intermediate 41.

TABLE-US-00011 Intermediate Structure LCMS data Intermediate 42 [00596] embedded image Method A: MS-ESI: 267 [M + H].sup.+ Intermediate 43 [00597] Method A: MS-ESI: 254 [M + H]+ Intermediate 44 [00598] Method A: MS-ESI: 329 [M + H]+

##STR00599##

Step 1: N-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide

[0743] N-(5-Bromo-7-fluoro-1H-indol-3-yl)acetamide (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5 g, 5.8 mmol, 1.5 equiv.), Cs.sub.2CO.sub.3 (2.5 g, 7.7 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.3 g, 0.4 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give N-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl) acetamide (880 mg) as a brown solid. LCMS Method A: [M+H].sup.+=319.

Step 2: N-(7-fluoro-5-hydroxy-1H-indol-3-yl)acetamide

[0744] N-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (830.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then a solution of NaOH in water (2% wt./wt., 11 mL, 5.5 mmol, 2.0 equiv.) was added. This was followed by the addition of H.sub.2O.sub.2 (30% wt./wt. in water, 2 mL, 19.2 mmol, 7.5 equiv.) dropwise at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give N-(7-fluoro-5-hydroxy-1H-indol-3-yl)acetamide (174.0 mg) as a black solid. LCMS Method A: [M+H].sup.+=209.

##STR00600##

Step 1: N-[7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide

[0745] N-(5-Bromo-7-methyl-1H-indol-3-yl)acetamide (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (213.9 mg, 0.8 mmol, 1.5 equiv.), KOAc (110.2 mg, 1.1 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (41.1 mg, 0.06 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 85° C. for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give N-[7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (100.0 mg) as a pale yellow solid. LCMS Method B: [M+H].sup.+=315.

Step 2: tert-butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate

[0746] N-[7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (50.0 mg, 0.2 mmol, 1.0 equiv.) and Boc.sub.2O (41.7 mg, 0.2 mmol, 1.2 equiv.) were dissolved in THE (5 mL), then TEA (0.1 mL, 0.3 mmol, 2.0 equiv.) and DMAP (4.0 mg, 0.03 mmol, 0.2 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:7) to give tert-butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (45.8 mg) as a pale yellow solid. LCMS Method B: [M+H].sup.+=415.

Step 3: tert-butyl 3-acetamido-5-hydroxy-7-methylindole-1-carboxylate

[0747] tert-Butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then aqueous NaOH (2% wt./wt., 2 mL, 1.0 mmol, 1.0 equiv.) was added. This was followed by the addition of H.sub.2O.sub.2 (30% wt./wt. in water, 0.5 mL, 5.0 mmol, 10.0 equiv.) dropwise at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (20:1) to give tert-butyl 3-acetamido-5-hydroxy-7-methylindole-1-carboxylate (60.0 mg) as a light yellow solid. LCMS Method B: [M+H].sup.+=305.

The intermediates in the following table were prepared using the same method described for Intermediate 46.

TABLE-US-00012 Intermediate Starting material Structure LCMS data Intermediate 47 [00601] embedded image [00602] Method A: MS-ESI: 292 [M + H].sup.+

##STR00603##

Step 1: N-(5-vinyl-1H-indol-3-yl)acetamide

[0748] N-(5-bromo-1H-indol-3-yl)acetamide (3.0 g, 11.9 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30 mL) and water (3 mL), then Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (1.9 g, 2.3 mmol, 0.2 equiv.), Cs.sub.2CO.sub.3 (7.7 g, 23.7 mmol, 2.0 equiv.) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.2 g, 14.2 mmol, 1.2 equiv.) were added under atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-(5-vinyl-1H-indol-3-yl)acetamide (1.5 g) as a brown solid. LCMS Method C: [M+H].sup.+=201.

Step 2: N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide

[0749] N-(5-vinyl-1H-indol-3-yl)acetamide (1.0 g, 5.0 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0° C., then BH.sub.3-THF (1 M, 20 mL, 20.0 mmol, 4.0 equiv.) was added dropwise. After 2 hours at ambient temperature, a solution of aqueous NaOH (1 M, 10 mL, 10.0 mmol, 2.0 equiv.) was added. This was followed by the addition of H.sub.2O.sub.2 (30% wt./wt. in water, 1.3 mL, 38.2 mmol, 7.6 equiv.), maintaining the reaction mixture at 0° C. The reaction mixture was stirred for an additional 30 min at 0° C., then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was adjusted to pH 6-7 with aqueousHCl (6M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (3:2) to give N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide (294.0 mg) as a pale brown solid. LCMS Method A: [M+H].sup.+=219.

The intermediates in the following table were prepared using the same method described for Intermediate 48.

TABLE-US-00013 Intermediate Starting material Structure LCMS data Intermediate 49 [00604] embedded image [00605] Method A: MS-ESI: 237 [M + H].sup.+ Intermediate 50 [00606] [00607] Method A: MS-ESI: 233 [M + H].sup.+ Intermediate 51 [00608] [00609] Method A: MS-ESI: 220 [M + H].sup.+ Intermediate 52 [00610] [00611] Method A: MS-ESI: 295 [M + H].sup.+ Intermediate 53 [00612] [00613] Method A: MS-ESI: 295 [M + H].sup.+ Intermediate 54 [00614] embedded image [00615] Method A: MS-ESI: 245 [M + H].sup.+ Intermediate 55 [00616] [00617] Method A: MS-ESI: 333 [M + H].sup.+

##STR00618##

Step 1: N1-(5-bromo-1H-indol-3-yl)-N2-methyloxalamide

[0750] 5-Bromo-1H-indol-3-amine (1.7 g, 8.0 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then TEA (3.3 mL, 24.1 mmol, 3.0 equiv.), 2-(methylamino)-2-oxoacetic acid (830.2 mg, 8.0 mmol, 1.0 equiv.) and T.sub.3P (50% wt., 3.84 g, 12.0 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 30 min at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N1-(5-bromo-1H-indol-3-yl)-N2-methyloxalamide (1.2 g) as a brown solid. LCMS Method A: [M+H].sup.+=296.

Step 2: tert-butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate

[0751] N1-(5-Bromo-1H-indol-3-yl)-N2-methyloxalamide (1.2 g, 4.0 mmol, 1.0 equiv.) was dissolved in DCM (12 mL), then DMAP (50.0 mg, 0.4 mmol, 0.1 equiv.) and (Boc).sub.2O (1.0 g, 4.8 mmol, 1.2 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (950.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=396

Step 3: tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate

[0752] tert-Butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (900.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), then (tributylstannyl)methanol (1823.2 mg, 5.6 mmol, 2.5 equiv.), butyl di-1-adamanthylphosphine (162.8 mg, 0.4 mmol, 0.20 equiv.) and CataCXium A-Pd-G2 (151.8 mg, 0.2 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (2:1) to give tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (750.0 mg) as an off-white solid. LCMS Method C: [M+H].sup.+=348.

The intermediates in the following table were prepared using the same method described for Intermediate 56.

TABLE-US-00014 Intermediate Starting material Structure LCMS data Intermediate 57 [00619] embedded image [00620] Method C: MS-ESI: 335 [M + H].sup.+

##STR00621## ##STR00622##

Step 1: 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine

[0753] 2-Chloro-4-methyl-5-nitropyridine (10 g, 57.9 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and cooled to −60° C., then bromo(ethenyl)magnesium (1M in THF, 173.8 mL, 173.8 mmol, 3.0 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at −60° C. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of saturated NH.sub.4Cl aqueous at 0° C. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (1.6 g) as a light yellow solid. LCMS Method A: [M+H].sup.+=167.

Step 2: 5-chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine

[0754] 5-Chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.0 mmol, 1.0 equiv.) was dissolved in H.sub.2SO.sub.4 (15 mL) and cooled to 0° C., then KNO.sub.3 (900.0 mg, 9.0 mmol, 1.5 equiv.) was added in portions, maintaining the solution at 0° C. The reaction mixture was stirred for 40 min at ambient temperature, then cooled to 0° C. and quenched by the addition of ice-water. The precipitated solids were collected by filtration, washed with ethyl acetate and dried under vacuum to give 5-chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (890.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=212.

Step 3: 5-chloro-7-methyl-1H-pyrrolo[3,2-b] pyridin-3-amine

[0755] 5-Chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (800.0 mg, 3.8 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pt/C (147.5 mg, 0.8 mmol, 0.2 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. This gave 5-chloro-7-methyl-1H-pyrrolo[3,2-b] pyridin-3-amine (550.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=182.

Step 4: N-{5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide

[0756] 5-Chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-amine (550.0 mg, 3.0 mmol, 1.0 equiv.) and TEA (0.8 mL, 6.1 mmol, 2.0 equiv.) were dissolved in THE (20 mL) and cooled to 0° C., then acetyl chloride (0.3 mL, 3.6 mmol, 1.2 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature, then quenched by the addition of MeOH. The resulting solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-{5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (600.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=224.

Step 5: N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide

[0757] N-{5-Chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (300.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in 1.4-dioxane (3 mL) and water (0.5 mL), then 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (398.5 mg, 2.0 mmol, 1.5 equiv.), Cs.sub.2CO.sub.3 (874.1 mg, 2.7 mmol, 2.0 equiv.), and Pd(dppf)Cl.sub.2 (196.3 mg, 0.3 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (200.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=260.

Step 6: N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide

[0758] N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and TFA (1 mL). The reaction mixture was stirred for 2 hours at 60° C., then cooled to ambient temperature and concentrated under vacuum to give N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (175.0 mg) as a brown solid, which was used in next step directly without further purification. LCMS Method A: [M+H].sup.+=232.

Step 7: N-[5-(2-hydroxyethyl)-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide

[0759] N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (175.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and cooled to 0° C., then NaBH.sub.4 (114.5 mg, 3.0 mmol, 3.8 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 100% gradient in 10 min; detector, UV 254 nm. This gave in N-[5-(2-hydroxyethyl)-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (85.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=234.

##STR00623##

Step 1: 1-tert-butyl 3-methyl 5-bromoindole-1,3-dicarboxylate

[0760] Methyl 5-bromo-1H-indole-3-carboxylate (5.0 g, 19.6 mmol, 1.0 equiv.) was dissolved in DCM (100 mL), then Boc.sub.2O (8.6 g, 39.3 mmol, 2.0 equiv.) and DMAP (480.8 mg, 3.9 mmol, 0.2 equiv.) were added. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 1-tert-butyl 3-methyl 5-bromoindole-1,3-dicarboxylate (6.5 g) as a white solid. LCMS Method A: [M+H].sup.+=354.

Step 2: 1-tert-butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate

[0761] 1-tert-Butyl 3-methyl 5-bromoindole-1,3-dicarboxylate (3.0 g, 8.4 mmol, 1.0 equiv.) and 1-propen-2-ol acetate (1.7 g, 16.9 mmol, 2.0 equiv.) were dissolved in toluene (60 mL), then Bu.sub.3SnOMe (3.2 g, 10.1 mmol, 1.2 equiv.), PdCl.sub.2 (0.3 g, 1.6 mmol, 0.2 equiv) and POT (0.6 g, 2.1 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 1-tert-butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate (2.5 g) as a white solid. LCMS Method A: [M+H].sup.+=332.

Step 3: 5-(2-oxopropyl)-1H-indole-3-carboxylic acid

[0762] 1-tert-Butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate (2.5 g, 7.5 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL) and water (4 mL), then KOH (0.8 g, 15.0 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 2 with aqueous HCl (2 N). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 5-(2-oxopropyl)-1H-indole-3-carboxylic acid (1.5 g) as a white solid. LCMS Method B: [M−H].sup.−=216.

Step 4: 5-(2-oxopropyl)-1H-indole-3-carbonyl azide

[0763] 5-(2-Oxopropyl)-1H-indole-3-carboxylic acid (1.5 g, 6.9 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then TEA (2.9 mL, 20.7 mmol, 3.0 equiv.) and DPPA (2.8 g, 10.3 mmol, 1.5 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum to give 5-(2-oxopropyl)-1H-indole-3-carbonyl azide (1.1 g) as a white solid, which was used in the next step directly without further purification. LCMS Method A: [M+H].sup.+=243.

Step 5: tert-butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate

[0764] 5-(2-Oxopropyl)-1H-indole-3-carbonyl azide (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in 2-methyl-2-propanol (30 mL). The reaction mixture was heated to 90° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, ACN in water (0.5% NH.sub.4HCO.sub.3), 0% ACN to 100% gradient in 15 min; detector, UV 254 nm. This gave tert-butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate (600.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=289.

Step 6: tert-butyl N-[5-(2-hydroxypropyl)-1H-indol-3-yl]carbamate

[0765] tert-Butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate (550.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then NaBH.sub.4 (144.3 mg, 3.8 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give tert-butyl N-[5-(2-hydroxypropyl)-1H-indol-3-yl]carbamate (550.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=291.

##STR00624##

[0766] 1-Iodo-4-(trifluoromethyl)benzene (1.0 g, 3.7 mmol, 1.0 equiv.) and azetidin-3-ol (0.5 g, 7.4 mmol, 2.0 equiv.) were dissolved in DMSO (5 mL), then L-proline (0.4 g, 3.7 mmol, 1.0 equiv.), K.sub.2CO.sub.3 (1.0 g, 7.4 mmol, 2.0 equiv.) and CuI (0.4 g, 1.8 mmol, 0.5 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C., then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-[4-(trifluoromethyl)phenyl]azetidin-3-ol (600.0 mg) as an off-white solid. LCMS Method B: [M+H].sup.+=218.

##STR00625##

[0767] [6-(Trifluoromethyl)pyridin-3-yl]acetic acid (4.8 g, 23.2 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to 0° C., then BH.sub.3-THF (1M, 69.5 mL, 69.5 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature, then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (95:5) to give 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (4.3 g) as a yellow oil. LCMS Method A: [M+H].sup.+=192.

The intermediates in the following table were prepared using the same method described for Intermediate 61.

TABLE-US-00015 Intermediate Starting material Structure LCMS data Intermediate 62 [00626] embedded image [00627] Method C: MS-ESI: 249 [M + H].sup.+

##STR00628##

Step 1: tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate

[0768] Triethyl phosphonoacetate (1.3 g, 5.7 mmol, 1.2 equiv.) was dissolved in THE (50 mL) and cooled to 0° C., then NaH (60% wt. in mineral oil, 0.3 g, 7.1 mmol, 1.5 equiv.). After 30 min at 0° C., tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 4.7 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g) as a yellow oil. LCMS Method A: [M+H].sup.+=282.

Step 2: ethyl 2-{2-azaspiro[3.3]heptan-6-ylidene}acetate TFA salt

[0769] tert-Butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 4.6 mmol, 1.0 equiv.) was dissolved in DCM (40 mL) and TFA (2 mL). The reaction mixture was stirred for 40 min at ambient temperature, then concentrated under vacuum to give in ethyl 2-{2-azaspiro[3.3]heptan-6-ylidene}acetate TFA salt (1.0 g) as a yellow oil. LCMS Method A: [M+H].sup.+=182.

Step 3: ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]acetate

[0770] Ethyl 2-{2-azaspiro[3.3]heptan-6-ylidene}acetate TFA salt (1.0 g, 5.5 mmol, 1.0 equiv.) was dissolved in ACN (40 mL), then K.sub.2CO.sub.3 (1.5 g, 11.0 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.4 g, 6.1 mmol, 1.1 equiv.) were added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]acetate (1.4 g) as a light yellow oil. LCMS Method A: [M+H].sup.+=264.

Step 4: ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate

[0771] Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]acetate (1.2 g, 4.6 mmol, 1.0 equiv.) was dissolved in MeOH (40 mL), then Pd/C (120.0 mg, 10% wt.) was added under an atmosphere of nitrogen. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate (260.0 mg) as a light yellow oil. LCMS Method A: [M+H].sup.+=266.

Step 5: 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethanol

[0772] Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate (260.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and cooled to 0° C., then LiAlH.sub.4 (74.4 mg, 2.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 60 min at ambient temperature, then cooled to 0° C. and quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethanol (210.0 mg) as a light yellow oil. LCMS Method A: [M+H].sup.+=224.

The intermediates in the following table were prepared using the same method described for Intermediate 63.

TABLE-US-00016 Intermediate Starting material Structure LCMS data Intermediate 64 [00629] embedded image [00630] Method C: MS-ESI: 238 [M + H].sup.+

##STR00631##

[0773] 1-[4-(Trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in THE (5 mL) and cooled to 0° C., then BH.sub.3-THF (1M, 4.3 mL, 4.3 mmol, 5.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature then concentrated under vacuum. The residue was diluted with of water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give [1-[4-(trifluoromethyl)phenyl]cyclopropyl]methanol (150.0 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=217.

##STR00632##

[0774] 1-[4-(Trifluoromethyl)phenyl]propan-2-one (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in MeOH (30 mL), then NaBH.sub.4 (0.2 g, 5.8 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 1-[4-(trifluoromethyl)phenyl]propan-2-ol (0.9 g) as a light yellow oil.

##STR00633##

[0775] 2-(Piperidin-3-yl)ethanol hydrochloride (2.0 g, 12.1 mmol, 1.0 equiv.) was dissolved in DMF (30 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.6 g, 24.2 mmol, 2.0 equiv.) and K.sub.2CO.sub.3 (3.3 g, 24.2 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 2-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]ethanol (1.4 g) as a yellow oil. LCMS Method A: [M+H].sup.+=212.

##STR00634##

Step 1: Ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate

[0776] Zinc powder (2.4 g, 37.3 mmol, 5.0 equiv.) was suspended in THE (25 mL) and cooled to 0° C., then I.sub.2 (1.9 g, 7.5 mmol, 1.0 equiv.) was added. After 10 min at 0° C., 4,4-difluorocyclohexan-1-one (1.0 g, 7.5 mmol, 1.0 equiv.) and ethyl 2-bromoacetate (1.5 g, 8.9 mmol, 1.2 equiv.) were added dropwise, maintaining the reaction mixture at 0° C. The reaction mixture was heated to 65° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of saturated aqueous NaHCO.sub.3. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (380.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=223.

Step 2: 4,4-difluoro-1-(2-hydroxyethyl)cyclohexan-1-ol

[0777] Ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (380.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then LiAlH.sub.4 (97.4 mg, 2.6 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of solid Na.sub.2SO.sub.4-10.H.sub.2O. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give 4,4-difluoro-1-(2-hydroxyethyl)cyclohexan-1-ol (120.0 mg) as colorless oil. LCMS Method A: [M+H].sup.+=181.

##STR00635##

Step 1: 3-phenylbicyclo[1.1.1]pentane-1-carbonyl chloride

[0778] 3-Phenylbicyclo[1.1.1]pentane-1-carboxylic acid (500.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled to 0° C., then (COCl).sub.2 (0.35 mL, 4.0 mmol, 1.5 equiv.) was added dropwise, maintaining the solution at 0° C. This was followed by the addition of DMF (0.03 mL, 0.3 mmol, 0.1 equiv.). The reaction mixture was stirred for 2.5 hours at ambient temperature, then concentrated under vacuum to give 3-phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (620 mg) as a yellow solid.

Step 2: 2-diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone

[0779] 3-Phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (600.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and ACN (10 mL) and cooled to 0° C. Then TEA (1.2 mL, 8.7 mmol, 3.0 equiv.) and TMSCHN.sub.2 (1.3 mg, 11.6 mmol, 4.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature and then quenched by the addition of saturated aqueous citric acid. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 2-diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone (610.0 mg) as a pale yellow solid.

Step 3: {3-phenylbicyclo[1.1.1]pentan-1-yl}acetic acid

[0780] 2-Diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone (600.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and H.sub.2O (5 mL), then TEA (1.6 mL, 11.3 mmol, 4.0 equiv.) and PhCO.sub.2Ag (129.5 mg, 0.6 mmol, 0.2 equiv.) were added. The reaction mixture was heated to 70° C. for 2 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient in 20 min; detector, UV 254 nm. This gave {3-phenylbicyclo[1.1.1]pentan-1-yl}acetic acid (330.0 mg) as a yellow solid. LCMS Method B: [M−H].sup.−=201.

Step 4: 2-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanol

[0781] {3-Phenylbicyclo[1.1.1]pentan-1-yl}acetic acid (300.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then BH.sub.3.THF (1M, 1.5 mL, 1.5 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated under vacuum. The residue was diluted with of water, extracted with ethyl acetate and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient in 20 min; detector, UV 254 nm. This gave 2-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanol (130.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=189.

##STR00636##

[0782] 2-Chloro-5-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), then 2-(piperidin-4-yl)ethan-1-ol (850 mg, 6.6 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (1.5 g, 11.0 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 70° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. Then resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/MeOH (10:1) to give 2-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (980 mg) as a white solid. LCMS Method A: [M+H].sup.+=275.

##STR00637##

Step 1: 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine

[0783] 5-Bromo-2,3-difluoropyridine (4.0 g, 20.6 mmol, 1.0 equiv.) and 4,4-difluoropiperidine (2.7 g, 22.7 mmol, 1.1 equiv.) were dissolved in DMF (20 mL), then K.sub.2CO.sub.3 (5.7 g, 41.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:9) to give 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (4.5 g) as a yellow solid. LCMS Method A: [M+H].sup.+=295.

Step 2: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine

[0784] 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (3.0 g, 10.2 mmol, 1.0 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 12.2 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (30 mL), then Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.4 g, 0.5 mmol, 0.05 equiv.) and Cs.sub.2CO.sub.3 (6.6 g, 20.3 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:7) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine (1.1 g) as a yellow oil. LCMS Method A: [M+H].sup.+=243.

Step 3: 2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)ethan-1-ol

[0785] 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in THE and cooled to 0° C., then BH.sub.3-THF (1M, 16.5 mL, 16.5 mmol, 4.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature. Then a solution of aqueous NaOH (1 M, 2.9 mL, 2.9 mmol, 0.7 equiv.) was added and the reaction mixture was cooled to 0° C. This was followed by the dropwise addition of H.sub.2O.sub.2 (30% wt./wt. in water, 4.8 mL, 7.2 mmol, 1.8 equiv.), maintaining the reaction mixture at 0° C. The reaction mixture was stirred for additional 1 hour at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/MeOH (10:1) to give 2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)ethan-1-ol (880.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=261.

[0786] The intermediates in the following table were prepared using the same method described for Intermediate 71.

TABLE-US-00017 Intermediate Starting material Structure LCMS data Intermediate 72 [00638] embedded image [00639] Method A: MS-ESI: 308 [M + H].sup.+

##STR00640##

Step 1: 1-bromo-4-(3,3-difluorocyclobutyl)benzene

[0787] 3-(4-Bromophenyl)cyclobutan-1-one (1.0 g, 4.4 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled to 0° C., then DAST (2.2 g, 13.3 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at 40° C., then cooled to 0° C. and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 1-bromo-4-(3,3-difluorocyclobutyl)benzene (870.0 mg) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.53 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 3.47-3.35 (m, 1H), 3.08-2.90 (m, 2H), 2.74-2.57 (m, 2H).

Step 2: 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0788] 1-Bromo-4-(3,3-difluorocyclobutyl)benzene (800.0 mg, 3.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (150 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.2 g, 4.9 mmol, 1.5 equiv.), Pd(dppf)Cl.sub.2 (236.9 mg, 0.3 mmol, 0.1 equiv.) and KOAc (635.5 mg, 6.5 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (805.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=295.

Step 3: 4-(3,3-difluorocyclobutyl)phenol

[0789] 2-(4-(3,3-Difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then aqueous NaOH (2% wt./wt., 10 mL, 5.0 mmol, 2.0 equiv.) and H.sub.2O.sub.2 (30% wt./wt., 1.0 mL, 8.8 mmol, 3.0 equiv.) were added dropwise. The reaction mixture was stirred for additional 2 hours at ambient temperature, then quenched by the addition of saturated NH.sub.4C.sub.1 aqueous. The mixture was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-(3,3-difluorocyclobutyl)phenol (320.0 mg) as a colorless oil. LCMS Method B: [M−H].sup.+=183.

##STR00641##

Step 1: 4-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran

[0790] 1-(Benzyloxy)-4-bromobenzene (1.0 g, 3.8 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (10 mL), then 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.7 mmol, 1.5 equiv.), Cs.sub.2CO.sub.3 (2.5 g, 7.6 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (309.0 mg, 0.4 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 6 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:8) to give 4-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran (712.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=267.

Step 2: 4-(oxan-4-yl)phenol

[0791] 4-[4-(Benzyloxy)phenyl]-3,6-dihydro-2H-pyran (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), then Pd/C (10% wt., 50.0 mg) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 5 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-(oxan-4-yl)phenol (150.0 mg) as a pale yellow solid. LCMS Method B: [M−H].sup.−=177.

The intermediates in the following table were prepared using the same method described for Intermediate 74.

TABLE-US-00018 Intermediate Starting material Structure LCMS data Intermediate 75 [00642] embedded image [00643] Method C: MS-ESI: 213 [M + H].sup.+ Intermediate 76 [00644] [00645] Method C: MS-ESI: 260 [M + H].sup.+

##STR00646##

Step 1: 4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol

[0792] 1-(2,2,2-Trifluoroethyl)piperidin-4-one (1.0 g, 5.5 mmol, 1.0 equiv.) was dissolved in Et.sub.2O (40 mL) and cooled to −55° C., then MeMgBr (1M in THF, 11.0 mL, 11.0 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at −5° C. The reaction mixture was stirred for 4 hours at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl at 0° C. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol (1.0 g) as a pale yellow oil. LCMS Method A: [M+H].sup.+=198.

Step 2: 2-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol

[0793] 4-Methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol (600.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in CF.sub.3SO.sub.3H (5 mL), then phenol (859.0 mg, 9.1 mmol, 3.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 100% gradient in 15 min; Detector, UV 254 nm. This gave 2-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol (170.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=274.

##STR00647##

Step 1: 4-methylidenepiperidine TFA salt

[0794] tert-Butyl 4-methylidenepiperidine-1-carboxylate (2.0 g, 10.1 mmol, 1.0 equiv.) was dissolved in DCM (40 mL), then TFA (3.1 mL, 40.6 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum to give 4-methylidenepiperidine TFA as a yellow solid, which was used in the next step directly without further purification. LCMS Method A: [M+H].sup.+=98.

Step 2: 2,2,2-trifluoro-1-(4-methylenepiperidin-1-yl)ethan-1-one

[0795] 4-Methylidenepiperidine (1.0 g, 10.3 mmol, 1.0 equiv.) and TEA (2.9 mL, 20.6 mmol, 2.0 equiv.) were dissolved in ACN (10 mL), then TFAA (2.9 mL, 20.6 mmol, 2.0 equiv.) was added dropwise. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 2,2,2-trifluoro-1-(4-methylidenepiperidin-1-yl)ethanone (710.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=194.

Step 3: 2,2,2-trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone

[0796] 2,2,2-Trifluoro-1-(4-methylidenepiperidin-1-yl)ethanone (700.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in CF.sub.3SO.sub.3H (10 mL), then phenol (1.0 g, 10.9 mmol, 3.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of ice-water. The resulting solution was adjusted to pH 6 with aqueous NaOH (20% wt./wt), extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 5% to 100% gradient in 25 min; detector, UV 254 nm. This gave 2,2,2-trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone (180.0 mg) as a yellow oil. LCMS Method B: [M−H].sup.−=286.

Step 4: 4-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol

[0797] 2,2,2-Trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone (180.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and cooled to 0° C., then BH.sub.3.THF (1M, 2.5 mL, 2.5 mmol, 4.0 equiv.) was added dropwise. The reaction mixture was heated to 70° C. for 1 hour, then cooled to 0° C. and quenched by the addition of MeOH. The resulting solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:8) to give 4-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol (150.0 mg) as a light yellow oil. LCMS Method B: [M−H].sup.−=272.

##STR00648##

[0798] 4-(Trifluoromethyl)-1H-pyrazole (500.0 mg, 3.7 mmol, 1.0 equiv.) and 2-bromoethanol (918.3 mg, 7.3 mmol, 2.0 equiv.) were dissolved in DMF (5 mL), then Cs.sub.2CO.sub.3 (2.4 g, 7.3 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mM NH.sub.4HCO.sub.3), 10% ACN to 50% gradient in 10 min; detector, UV 254 nm. This gave 2-[4-(trifluoromethyl)pyrazol-1-yl]ethanol (310.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=181.

##STR00649##

Step 1: ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate

[0799] 3-(Trifluoromethyl)-1H-pyrazole (2.0 g, 14.7 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), then K.sub.2CO.sub.3 (4.1 g, 29.4 mmol, 2.0 equiv.) and ethyl bromoacetate (2.5 g, 14.7 mmol, 1.0 equiv.) were added. The reaction mixture was heated to 60° C. for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate (1.8 g) as a yellow solid. LCMS Method A: [M+H].sup.+=223.

Step 2: 2-[3-(trifluoromethyl)pyrazol-1-yl]ethanol

[0800] Ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate (800.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then LiAlH.sub.4 (164.0 mg, 4.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 2 hours at 0° C. and then quenched by the addition of saturated aqueous sodium hyposulfite. The solid was removed by filtration, and the filtrate was concentrated under vacuum to give 2-[3-(trifluoromethyl)pyrazol-1-yl]ethanol (560.0 mg) as a yellow oil, which was used in the next step directly without further purification. LCMS Method A: [M+H].sup.+=181.

##STR00650##

Step 1: tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate

[0801] tert-Butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in THE (3 mL), then phthalimide (277.3 mg, 1.9 mmol, 2.0 equiv.) and PPh.sub.3 (494.3 mg, 1.9 mmol, 2.0 equiv.) were added. The reaction mixture was cooled to 0° C., then DIAD (381.1 mg, 1.9 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 6 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 5-[2-(1,3-dioxoisoindol-2-yl)ethyl]-3-acetamidoindole-1-carboxylate (340.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=448.

Step 2: tert-butyl 5-(2-aminoethyl)-3-acetamidoindole-1-carboxylate

[0802] tert-Butyl 5-[2-(1,3-dioxoisoindol-2-yl)ethyl]-3-acetamidoindole-1-carboxylate (310.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in EtOH (3.5 mL), then hydrazine (44.4 mg, 1.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 5 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give crude tert-butyl 5-(2-aminoethyl)-3-acetamidoindole-1-carboxylate (280.0 mg) as brown solid. LCMS Method A: [M+H].sup.+=318.

The intermediate in the following table were prepared using the same method described for Intermediate 81.

TABLE-US-00019 Intermediate Starting material Structure LCMS data Intermediate 82 [00651] embedded image [00652] Method A: MS-ESI: 304 [M + H].sup.+

##STR00653##

[0803] [4-(Trifluoromethyl)phenyl]methanol (5.0 g, 28.4 mmol, 1.0 equiv.) was dissolved in THE (50 mL) and cooled to 0° C., then NaH (60% wt., 1.4 g, 34.1 mmol, 1.2 equiv.) was added. After 30 min at 0° C., tributyl(iodomethyl)stannane (13.4 g, 31.2 mmol, 1.1 equiv.) was added. The reaction mixture was stirred for an additional 4 hours at ambient temperature, then cooled to 0° C. and quenched by the addition of MeOH. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/petroleum ether (5:1) to give tributyl({[4-(trifluoromethyl)phenyl]methoxy}methyl)stannane (9.5 g) as a colorless oil. LCMS Method A: [M+H].sup.+=481.

##STR00654##

Step 1: tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate

[0804] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.1 mmol, 1.0 equiv.) was dissolved in THE (80.0 mL), then (Boc).sub.2O (4.2 g, 19.3 mmol, 1.2 equiv.), DMAP (0.2 g, 1.6 mmol, 0.1 equiv.) and TEA (4.6 mL, 32.1 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.5 g) as a white solid.

Step 2: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

[0805] tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.0 g, 14.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100.0 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.6 g, 21.9 mmol, 1.5 equiv.), Pd(dppf)Cl.sub.2 (1.1 g, 1.5 mmol, 0.1 equiv.) and Cs.sub.2CO.sub.3 (9.5 g, 29.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C. under nitrogen, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g) as a white solid.

Step 3: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate

[0806] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g, 13.1 mmol, 1.0 equiv.) was dissolved in THE (80.0 mL) and cooled to 0° C. Then NaOH (1.6 g, 39.3 mmol, 3.0 equiv.) was added at 0° C., followed by the dropwise addition of H.sub.2O.sub.2 (30% w.t/wt/, 3.0 g, 26.2 mmol, 2.0 equiv), maintaining the reaction mixture at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of brine. The resulting resolution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (2.2 g) as a grey solid.

Step 4: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate

[0807] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.) and cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.2 g, 5.7 mmol, 2.0 equiv.) were dissolved in THE (20.0 mL) and cooled to 0° C., then TBUP (1.7 g, 8.6 mmol, 3.0 equiv.) was added at 0° C. under an atmosphere of nitrogen. This was followed by the dropwise addition of ADDP (2.2 g, 8.6 mmol, 3.0 equiv.), maintaining the solution at 0° C. The reaction mixture was heated to 50° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 45% phase B to 70% gradient in 20 min; detector, UV 254 nm. This gave tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.2 g) as an off-white solid.

Step 5: 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt

[0808] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (190.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DCM (2.0 mL), then TFA (2.0 mL) was added. The resulting mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum to give 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (120.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=347.

The intermediates in the following table were prepared using the same method described for Intermediate 85.

TABLE-US-00020 Intermediate Starting material Structure LCMS data Intermediate 86 [00655] embedded image [00656] Method A: MS-ESI: 347 [M + H].sup.+ Intermediate 87 [00657] [00658] Method A: MS-ESI: 348 [M + H].sup.+ Intermediate 88 [00659] [00660] Method C: MS-ESI: 322 [M + H] .sup.+ Intermediate 89 [00661] [00662] Method C: MS-ESI: 391 [M + H].sup.+ Intermediate 90 [00663] [00664] Method C: MS-ESI: 368 [M + H].sup.+ Intermediate 91 [00665] embedded image [00666] Method C: MS-ESI: 307 [M + H].sup.+

##STR00667##

Step 1-2: tert-butyl(5-(2-hydroxyethyl)-1H-indol-3-yl)carbamate

[0809] The title compound was prepared using the same methods described for Intermediate 48 (Step 1 to 2). LCMS Method A: [M+H].sup.+=277.

Step 3: tert-butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate

[0810] tert-Butyl N-[5-(2-hydroxyethyl)-1H-indol-3-yl]carbamate (338.0 mg, 1.2 mmol, 1.0 equiv.) and 4-(trifluoromethyl)phenol (198.2 mg, 1.2 mmol, 1.0 equiv.) were dissolved in THE (10 mL), then ADDP (612.4 mg, 2.4 mmol, 2.0 equiv.) and TBUP (494.9 mg, 2.4 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 70° C. for 5 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate (260.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=421.

Step 4: 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt

[0811] tert-Butyl N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)carbamate (260.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DCM (2 mL) and TFA (2 mL). The reaction mixture was stirred for 30 min at ambient temperature then concentrated under vacuum to give 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt (350.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=321.

The intermediates in the following table were prepared using the same method described for Intermediate 92.

TABLE-US-00021 Starting Starting LCMS Intermediate material A material B Structure data Intermediate 93 [00668] embedded image [00669] [00670] Method A: MS-ESI: 335 [M + H].sup.+ Intermediate 94 [00671] [00672] [00673] Method C: MS-ESI: 339 [M + H].sup.+ Intermediate 95 [00674] [00675] [00676] Method C: MS-ESI: 339 [M + H].sup.+

##STR00677## ##STR00678##

Step 1: 4-methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine

[0812] 2-[4-(Trifluoromethyl)phenyl]ethanol (5.0 g, 26.3 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0° C., then 4-methyl-5-nitropyridin-2-ol (4.1 g, 26.3 mmol, 1.0 equiv.) and DIAD (10.6 g, 52.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 6 hours at ambient temperature under an atmosphere of nitrogen, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine (6.2 g) as a pale yellow solid. LCMS Method A: [M+H].sup.+=327.

Step 2: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine

[0813] 4-Methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine (1.0 g, 3.15 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to −60° C., then bromo(ethenyl)magnesium (1M in THF, 70.0 mL, 70.0 mmol, 22 equiv.) was added dropwise, maintaining the solution at −60° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 8 hours at ambient temperature and then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine (380.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=321.

Step 3: 2,2,2-trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone

[0814] 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine (500.0 mg, 1.6 mmol, 1 equiv.) and Pyridine (246.9 mg, 3.1 mmol, 2.0 equiv.) were dissolved in CHCl.sub.3 (20 mL), then trichloroacetyl chloride (851.4 mg, 4.7 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was heated to 65° C. for 2 days, then concentrated vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 5% to 100% gradient in 10 min; detector, UV 254 nm. This gave 2,2,2-trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (130.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=465.

Step 4: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

[0815] 2,2,2-Trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (220.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and water (3 mL), then NaOH (37.8 mg, 0.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 65° C. for 1 hour, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and then adjusted to pH 5 with aqueous HCl (4M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (150.0 mg) as a yellow solid. LCMS Method B: [M−H].sup.+=363.

Step 5: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide

[0816] 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THE (15 mL), then TEA (0.1 mL, 0.8 mmol, 2.0 equiv.) and DPPA (226.6 mg, 0.8 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 6 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (150.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=390.

Step 6: tert-butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate

[0817] 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in toluene (3 mL), then t-BuOH (142.8 mg, 1.9 mmol, 5 equiv.) was added. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 5% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (50.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=436.

Step 7: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-amine TFA salt

[0818] tert-Butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl) carbamate (50.0 mg, 0.1 mmol, 1.0 equiv.) was dissolved in DCM (2 mL) and TFA (0.5 mL). The reaction mixture was stirred for 50 min at ambient temperature and then concentrated under vacuum to give crude 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-amine TFA salt (35.0 mg) as a light yellow solid. LCMS Method A: [M+H].sup.+=336.

The intermediates in the following table were prepared using the same method described for Intermediate 96.

TABLE-US-00022 Intermediate Structure LCMS data Intermediate 97 [00679] embedded image Method A: MS-ESI: 322 [M+H].sup.+

##STR00680##

Step 1: 1-(prop-2-en-1-yl)-4-(trifluoromethyl)pyrazole

[0819] 4-(Trifluoromethyl)-1H-pyrazole (500.0 mg, 3.6 mmol, 1.0 equiv.) and K.sub.2CO.sub.3 (1.0 g, 7.3 mmol, 2.0 equiv.) was dissolved in ACN (10 mL), then allyl bromide (666.7 mg, 5.5 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 100° C. for 2 hours and then cooled to ambient temperature. After removing the solid by filtration, the filtrate was used in the next step directly without further manipulation. LCMS Method A: [M+H].sup.+=165.

Step 2: tert-butyl N-{5-[(1E)-3-[4-(trifluoromethyl)pyrazol-1-yl]prop-1-en-1-yl]-1H-indol-3-yl}carbamate

[0820] To the above solution of 1-(prop-2-en-1-yl)-4-(trifluoromethyl)pyrazole in ACN (10 mL), tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (1.3 g, 4.2 mmol, 1.5 equiv.), TEA (0.8 mL, 5.6 mmol, 2.0 equiv.), POT (172.8 mg, 0.5 mmol, 0.2 equiv.) and Pd(OAc).sub.2 (127.4 mg, 0.5 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 5 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-{5-[(1E)-3-[4-(trifluoromethyl)pyrazol-1-yl]prop-1-en-1-yl]-1H-indol-3-yl}carbamate (370.0 mg) as a brown oil. LCMS Method A: [M+H].sup.+=407.

Step 3: tert-butyl N-(5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-yl)carbamate

[0821] tert-Butyl N-{5-[(1E)-3-[4-(trifluoromethyl)pyrazol-1-yl]prop-1-en-1-yl]-1H-indol-3-yl}carbamate (300 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), placed under an atmosphere of nitrogen, then Pd/C (10% wt., 60.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl N-(5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-yl)carbamate (250.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=409.

Step 4: 5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-amine TFA salt

[0822] tert-Butyl N-(5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-yl)carbamate (210.0 mg, 0.5 mmol, 1 equiv.) was dissolved in DCM (15 mL) and TFA (5 mL). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum. This gave 5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-amine TFA salt (150.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=309.

##STR00681##

Step 1: 1-(2,2,2-trifluoroethyl)piperidin-4-ol

[0823] Piperidin-4-ol (1.0 g, 9.9 mmol, 1.0 equiv.) was dissolved in ACN (6 mL), then K.sub.2CO.sub.3 (2.7 g, 19.8 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.8 g, 11.9 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 70° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give 1-(2,2,2-trifluoroethyl)piperidin-4-ol (1.5 g) as a colorless oil. LCMS Method A: [M+H].sup.+=184.

Step 2: 4-(ethenyloxy)-1-(2,2,2-trifluoroethyl)piperidine

[0824] 1-(2,2,2-Trifluoroethyl)piperidin-4-ol (1.0 g, 5. mmol, 1.0 equiv.) was dissolved in toluene (5 mL), then vinyl acetate (0.9 g, 10.9 mmol, 2.0 equiv.), Na.sub.2CO.sub.3 (1.2 g, 10.9 mmol, 2.0 equiv.) and [Ir(cod)Cl].sub.2 (0.4 g, 0.5 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:6) to give 4-(ethenyloxy)-1-(2,2,2-trifluoroethyl)piperidine (500.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=210.

##STR00682##

Step 1: ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate

[0825] Ethyl 2-methyl-2-(piperidin-4-yl)propanoate (2.0 g, 10.0 mmol, 1.0 equiv.) was dissolved in ACN (30 mL), then TEA (2.8 mL, 20.1 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.8 g, 12.0 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (2.3 g) as a colorless oil. LCMS Method A: [M+H].sup.+=282.

Step 2: 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol

[0826] Ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (2.3 g, 8.2 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then LiAlH.sub.4 (0.9 g, 24.5 mmol, 3.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 6 hours at ambient temperature and then quenched by the addition of MeOH. The resulting mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol (1.1 g) as a yellow oil. LCMS Method A: [M+H].sup.+=240.

Step 3: 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanal

[0827] Oxalyl chloride (1.0 mL, 11.5 mmol, 2.5 equiv.) was dissolved in DCM (30 mL) and cooled to −70° C., then DMSO (1.6 mL, 23.0 mmol, 5.0 equiv.) was added dropwise, maintaining the solution at −70° C. After 30 min at −70° C., a solution of 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol (1.1 g, 4.6 mmol, 1.0 equiv.) in DCM (10 mL) was added dropwise. The reaction mixture was stirred for an additional 4 hours at −70° C. This was followed by the addition of TEA (6.4 mL, 46.0 mmol, 10.0 equiv.). The reaction mixture was allowed to warm to ambient temperature and stir for 1 hour, then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum.

[0828] The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanal (510.0 mg) as a pale yellow oil. LCMS Method A: [M+H].sup.+=238.

Step 4: 4-(2-methylbut-3-en-2-yl)-1-(2,2,2-trifluoroethyl)piperidine

[0829] Methyltriphenylphosphanium bromide (2.3 g, 6.4 mmol, 3.0 equiv.) was dissolved in THF (25 mL), then NaHMDS (1.2 g, 6.4 mmol, 3.0 equiv.) was added. After 30 min, 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanal (510.0 mg, 2.1 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-(2-methylbut-3-en-2-yl)-1-(2,2,2-trifluoroethyl)piperidine (310.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=236.

##STR00683##

Step 1: ethyl 1-(3,3,3-trifluoropropyl)azetidine-3-carboxylate

[0830] Ethyl azetidine-3-carboxylate hydrochloride (2.6 g, 15.5 mmol, 1.0 equiv.) and 1,1,1-trifluoro-3-iodopropane (2.9 g, 13.3 mmol, 0.9 equiv.) were dissolved in ACN (10 mL), then K.sub.2CO.sub.3 (5.0 g, 36.4 mmol, 2.3 equiv.) was added. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give ethyl 1-(3,3,3-trifluoropropyl)azetidine-3-carboxylate (1.8 g) as a yellow oil. LCMS Method A: [M+H]+=226.

Step 2: 1-(3,3,3-trifluoropropyl)azetidine-3-carboxylic acid

[0831] Ethyl 1-(3,3,3-trifluoropropyl)azetidine-3-carboxylate (1.0 g, 4.4 mmol, 1.0 equiv.) was dissolved in THF/H.sub.2O (10/1 mL), LiOH (0.3 g, 13.4 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 6 hours at ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 4 with aqueous HCl (6M). The resulting solution was extracted with DCM and concentrated under vacuum to give crude 1-(3,3,3-trifluoropropyl)azetidine-3-carboxylic acid (1.2 g) as a yellow oil. LCMS Method A: [M−H].sup.−=196.

##STR00684##

Step 1: 5-bromo-1H-indol-3-amine hydrochloride

[0832] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred for 2 hours at rt and then concentrated under vacuum to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A: [M+H].sup.+=211.2.

Step 2: N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide

[0833] Cyclopropanecarboxylic acid (172.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in DCM (20 mL), then DIEA (1.0 mL, 6.0 mmol, 3.0 equiv.), HATU (1.1 g, 3.0 mmol, 1.5 equiv.) and 5-bromo-1H-indol-3-amine hydrogen chloride (500.0 mg, 2.0 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1) to give N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide (510.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=279.2.

Step 3: tert-butyl 5-bromo-3-(cyclopropanecarboxamido)-1H-indole-1-carboxylate

[0834] N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide (200.0 mg, 0.7 mmol, 1.0 equiv.) and (Boc).sub.2O (156.3 mg, 0.7 mmol, 1.0 equiv.) were dissolved in THE (10 mL), then DMAP (8.7 mg, 0.07 mmol, 0.1 equiv.) and TEA (0.2 mL, 1.4 mmol, 2.0 equiv.) were added. The reaction mixture was stirred overnight at rt and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol/L NH.sub.4HCO.sub.3), 30% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 5-bromo-3-(cyclopropanecarboxamido)-1H-indole-1-carboxylate (106.0 mg) as a brown yellow oil. LCMS Method A: [M+H]+=379.2.

Step 4: tert-butyl 3-(cyclopropanecarboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

[0835] tert-Butyl 5-bromo-3-cyclopropaneamidoindole-1-carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) and bis(pinacolato)diboron (200.9 mg, 0.8 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (10 mL), then Pd(dppf)Cl.sub.2 (38.6 mg, 0.05 mmol, 0.1 equiv.) and KOAc (103.5 mg, 1.05 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C., then cooled to rt and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:7) to give tert-butyl 3-(cyclopropanecarboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (186.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=427.2.

Step 5: tert-butyl 3-(cyclopropanecarboxamido)-5-hydroxy-1H-indole-1-carboxylate

[0836] tert-Butyl 3-(cyclopropanecarboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and cooled to 0° C., then a solution of NaOH in water (30% wt./wt., 4.0 mL, 3.5 mmol, 2.0 equiv.) was added. This was followed by the addition of H.sub.2O.sub.2 (30% wt./wt. in water, 0.3 mL, 2.4 mmol, 2.0 equiv.) dropwise at 0° C. The reaction mixture was stirred overnight at rt and then concentrated under vacuum. The residue was diluted with water, extracted with EtOAc, washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (20:1) to give tert-butyl 3-(cyclopropanecarboxamido)-5-hydroxy-1H-indole-1-carboxylate (161.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=317.2.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 103.

TABLE-US-00023 Intermediate Starting material Structure LCMS data Intermediate 104 [00685] embedded image [00686] Method A: MS-ESI: 292.0 [M + H].sup.+

##STR00687##

Step 1: 3-(benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol

[0837] 5-Bromo-2-(trifluoromethyl)pyridine (4.0 g, 17.6 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and cooled to −70° C., then n-BuLi (2.5M in hexane, 8.5 mL, 21.3 mmol, 1.2 equiv.) added dropwise, maintaining the solution at −70° C. under an atmosphere of nitrogen. After stirred for 30 min at −70° C., 3-(benzyloxy)cyclobutan-1-one (3.7 g, 21.2 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred for additional 2 hours at rt and then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash column with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.5% NH.sub.4HCO.sub.3), 10% to 100% gradient in 25 min; detector, UV 254 nm. This resulted in 3-(benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (2.7 g) as a pale yellow solid. LCMS Method A: [M+H].sup.+=324.2.

Step 2: 5-(3-(benzyloxy)-1-fluorocyclobutyl)-2-(trifluoromethyl)pyridine

[0838] 3-(Benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (2.7 g, 8.3 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to −70° C., then DAST (2.6 g, 16.6 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at −70° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash column with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH.sub.4HCO.sub.3), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 5-(3-(benzyloxy)-1-fluorocyclobutyl)-2-(trifluoromethyl)pyridine (2.5 g) as a pale yellow solid. LCMS Method A: [M+H].sup.+=326.0

Step 3: 3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol

[0839] 5-[3-(Benzyloxy)-1-fluorocyclobutyl]-2-(trifluoromethyl)pyridine (2.0 g, 6.1 mmol, 1.0 equiv.) was dissolved in MeOH (40 ml), then HCOOH (282.9 mg, 6.1 mmol, 1.0 equiv.) was added. This was followed by the addition of Pd/C (10% wt., 130.8 mg) under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 4 hours at 40° C. The solids were removed by filtration and the filter cake was washed with MeOH. The combined filtrate was concentrated under vacuum. The residue was purified by reverse flash column with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH.sub.4HCO.sub.3), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (1.0 g) as a pale yellow oil. LCMS Method A: [M+H].sup.+=261.0.

Step 4: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate and tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(cis-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate

[0840] 3-[6-(Trifluoromethyl)pyridin-3-yl]cyclobutan-1-ol (1.0 g, 4.6 mmol, 1.0 equiv.) was dissolved in THE (13 mL), then tert-butyl 3-[(tert-butoxycarbonyl)amino]-5-hydroxyindole-1-carboxylate (1.6 g, 4.6 mmol, 1.0 equiv.), TBUP (1.8 g, 9.2 mmol, 2.0 equiv.) and ADDP (2.3 g, 9.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 5 hours at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH.sub.4HCO.sub.3), 10% to 100% gradient in 25 min; detector, UV 254 nm. This resulted in tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (1.0 g) as a pale yellow solid. The mixture was separated by Chiral-HPLC with the following conditions: Column: JW-CHIRAL-Amylose-SA, 20*250 mm, 5 um; Mobile Phase A: IPA-HPLC, Mobile Phase B: Hex (0.5% 2M NH.sub.3-MeOH)-HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 14 min; Wave Length: 220/254 nm; RT1: 8.2 min; RT2: 10.22 min. This resulted in tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(cis-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (710.0 mg) as a pale yellow solid. LCMS Method B: [M−H].sup.−=548. And tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (170.0 mg) as a pale yellow solid. LCMS Method B: [M−H].sup.−=548.1.

Step 5: 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt

[0841] tert-Butyl 3-[(tert-butoxycarbonyl)amino]-5-[trans-3-[6-(trifluoromethyl)pyridin-3-yl]cyclobutoxy]indole-1-carboxylate (160.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (2 mL) was added. The reaction mixture was stirred for 1 hours at rt and then concentrated under vacuum to give crude 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt (103.0 mg) as a red solid. LCMS Method B: [M+H].sup.+=348.2.

##STR00688##

[0842] tert-Butyl 3-[(tert-butoxycarbonyl)amino]-5-[cis-3-[6-(trifluoromethyl)pyridin-3-yl]cyclobutoxy]indole-1-carboxylate (500.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), then TFA (3 mL) was added. The reaction mixture was stirred for 1 hour at rt and then concentrated under vacuum to give crude 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt (400.0 mg) as a brown solid. LCMS Method B: [M+H].sup.+=348.2

##STR00689##

Step 1: tert-butyl 5-allyl-3-((tert-butoxycarbonyl) amino)-1H-indole-1-carboxylate

[0843] tert-Butyl 5-bromo-3-((tert-butoxycarbonyl) amino)-1H-indole-1-carboxylate (4.0 g, 9.7 mmol, 1.0 equiv.), 2-(but-3-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 19.5 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (120 mL) and H.sub.2O (12 mL), then Cs.sub.2CO.sub.3 (6.3 g, 19.5 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (0.7 g, 1.0 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 4 hours at 90° C., then cooled to rt and concentrated under vacuum. The residue was diluted with water, extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 5-allyl-3-((tert-butoxycarbonyl) amino)-1H-indole-1-carboxylate (3.3 g) as a white solid. LCMS Method A: [M+H].sup.+=373.2.

Step 2: tert-butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) allyl)-1H-indole-1-carboxylate

[0844] tert-Butyl 5-allyl-3-((tert-butoxycarbonyl) amino)-1H-indole-1-carboxylate (1.8 g, 4.8 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.2 g, 14.5 mmol, 3.0 equiv.) were dissolved in DCM (10 mL), then Grubbs 2nd (410.2 mg, 0.5 mmol, 0.1 equiv.) was added under an atmosphere of nitrogen. The reaction mixture was stirred for 3 days at 50° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give tert-butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) allyl)-1H-indole-1-carboxylate (900 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=499.2.

Step 3: tert-butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) allyl)-1H-indole-1-carboxylate

[0845] tert-Butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) allyl)-1H-indole-1-carboxylate (900.0 mg, 1.8 mmol, 1.0 equiv.) and 2-iodo-5-(trifluoromethyl) pyridine (985.8 mg, 3.6 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (10 mL) and H.sub.2O (1 mL), then Pd(dppf)Cl.sub.2 (264.2 mg, 0.4 mmol, 0.2 equiv.) and Cs.sub.2CO.sub.3 (1.8 g, 5.4 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C., then cooled to rt and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (3:1) to give tert-butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) allyl)-1H-indole-1-carboxylate (450.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=518.2.

Step 4: tert-butyl 3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) propyl)-1H-indole-1-carboxylate

[0846] tert-Butyl (E)-3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) allyl)-1H-indole-1-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt, 10 mg) was added under an atmosphere of nitrogen.

[0847] The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at rt. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl 3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) propyl)-1H-indole-1-carboxylate (60.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=520.2.

Step 5: 5-(3-(5-(trifluoromethyl) pyridin-2-yl) propyl)-1H-indol-3-amine TFA salt

[0848] tert-Butyl 3-((tert-butoxycarbonyl) amino)-5-(3-(5-(trifluoromethyl) pyridin-2-yl) propyl)-1H-indole-1-carboxylate (60.0 mg, 0.1 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (0.4 mL) was added. The reaction mixture was stirred for 1 hour at rt and concentrated under vacuum to give crude 5-(3-(5-(trifluoromethyl) pyridin-2-yl) propyl)-1H-indol-3-amine TFA salt (65.0 mg) as a yellow oil, that was used in the next step directly without further purification. LCMS Method B: [M+H].sup.+=320.2.

##STR00690##

Step 1: tert-butyl 3-acetylpyrrolidine-1-carboxylate

[0849] tert-Butyl 3-acetylpyrrolidine-1-carboxylate (2.0 g, 9.4 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to −10° C., then MeMgBr (3M in THF, 6.3 mL, 18.9 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at −10° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at 0° C., then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/petroleum ether (5:1) to give tert-butyl 3-(2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.5 g) as a yellow oil. LCMS Method C: [M+H].sup.+=230.1.

Step 2: tert-butyl 3-(2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

[0850] tert-Butyl 3-(2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.3 g, 5.7 mmol, 1.0 equiv.) was dissolved in DCM (15 mL) and cooled to 0° C., then ethyl diazoacetate (1.3 g, 11.3 mmol, 2.0 equiv.) and R.sup.h2(OAc).sub.4 (0.3 g, 0.6 mmol, 0.1 equiv.) were added, maintaining the solution at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 0° C. and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 3-[2-(2-ethoxy-2-oxoethoxy) propan-2-yl] pyrrolidine-1-carboxylate (1.3 g) as a yellow oil. LCMS Method A: [M+H].sup.+=316.2

Step 3: tert-butyl 3-(2-(2-ethoxy-2-oxoethoxy) propan-2-yl) pyrrolidine-1-carboxylate

[0851] tert-Butyl 3-[2-(2-ethoxy-2-oxoethoxy) propan-2-yl] pyrrolidine-1-carboxylate (1.0 g, 3.2 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then LiAlH.sub.4 (0.2 g, 4.8 mmol, 1.5 equiv.) was added in portions. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of ice-water at 0° C. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give tert-butyl 3-[2-(2-hydroxyethoxy) propan-2-yl] pyrrolidine-1-carboxylate (0.7 g) as a yellow oil. LCMS Method A: [M+H].sup.+=274.2.

Step 4: tert-butyl 3-(2-(2-hydroxyethoxy) propan-2-yl) pyrrolidine-1-carboxylate

[0852] tert-Butyl 3-[2-(2-hydroxyethoxy) propan-2-yl] pyrrolidine-1-carboxylate (1.2 g, 4.4 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then PPh.sub.3 (1.7 g, 6.6 mmol, 1.5 equiv.) and CBr.sub.4 (2.2 g, 6.6 mmol, 1.5 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at 0° C. and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (10:1) to give tert-butyl 3-[2-(2-bromoethoxy) propan-2-yl] pyrrolidine-1-carboxylate (0.8 g) as a yellow oil. LCMS Method C: [M+H].sup.+=336.2.

##STR00691##

[0853] tert-Butyl (3aR,5r,6aS)-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.0 g, 7.8 mmol, 1.0 equiv.) and 1-nitro-2-selenocyanatobenzene (2.3 g, 10.2 mmol, 1.3 equiv.) were dissolved in THF (40 mL) and cooled to 0° C., then TBUP (2.1 g, 10.2 mmol, 1.3 equiv.) was added under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at rt and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (2:1) to give intermediate product as a brown oil. Then the intermediate product was dissolved in THF (30 mL), H.sub.2O.sub.2 (30% wt., 6 mL) was added dropwise at 0° C. The resulting mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (20:1) to give tert-butyl (3aR,5r,6aS)-5-vinylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (430.0 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=238.0.

##STR00692##

Step 1: ethyl 2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]acetate

[0854] Ethyl 2-(4-oxocyclohexyl)acetate (500.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in DME (5.0 mL), then CsF (825.0 mg, 5.4 mmol, 2.0 equiv.) and trifluoromethyltrimethylsilane (772.0 mg, 5.4 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 5 hours at rt and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give ethyl 2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]acetate (200.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=255.1.

Step 2: 4-(2-hydroxyethyl)-1-(trifluoromethyl)cyclohexan-1-ol

[0855] Ethyl 2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]acetate (200 mg, 0.787 mmol, 1 equiv) was dissolved in THE (4 mL) and cooled to 0° C., then LiAlH.sub.4 (60.0 mg, 1.6 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 5 hours at 0° C. and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give 4-(2-hydroxyethyl)-1-(trifluoromethyl)cyclohexan-1-ol (170.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=213.2.

##STR00693##

[0856] 1-Fluoro-4-(trifluoromethyl)benzene (4.0 g, 24.3 mmol, 1.0 equiv.) was dissolved in DMSO (120 mL), then DIEA (8.0 mL, 48.7 mmol, 2.0 equiv.) and pyrrolidin-3-ol (2.1 g, 24.3 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 16 hours at 100° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give 1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-ol (1.4 g) as a yellow solid. LCMS Method B: [M+H].sup.+=232.2.

##STR00694##

[0857] ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methanol hydrochloride (500.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), then K.sub.2CO.sub.3 (1.2 g, 8.4 mmol, 3.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (720.0 mg, 3.1 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 2 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (99:1) to give [(1R,3R,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl]methanol (530.0 mg) as a yellow oil. LCMS Method B: [M−H].sup.−=222.1.

##STR00695##

[0858] 2-(4-Methylthiazol-5-yl) ethan-1-ol (3.0 g, 21.0 mmol, 1.0 equiv.) and ferrocene (2.2 g, 10.5 mmol, 0.5 equiv.) were dissolved in DMSO (10 mL), then CF.sub.3I (12.3 g, 62.9 mmol, 3.0 equiv.) was added dropwise. This was followed by the addition of H.sub.2O.sub.2 (30%, 162.6 mL, 209.5 mmol, 10.0 equiv.) dropwise at 0° C. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of aqueous Na.sub.2CO.sub.3. The resulting solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give 2-(4-methyl-2-(trifluoromethyl) thiazol-5-yl) ethan-1-ol (1.7 g) as a brown oil. LCMS Method A: [M+H].sup.+=212.2.

##STR00696##

Step 1: tert-butyl (E)-7-(2-ethoxy-2-oxoethylidene)-5-azaspiro[2.4]heptane-5-carboxylate

[0859] Ethyl 2-(diethoxyphosphoryl)acetate (1.6 g, 7.1 mmol, 1.5 equiv.) was dissolved in THF (15 mL) and cooled to 0° C., then NaH (60%, 284.0 mg, 7.1 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 30 min at rt, then tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.0 g, 4.7 mmol, 1.0 equiv.) was added dropwise. The resulting mixture was stirred overnight at rt and quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give tert-butyl (E)-7-(2-ethoxy-2-oxoethylidene)-5-azaspiro[2.4]heptane-5-carboxylate (750.0 mg) as a pale white solid.

LCMS Method A: [M+H].SUP.+.=282.2.

Step 2: tert-butyl 7-(2-ethoxy-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylate

[0860] tert-Butyl (E)-7-(2-ethoxy-2-oxoethylidene)-5-azaspiro[2.4]heptane-5-carboxylate (400.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in EtOAc (5.0 mL), then PtO.sub.2 (40.0 mg, 0.2 mmol, 0.1 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at rt. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl 7-(2-ethoxy-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylate (380.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=284.2.

Step 3: tert-butyl 7-(2-hydroxyethyl)-5-azaspiro[2.4]heptane-5-carboxylate

[0861] tert-Butyl 7-(2-ethoxy-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylate (380.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in THE (8.0 mL) and cooled to 0° C., then LAH (101.8 mg, 2.7 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of Na.sub.2SO.sub.4-10H.sub.2O. The resulting mixture was filtered, the filter cake was washed with EtOAc and the combined filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give tert-butyl 7-(2-hydroxyethyl)-5-azaspiro[2.4]heptane-5-carboxylate (250.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=242.2.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 114.

TABLE-US-00024 Intermediate Starting material Structure LCMS data Intermediate 115 [00697] embedded image [00698] Method A: MS-ESI: 197.2 [M + H].sup.+

##STR00699##

[0862] 2-(3-(Trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid (250.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in THE (8 mL) and cooled to 0° C., then LiAlH.sub.4 (97.7 mg, 2.6 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for 2 hours at 0° C. and then quenched by the addition of Na.sub.2SO.sub.4-10H.sub.2O. The resulting mixture was filtered and the filter cake was washed with EtOAc. The combined filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give 2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (90.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=181.2.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 116.

TABLE-US-00025 Intermediate Starting material Structure LCMS data Intermediate 117 [00700] embedded image [00701] Method C: MS-ESI: 183.2 [M + H].sup.+

##STR00702##

Step 1: 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol

[0863] 6-(Trifluoromethyl)-2,3-dihydroinden-1-one (5.0 g, 24.9 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL) and cooled to 0° C., then NaBH.sub.4 (1.9 g, 49.9 mmol, 2.0 equiv.) was added in portions. The reaction mixture was stirred for 16 hours at rt and then quenched by the addition of eater. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol (5.0 g) as a pale yellow oil. LCMS Method B: [M−H].sup.−=201.1.

Step 2: 5-(trifluoromethyl)-1H-indene

[0864] 6-(Trifluoromethyl)-2,3-dihydro-1H-inden-1-ol (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in toluene (5 mL), then TsOH (425.8 mg, 2.5 mmol, 0.5 equiv.) was added. The reaction mixture was stirred overnight at 110° C., then cooled to rt and concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether (100%) to give 5-(trifluoromethyl)-1H-indene (505.0 mg) as an off-white oil.

Step 3: 5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-ol

[0865] 5-(Trifluoromethyl)-1H-indene (500.0 mg, 2.7 mmol, 1.0 equiv.) and (phenyldisulfanyl)benzene (118.6 mg, 0.5 mmol, 0.2 equiv.) were dissolved in ACN (10 mL) and water (1 mL), then 9-Mesityl-10-methylacridinium Perchlorate (33.5 mg, 0.08 mmol, 0.03 equiv.) was added. The reaction mixture was stirred for 16 hours at 3 W blue LEDs at rt, then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-ol (300.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=203.2 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.56 (s, 1H), 7.48 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 4.94 (d, J=3.6 Hz, 1H), 4.57-4.52 (m, 1H), 3.13 (dd, J=16.4, 5.6 Hz, 2H), 2.85-2.79 (m, 2H).

The Intermediates in Following Table were Prepared Using the Same Method Described for Intermediates 118.

TABLE-US-00026 Intermediate Starting material Structure LCMS data Intermediate 119 [00703] embedded image [00704] Method A: MS-ESI: 217.2 [M + H].sup.+

##STR00705##

Step 1: 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one

[0866] 1-(Trifluoromethyl)-4-vinylbenzene (5.0 g, 29.0 mmol, 1.0 equiv.) was dissolved in DCE (100 mL) and cooled to 0° C., then Tf.sub.2O (11.5 g, 40.7 mmol, 1.4 equiv.) was added dropwise, maintaining the solution at 0° C. After stirred for 30 min at 0° C., N,N-dimethylpropionamide (3.5 g, 34.8 mmol, 1.2 equiv.) and 2,4,6-trimethylpyridine (4.9 g, 40.6 mmol, 1.4 equiv.) was added. The reaction mixture was stirred for additional 2 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (20:1) to give 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (3.0 g) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 3.52-3.42 (m, 1H), 3.42-3.34 (m, 1H), 3.33-3.24 (m, 2H), 1.18 (d, J=7.2 Hz, 3H).

Step 2: 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0867] 2-Methyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (3.2 g, 13.8 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then NaBH.sub.4 (522.1 mg, 13.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 0° C., then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (2.6 g) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.65 (d, J=8.0 Hz, 2H), 7.46-7.43 (m, 2H), 5.13 (d, J=7.6 Hz, 1H), 3.58-3.56 (m, 1H), 2.57-2.51 (m, 1H), 2.09-2.00 (m, 1H), 1.82-1.73 (m, 1H), 1.10 (d, J=6.4 Hz, 3H).

##STR00706##

Step 1: 2-(bis(methylthio)methylene)-7-(trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one

[0868] 7-(Trifluoromethyl)-3,4-dihydro-2H-naphthalen-1-one (2.0 g, 9.3 mmol, 1.0 equiv.) and t-BuOK (2.1 g, 18.7 mmol, 2.0 equiv.) were dissolved in DMF (15 mL) and toluene (15 mL), then CS.sub.2 (1.4 g, 18.7 mmol, 2.0 equiv.) was added dropwise under an atmosphere of nitrogen. The reaction mixture was stirred for 4 hours at rt, then MeI (2.7 g, 18.7 mmol, 2.0 equiv.) was added dropwise. The resulting mixture was stirred overnight at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (8:1) to give 2-[bis(methylsulfanyl)methylidene]-7-(trifluoromethyl)-3,4-dihydronaphthalen-1-one (1.5 g) as a yellow solid. LCMS Method A: [M+H].sup.+=319.1.

Step 2: methyl 7-(trifluoromethyl)-3,4-dihydronaphthalene-2-carboxylate

[0869] 2-[bis(methylsulfanyl)methylidene]-7-(trifluoromethyl)-3,4-dihydronaphthalen-1-one (1.5 g, 4.7 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL) and cooled to 0° C., the NaBH.sub.4 (267.0 mg, 7.1 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 30 min at rt, then BF.sub.3.Et.sub.2O (1.2 g, 85.1 mmol, 18.0 equiv.) was added dropwise. The reaction mixture was stirred overnight at 50° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give 2-[bis(methylsulfanyl)methylidene]-7-(trifluoromethyl)-3,4-dihydronaphthalen-1-one (810 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=257.1.

Step 3: methyl 7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate

[0870] Methyl 7-(trifluoromethyl)-3,4-dihydronaphthalene-2-carboxylate (800.0 mg, 3.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (166.1 mg, 1.6 mmol, 0.5 equiv.) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 5 hours at rt. The solids were removed by filtration and the filtrate was concentrated under vacuum to give methyl 7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate (705 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=259.2.

Step 4: 7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

[0871] Methyl 7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate (700.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and H.sub.2O (5 mL), then NaOH (542.1 mg, 13.6 mmol, 5.0 equiv.) was added. The reaction mixture was stirred overnight at rt and concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with aqueous HCl. The precipitated solids were collected by filtration, washed with water and dried to give 7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (350.0 mg) as an off-white solid. LCMS Method B: [M−H].sup.−=243.1.

Step 5: (7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol

[0872] 7-(Trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (350.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in THE (5 mL) and cooled to 0° C., then BH.sub.3-Me.sub.2S (181.1 mg, 7.2 mmol, 5.0 equiv.) was added. The reaction mixture was stirred for 4 hours at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (5:1) to give (7-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methanol (300.0 mg) as a yellow solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.40 (d, J=9.2 Hz, 2H), 7.28 (d, J=7.6 Hz, 1H), 4.62 (s, 1H), 3.38 (d, J=6.4 Hz, 2H), 2.93-2.82 (m, 2H), 2.76-2.69 (m, 1H), 2.48-2.45 (m, 1H), 1.99-1.89 (m, 1H), 1.82-1.72 (m, 1H), 1.35-1.22 (m, 1H).

##STR00707##

Step 1: 2-methyl-4-(trifluoromethyl)-1-vinylbenzene

[0873] 1-Bromo-2-methyl-4-(trifluoromethyl)benzene (5.0 g, 20.9 mmol, 1.0 equiv.) and potassium 1-(trifluoro-lambda4-boranyl)eth-1-enide (4.2 g, 31.6 mmol, 1.5 equiv) were dissolved in THE (40 mL) and H.sub.2O (4 mL), then Cs.sub.2CO.sub.3 (13.6 g, 41.8 mmol, 2.0 equiv.), PPh.sub.3 (1.1 g, 4.2 mmol, 0.2 N/equiv.) and Pd(OAc).sub.2 (0.5 g, 2.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 4 hours at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (99:1) to give 2-methyl-4-(trifluoromethyl)-1-vinylbenzene (2.2 g) as a yellow oil. 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (d, J=8.0 Hz, 1H), 7.62-7.51 (m, 2H), 7.03-6.98 (m, 1H), 5.86 (dd, J=17.2 Hz, 2.1 Hz, 1H), 5.50-5.44 (m, 1H), 2.39 (s, 3H).

Step 2: 3-(2-methyl-4-(trifluoromethyl)phenyl)cyclobutan-1-one

[0874] DMA (1.1 g, 12.9 mmol, 2.4 equiv.) was dissolved in DCE (10 mL) and cooled to 0° C., then a solution of Tf.sub.2O (6.1 g, 21.5 mmol, 4.0 equiv.) in DCE (1 mL) was added dropwise under an atmosphere of nitrogen. The reaction mixture was stirred for 30 min at 0° C., then a mixture of 2,4,6-collidine (2.6 g, 21.5 mmol, 4.0 equiv.) and 2-methyl-4-(trifluoromethyl)-1-vinylbenzene (1.0 g, 5.4 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at 0° C. The resulting mixture was stirred for 16 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (20:1) to give 3-(2-methyl-4-(trifluoromethyl)phenyl)cyclobutan-1-one (380 mg) as a yellow oil. 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.62-7.60 (m, 1H), 7.56-7.53 (m, 2H), 3.88-3.79 (m, 1H), 3.50-3.41 (m, 2H), 3.30-3.24 (m, 2H), 2.37 (s, 3H).

Step 3: cis-3-(2-methyl-4-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0875] 3-(2-Methyl-4-(trifluoromethyl)phenyl)cyclobutan-1-one (380.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and cooled to 0° C., then NaBH.sub.4 (127.0 mg, 3.3 mmol, 2.0 equiv.) was added in portions. The reaction mixture was stirred for 1 hour at 0° C. and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum to give cis-3-(2-methyl-4-(trifluoromethyl)phenyl)cyclobutan-1-ol (300.0 mg) as a yellow solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.60-7.46 (m, 2H), 7.42-7.40 (m, 1H), 5.13 (d, J=7.2 Hz, 1H), 4.12-4.06 (m, 1H), 3.05-2.98 (m, 1H), 2.68-2.62 (m, 2H), 2.28 (s, 3H), 1.89-1.81 (m, 2H).

##STR00708##

Step 1: ethyl (3Z)-3-[(dimethylamino)methylidene]-4-oxocyclopentane-1-carboxylate

[0876] Ethyl 3-oxocyclopentane-1-carboxylate (4.0 g, 25.6 mmol, 1.0 equiv.) was dissolved in DMF-DMA (40.0 mL). The reaction mixture was stirred for 4 hours at 100° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give ethyl (3Z)-3-[(dimethylamino)methylidene]-4-oxocyclopentane-1-carboxylate (2.0 g) as a yellow oil. LCMS Method A: [M+H].sup.+=212.2.

Step 2: ethyl 2H,4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate

[0877] Ethyl (3Z)-3-[(dimethylamino)methylidene]-4-oxocyclopentane-1-carboxylate (2.0 g, 9.5 mmol, 1.0 equiv.) was dissolved in EtOH (20 mL), hydrazine (910.0 mg, 28.4 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 5 hours at rt and then quenched by the addition of FeCl.sub.3 (900 mg). The resulting solution was filtered and the filter cake was washed with -ethanol. The combined filtrate was concentrated under vacuum. The residue was purified by Prep Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 5*15 cm, 10 m; Mobile Phase A: CO.sub.2, Mobile Phase B: EtOH:DCM=1:1; Flow rate: 200 mL/min; Gradient: isocratic 30% B; Column Temperature (° C.): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 3.88. This resulted in ethyl 2H,4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate (920.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=181.2.

Step 3: mixture of ethyl 2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate and ethyl 1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate

[0878] Ethyl 2H,4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate (900.0 mg, 5.0 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), Cs.sub.2CO.sub.3 (3.3 g, 10.0 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.7 g, 7.5 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 16 hours at 65° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give a mixture of ethyl 2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate and ethyl 1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate (585.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=263.2.

Step 4: mixture of [2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol and [1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol

[0879] The mixture of ethyl 2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate and ethyl 1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazole-5-carboxylate (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in THE (8 mL) and cooled to 0° C., LiAlH.sub.4 (44 mg, 1.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 5 hours at rt and then quenched by the addition of ice-water at 0° C. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (5:1) to give a mixture of [2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol and [1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol (81.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=221.2.

##STR00709##

[0880] (2-Azabicyclo[2.1.1]hexan-1-yl)methanol (300.0 mg, 2.7 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (923.0 mg, 4.0 mmol, 1.5 equiv.) were dissolved in ACN (10.0 mL), K.sub.2CO.sub.3 (732.8 mg, 5.3 mmol, 2.0 equiv.) was added at rt. The reaction mixture was stirred for 2 h at 50° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (3:1) to give (2-(2,2,2-trifluoroethyl)-2-azabicyclo[2.1.1]hexan-1-yl)methanol (400.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=196.2.

##STR00710##

[0881] cis-3-[4-(Trifluoromethyl)phenyl]cyclobutan-1-ol (1.0 g, 4.0 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then NaH (60% wt., 221.0 mg, 5.5 mmol, 1.4 equiv.) was added. After stirred for 15 min at 0° C., tributyl(iodomethyl)stannane (1.8 g, 4.2 mmol, 0.9 equiv.) was added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (99:1) to give tributyl({[cis-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]methyl})stannane (630.0 mg) as a yellow oil.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 126.

TABLE-US-00027 Intermediate Starting material Structure LCMS data Intermediate 127 [00711] embedded image [00712] N/A Intermediate 128 [00713] [00714] N/A

##STR00715##

Step 1: methyl 3-methoxy-1-methylcyclobutane-1-carboxylate

[0882] Methyl 3-hydroxy-1-methylcyclobutane-1-carboxylate (1.5 g, 10.4 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then NaH (60% wt, 624.2 mg, 15.6 mmol, 1.5 equiv.) was added under an atmosphere of nitrogen. After 5 min at 0° C., MeI (3.7 g, 26.0 mmol, 2.5 equiv.) was added. The reaction mixture was stirred for additional 1 hour at 0° C. and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (10:1) to give methyl 3-methoxy-1-methylcyclobutane-1-carboxylate (1.3 g) as a yellow oil.

Step 2: 3-methoxy-1-methylcyclobutane-1-carboxylic acid

[0883] Methyl 3-methoxy-1-methylcyclobutane-1-carboxylate (1.3 g, 8.5 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then aqueous NaOH (5 mL, 2 M, 10 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 1 hour at rt and concentrated under vacuum. The residue was diluted with water, adjusted to pH 3 with aqueous HCl (4M). The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to afford 3-methoxy-1-methylcyclobutane-1-carboxylic acid (960 mg) as a colorless oil. LCMS Method B: [M−H].sup.−=143.0.

##STR00716##

Step 1: (2-(4-methoxyphenyl)-1,3-dioxan-5-yl)methanol

[0884] 2-(Hydroxymethyl)propane-1,3-diol (8.0 g, 75.4 mmol, 1.0 equiv.) and 4-methoxybenzaldehyde (12.3 g, 90.5 mmol, 1.2 equiv.) were dissolved in DCM (100 mL), then [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonic acid (3.5 g, 15.1 mmol, 0.2 equiv.) was added in portions. The reaction mixture was stirred for 2 days at 40° C., then cooled to 0° C. and quenched by the addition of TEA (5.2 mL, 37.7 mmol, 0.5 equiv.). The solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give (2-(4-methoxyphenyl)-1,3-dioxan-5-yl)methanol (6.0 g) as a white solid. LCMS Method A: [M+H].sup.+=225.1.

Step 2: 2-(4-methoxyphenyl)-1,3-dioxane-5-carbaldehyde

[0885] (2-(4-Methoxyphenyl)-1,3-dioxan-5-yl)methanol (6.0 g, 26.8 mmol, 1.0 equiv.) was dissolved in DCM (60 mL), then IBX (15.0 g, 53.5 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for overnight at 40° C., then cooled to rt and remove the solid by filtration. The filter cake was washed with DCM and the combined filtrate was concentrated under vacuum to give crude 2-(4-methoxyphenyl)-1,3-dioxane-5-carbaldehyde (6.5 g) as a colorless oil. LCMS Method A: [M+H].sup.+=223.1.

Step 3: 1-(2-(4-methoxyphenyl)-1,3-dioxan-5-yl)ethan-1-ol

[0886] 2-(4-Methoxyphenyl)-1,3-dioxane-5-carbaldehyde (6.5 g, 29.2 mmol, 1.0 equiv.) was dissolved in THE (80 mL) and cooled to 0° C., then MgMgBr (1M in THF, 58.5 mL, 58.5 mmol, 2.0 equiv.) was added dropwise under an atmosphere of nitrogen. The reaction mixture was stirred for 4 hours at 0° C. and then quenched by the addition of saturated aqueous NH.sub.4Cl (aq.). The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give 1-(2-(4-methoxyphenyl)-1,3-dioxan-5-yl)ethan-1-ol (3.2 g) as a white solid. LCMS Method A: [M+H].sup.+=239.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 7.32-7.31 (m, 2H), 6.94-6.86 (m, 2H), 5.45 (d, J=1.2 Hz, 1H), 4.66 (dd, J=5.6, 1.6 Hz, 1H), 4.35-4.33 (m, 1H), 4.10-4.00 (m, 2H), 3.95-3.88 (m, 1H), 3.68-3.65 (m, 1H), 3.41 (p, J=6.2 Hz, 1H), 1.26-1.15 (m, 3H).

Step 4: 2-(((4-methoxybenzyl)oxy)methyl)butane-1,3-diol

[0887] 1-(2-(4-Methoxyphenyl)-1,3-dioxan-5-yl)ethan-1-ol (3.2 g, 13.4 mmol, 1.0 equiv.) was dissolved in DCM (50 mL) and cooled to 0° C., then DIBAL-H (1M, 26.9 mL, 26.9 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred overnight at 0° C. and then quenched by the addition of Na.sub.2SO.sub.4-10H.sub.2O. The resulting mixture was filtered and the filter cake was washed with DCM. The combined filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give 2-(((4-methoxybenzyl)oxy)methyl)butane-1,3-diol (2.5 g) as a white solid. LCMS Method A: [M+H].sup.+=241.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.23 (d, J=8.4 Hz, 2H), 6.94-6.87 (m, 2H), 4.43-4.27 (m, 3H), 4.01-3.99 (m, 1H), 3.74 (s, 3H), 3.56-3.47 (m, 1H), 3.46-3.35 (m, 4H), 1.68-1.66 (m, 1H), 1.10-1.08 (m, 3H).

Step 5: 3-(((4-methoxybenzyl)oxy)methyl)-2-methyloxetane

[0888] 2-(((4-Methoxybenzyl)oxy)methyl)butane-1,3-diol (2.5 g, 10.4 mmol, 1.0 equiv.) was dissolved in DCM (25 mL) and cooled to 0° C., then n-BuLi (2.5 M in hexane, 4.2 mL, 10.4 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 30 min at 0° C., then a solution of TsCl (2.0 g, 10.4 mmol, 1.0 equiv.) in DCM (10 mL) was added dropwise at 0° C. The resulting mixture was stirred for additional 2 hours at 0° C., then an addition batch of n-BuLi (2.5 M in hexane, 4.2 mL, 10.4 mmol, 1.0 equiv.) dropwise. The resulting mixture was stirred overnight at 40° C., then cooled to rt and quenched by the addition of saturated aqueous NH.sub.4C.sub.1 at 0° C. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give 3-(((4-methoxybenzyl)oxy)methyl)-2-methyloxetane (1.0 g) as an off-white solid. LCMS Method A: [M+H].sup.+=223.1.

Step 6: (2-methyloxetan-3-yl)methanol

[0889] 3-(((4-Methoxybenzyl)oxy)methyl)-2-methyloxetane (1.0 g, 4.5 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then Pd/C (100.0 mg, 10% wt) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at rt. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give to (2-methyloxetan-3-yl)methanol (300.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=103.0. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 4.23 (t, J=5.6 Hz, 1H), 4.01-3.99 (m, 1H), 3.53-3.51 (m, 1H), 3.45-3.42 (m, 3H), 1.53-1.49 (m, 1H), 1.10 (d, J=6.4 Hz, 3H).

Step 7: 2-methyloxetane-3-carboxylic acid

[0890] (2-Methyloxetan-3-yl)methanol (300.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in ACN (5 mL) and H.sub.2O (1 mL), then NaIO.sub.4 (1.3 g, 5.9 mmol, 2.0 equiv.) and RuCl3.H.sub.2O (66.2 mg, 0.3 mmol, 0.1 equiv.) were added in portions. The reaction mixture was stirred overnight at rt and then quenched by the addition of water. The resulting solution was adjusted to pH 4 with conc. HCl, extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give 2-methyloxetane-3-carboxylic acid (280.0 mg) as a brown oil. LCMS Method A: [M+H].sup.+=117.2.

##STR00717##

Step 1: methyl 1-(2-methoxyethyl)-3-methylazetidine-3-carboxylate

[0891] 2-Bromoethyl methyl ether (0.9 g, 6.6 mmol, 1.1 equiv.) and methyl 3-methylazetidine-3-carboxylate hydrochloride (1.0 g, 6.0 mmol, 1.0 equiv.) were dissolved in ACN (10 mL), then K.sub.2CO.sub.3 (1.7 g, 12.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum to give methyl 1-(2-methoxyethyl)-3-methylazetidine-3-carboxylate (680 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=188.1.

Step 2: 1-(2-methoxyethyl)-3-methylazetidine-3-carboxylic acid

[0892] Methyl 1-(2-methoxyethyl)-3-methylazetidine-3-carboxylate (680.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL), then aqueous NaOH (3 mL, 2M, 6.0 mmol, 2.0 equiv.) was added dropwise. The reaction mixture was stirred for 2 hours at 80° C., then cooled to rt and concentrated under vacuum. The residue was diluted with water, adjusted to pH 2 with aqueous HCl (1M). The resulting solution was extracted with dichloromethane and concentrated under vacuum to give crude 1-(2-methoxyethyl)-3-methylazetidine-3-carboxylic acid (640 mg) as a yellow syrup. LCMS Method A: [M+H].sup.+=174.2.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 131.

TABLE-US-00028 Intermediate Starting material Structure LCMS data Intermediate 132 [00718] embedded image [00719] Method C: MS-ESI: 180.2 [M + H].sup.+

##STR00720##

Step 1: methyl trans-3-amino-1-methylcyclobutane-1-carboxylate HCi salt

[0893] Methyl trans-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutane-1-carboxylate (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (5 mL). The reaction mixture was stirred for 1 hour at rt and concentrated under vacuum to give crude methyl trans-3-amino-1-methylcyclobutane-1-carboxylate (500 mg) as a white solid. LCMS Method A: [M+H].sup.+=144.1.

Step 2: methyl trans-3-acetamido-1-methylcyclobutane-1-carboxylate

[0894] Methyl trans-3-amino-1-methylcyclobutane-1-carboxylate (500.0 mg, 3.5 mmol, 1.0 equiv.) and TEA (2.4 mL, 17.5 mmol, 5.0 equiv.) were dissolved in DCM (10 mL) and cooled to 0° C., then acetyl chloride (274.1 mg, 3.5 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 2 hour at rt and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to give methyl trans-3-acetamido-1-methylcyclobutane-1-carboxylate (425.0 mg) as a yellow oil. LCMS Method A: [M+H].sup.+=186.1.

Step 3: trans-3-acetamido-1-methylcyclobutane-1-carboxylic acid

[0895] Methyl trans-3-acetamido-1-methylcyclobutane-1-carboxylate (425.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and H.sub.2O (2 mL), then LiOH (109.9 mg, 4.6 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 4 hours at rt and concentrated under vacuum. The residue was diluted with water, adjusted to pH 3 with aqueous HCl (1 M). The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum to afford trans-3-acetamido-1-methylcyclobutane-1-carboxylic acid (630 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=172.0.

The Intermediates in the Following Table were Prepared Using the Same Method Described for Intermediates 133.

TABLE-US-00029 Intermediate Starting material Structure LCMS data Intermediate 134 [00721] embedded image [00722] Method A: MS-ESI: 172.0 [M + H].sup.+

Example 1: N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indol-3-yl)acetamide (Compound 111)

[0896] ##STR00723##

Step 1: tributyl([[4-(trifluoromethyl)phenyl]methoxy]methyl)stannane

[0897] [4-(trifluoromethyl)phenyl]methanol (3.0 g, 17.0 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to 0° C., then NaH (60% wt., 0.8 g, 15.3 mmol, 1.2 equiv.) was added. After 1 hour at 0° C., a solution of tributyl(iodomethyl)stannane (6.6 g, 15.3 mmol, 0.9 equiv.) in THE (3 mL) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for an additional 72 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with petroleum ether and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/petroleum ether (1:5) to give tributyl([[4-(trifluoromethyl)phenyl]methoxy]methyl)stannane (4.5 g) as a pale yellow oil.

Step 2: tert-butyl 3-acetamido-5-([[4-(trifluoromethyl)phenyl]methoxy]methyl)indole-1-carboxylate

[0898] tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL), then Pd(PPh.sub.3).sub.4 (65.4 mg, 0.1 mmol, 0.1 equiv.) and tributyl([[4-(trifluoromethyl)phenyl]methoxy]methyl)stannane (407.0 mg, 0.8 mmol, 1.5 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 14 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 3-acetamido-5-([[4-(trifluoromethyl)phenyl]methoxy]methyl)indole-1-carboxylate (100.5 mg) as a yellow semi-solid. LCMS Method A: [M+H].sup.+=463.

Step 3: N-[5-([[4-(trifluoromethyl)phenyl]methoxy]methyl)-1H-indol-3-yl]acetamide

[0899] tert-Butyl 3-acetamido-5-([[4-(trifluoromethyl)phenyl]methoxy]methyl)indole-1-carboxylate (90.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then K.sub.2CO.sub.3 (80.7 mg, 0.6 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 65° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220 nm; RT1: 7.53 min. This resulted in N-[5-([[4-(trifluoromethyl)phenyl]methoxy]methyl)-1H-indol-3-yl]acetamide (35.1 mg) as a pale yellow solid. LCMS Method D: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.78 (s, 1H), 9.84 (s, 1H), 7.80 (s, 1H), 7.74-7.70 (m, 3H), 7.60-7.58 (m, 2H), 7.33-7.31 (m, 1H), 7.13-7.10 (m, 1H), 4.63 (s, 4H), 2.09 (s, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 1.

TABLE-US-00030 Compound Starting Example # No. materials Used Structure LCMS data 2 109 (4-(trifluoromethyl) phenyl)methanol/ Intermediate 6 [00724] embedded image Method D: MS-ESI: 401 [M − H].sup.−. 3 106 (3-(trifluoromethyl) phenyl)methanol/ Intermediate 2 [00725] Method F: MS-ESI: 361 [M − H].sup.−. 4 101 (3,4-dichlorophenyl) methanol/ Intermediate 2 [00726] Method F: MS-ESI: 370 [M + H].sup.+.

Example 5: N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)propionamide (Compound 138)

[0900] ##STR00727##

[0901] N-(5-hydroxy-1H-indol-3-yl)propenamide (160.0 mg, 0.8 mmol, 1.0 equiv.) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (280.9 mg, 1.2 mmol, 1.5 equiv.) were dissolved in ACN (10 mL), then K.sub.2CO.sub.3 (216.6 mg, 1.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 75° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 220 nm; RT1: 6.68 min. This resulted in N-(5-[[4-(trifluoromethyl)phenyl]methoxy]-1H-indol-3-yl)propenamide (29.2 mg) as a white solid. LCMS Method D: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.62 (s, 1H), 9.66 (s, 1H), 7.79-7.77 (m, 2H), 7.73-7.68 (m, 3H), 7.45 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.86-6.83 (m, 1H), 5.21 (s, 2H), 2.41-2.33 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 5.

TABLE-US-00031 Compound Starting Example # No. materials Used Structure LCMS data 6 113 Intermediate 27/ Intermediate 7 [00728] embedded image Method D: MS-ESI: 364 [M + H].sup.+. 7 112 Intermediate 28/ Intermediate 7 [00729] Method F: MS-ESI: 388 [M + H].sup.+.

Example 8: N-(5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethoxy)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 142)

[0902] ##STR00730##

[0903] N-(5-Hydroxy-1H-indol-3-yl)cyclobutanecarboxamide (150.0 mg, 0.7 mmol, 1.0 equiv.) and 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (249.0 mg, 1.3 mmol, 2.0 equiv.) were dissolved in THE (10 mL), then PPh.sub.3 (341.7 mg, 1.3 mmol, 2.0 equiv.) was added. This was followed by the addition of DBAD (300.0 mg, 1.3 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give material, that was further purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43 B to 55 B in 8 min; 254/220 nm; RT1: 6.62 min. This resulted in N-(5-[2-[6-(trifluoromethyl)pyridin-3-yl]ethoxy]-1H-indol-3-yl)cyclobutanecarboxamide (22.3 mg) as a white solid. LCMS Method D: [M+H].sup.+=404. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 9.50 (s, 1H), 8.78 (s, 1H), 8.10-8.08 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.73-6.71 (m, 1H), 4.23 (t, J=6.4 Hz, 2H), 3.33-3.30 (m, 1H), 3.22 (t, J=6.4 Hz, 2H), 2.27-2.22 (m, 2H), 2.13-2.08 (m, 2H), 1.96-1.94 (m, 1H), 1.84-1.80 (m, 1H).

[0904] The analogs prepared in the following table were prepared using the same method described for Example 8.

TABLE-US-00032 Starting Example Compound materials LCMS # No. Used Structure Condition data 9 140 tert-butyl 4- (2- hydroxy- ethyl) piperidine-1- carboxylate/ Intermediate 9 [00731] embedded image PPh.sub.3, DIAD, THF Method D: MS-ESI: 440 [M − H].sup.−. 10 146 2-(4- (trifluoro- methyl) phenyl) ethan-1-ol/ Intermediate 8 [00732] PPh.sub.3, DEAD, DCM Method D: MS-ESI: 377 [M + H].sup.+. 11 129 Intermediate 20/ Intermediate 9 [00733] P(n-Bu).sub.3, ADDP, DCM Method E: MS-ESI: 424 [M + H].sup.+. 12 120 Intermediate 22/ Intermediate 7 [00734] embedded image PPh.sub.3, DIAD, THF Method F: MS-ESI: 368 [M + H].sup.+. 13 119 Intermediate 21/ Intermediate 7 [00735] PPh.sub.3, DIAD, THF Method F: MS-ESI: 370 [M + H].sup.+. 14 110 Intermediate 24/ Intermediate 7 [00736] P(n-Bu).sub.3, ADDP, THF Method E: MS-ESI: 382 [M + H].sup.+. 15 105 Intermediate 18/ Intermediate 7 [00737] embedded image P(n-Bu).sub.3, ADDP, DCM Method E: MS-ESI: 402 [M + H].sup.+. 16 104 Intermediate 19/ Intermediate 7 [00738] P(n-Bu).sub.3, ADDP, DCM Method D: MS-ESI: 446 [M + H].sup.+. 17 145 4-(trifluoro- methyl) phenol/ Intermediate 12 [00739] PPh.sub.3, DIAD, THF Method E: MS-ESI: 403 [M + H].sup.+.

Example 18: N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)acetamide (Compound 127)

[0905] ##STR00740##

Step 1: tert-butyl 3-acetamido-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]indole-1-carboxylate (compound 46)

[0906] tert-Butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then 4-(trifluoromethyl)phenol (229.1 mg, 1.4 mmol, 1.5 equiv.) and PPh.sub.3 (494.3 mg, 1.9 mmol, 2.0 equiv.) were added. This was followed by the dropwise addition of DIAD (0.2 mL, 1.3 mmol, 2.0 equiv.). The reaction mixture was stirred for an additional 2 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl 3-acetamido-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]indole-1-carboxylate (280.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=463

Step 2: N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)acetamide

[0907] tert-Butyl 3-acetamido-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]indole-1-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then K.sub.2CO.sub.3 (64.8 mg, 0.5 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 65° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 8 min, 220 nm; RT1: 7.53 min. This resulted in N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)acetamide (36.8 mg) as a white solid. LCMS Method D: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (s, 1H), 9.75 (s, 1H), 7.69-7.63 (m, 4H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.8 Hz, 2H), 7.10-7.07 (m, 1H), 4.30 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 2.09 (s, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 18.

TABLE-US-00033 Compound Starting Example # No. materials Used Structure Condition LCMS data 19 103 Intermediate 25/ Intermediate 10 [00741] embedded image P(n-Bu).sub.3, ADDP, THF Method F: MS-ESI: 389 [M + H].sup.+. 20 102 Intermediate 26/ Intermediate 10 [00742] P(n-Bu).sub.3, ADDP, THF Method F: MS-ESI: 389 [M + H].sup.+. 21 130 4-(trifluoromethyl) phenol/ Intermediate 14 [00743] PPh.sub.3, DEAD, THF Method D: MS-ESI: 361 [M − H].sup.−. 22 115 4-(trifluoromethyl) phenol/ Intermediate 13 [00744] embedded image P(n-Bu).sub.3, ADDP, THF Method F: MS-ESI: 347 [M − H].sup.−. 23 108 Intermediate 23/ Intermediate 10 [00745] 2-(tributyl- phosphoranyl- idene)acetonitrile Method F: MS-ESI: 412 [M + H].sup.+.

Example 19: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide (Compound 103)

[0908] ##STR00746##

Step 1: tert-butyl 3-acetamido-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate

[0909] Cis-3-(4-(Trifluoromethyl)phenyl)cyclobutan-1-ol (2.5 g, 11.5 mmol, 1.0 equiv.) was dissolved in THE (40.0 mL) and cooled to 0° C., then tert-butyl 3-acetamido-5-hydroxy-1H-indole-1-carboxylate (4.0 g, 13.8 mmol, 1.2 equiv.) and n-Bu.sub.3P (3.5 g, 17.3 mmol, 1.5 equiv.) were added. This was followed by the addition of ADDP (5.7 g, 23.1 mmol, 2.0 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 3 hours, then cooled to ambient temperature and quenched by the addition of brine. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (10:1) to give tert-butyl 3-acetamido-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.5 g) as a white solid. [M+H].sup.+=489.

Step 2: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide

[0910] tert-Butyl 3-acetamido-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.5 g, 3.0 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then K.sub.2CO.sub.3 (848.7 mg, 6.1 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for 1 hour at 70° C., then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 70% B in 7 min, 70% B; Wave Length: 220 nm; RT1 (min): 7.53. This resulted in N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide (435.0 mg) as a white solid. [M+H].sup.+=389. 1H NMR (400 MHz, DMSO-d.sub.6) δ 10.58 (s, 1H), 9.68 (s, 1H), 7.73-7.59 (m, 5H), 7.24-7.22 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.75-6.72 (m, 1H), 4.95-4.89 (m, 1H), 3.84-3.77 (m, 1H), 2.72-2.60 (m, 4H), 2.08 (s, 3H).

Examples 24/25: (E)-N-(5-(4-(trifluoromethyl)styryl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 144) and N-(5-(4-(trifluoromethyl)phenethyl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 141)

[0911] ##STR00747##

Step 1: (E)-N-(5-(4-(trifluoromethyl)styryl)-1H-indol-3-yl)cyclobutanecarboxamide

[0912] N-(5-bromo-1H-indol-3-yl)cyclobutanecarboxamide (1.0 g, 3.4 mmol, 1.0 equiv.) was dissolved in TEA (10 mL), then 1-(trifluoromethyl)-4-vinylbenzene (704.7 mg, 4.1 mmol, 1.2 equiv.), Pd(OAc).sub.2 (76.6 mg, 0.3 mmol, 0.1 equiv.) and tri(o-tolyl)phosphine (207.6 mg, 0.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give material that was further purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; Flow rate: 60 mL/min; Gradient: 55% B to 70% B in 7 min; Wave Length: 254 nm; RT1: 6.97 min. This resulted in (E)-N-(5-(4-(trifluoromethyl)styryl)-1H-indol-3-yl)cyclobutanecarboxamide (33.3 mg) as a white solid. LCMS Method D: [M+H].sup.+=385. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.91 (s, 1H), 9.71 (s, 1H), 8.03 (s, 1H), 7.82-7.80 (m, 2H), 7.74-7.72 (m, 3H), 7.53-7.42 (m, 2H), 7.35 (d, 1H), 7.20 (d, 1H), 3.38-3.34 (m, 1H), 2.30-2.23 (m, 2H), 2.18-2.10 (m, 2H), 2.04-1.96 (m, 1H), 1.88-1.81 (m, 1H).

Step 2: N-(5-(4-(trifluoromethyl)phenethyl)-1H-indol-3-yl)cyclobutanecarboxamide

[0913] (E)-N-(5-(4-(trifluoromethyl)styryl)-1H-indol-3-yl)cyclobutanecarboxamide (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt, 1.0 g) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 10 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give material that was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 75% B in 7 min; Wave Length: 220 nm; RT1r: 6.5 min. This resulted in N-(5-(4-(trifluoromethyl)phenethyl)-1H-indol-3-yl)cyclobutanecarboxamide (40.2 mg) as a white solid. LCMS Method D: [M−H].sup.−=385. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.64 (s, 1H), 9.56 (s, 1H), 7.69 (s, 1H), 7.64-7.62 (m, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.00-6.97 (m, 1H), 3.38-3.33 (m, 1H), 3.05-2.95 (m, 4H), 2.28-2.23 (m, 2H), 2.14-2.10 (m, 1H), 2.04-1.95 (m, 1H), 1.84-1.81 (m, 1H).

The analogs prepared in following table were prepared using the same method described for Example 25.

TABLE-US-00034 Example Compound Starting LCMS # No. materials Used Structure data 26 137 Intermediate 35/ Intermediate 5 [00748] embedded image Method E: MS-ESI: 415 [M + H].sup.+. 27 133 Intermediate 36/ Intermediate 5 [00749] Method D: MS-ESI: 431 [M + H].sup.+.

Example 28: N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indol-3-yl)acetamide (Compound 114)

[0914] ##STR00750##

Step 1: tert-butyl 4-[(E)-2-(3-acetamido-1H-indol-5-yl)ethenyl]piperidine-1-carboxylate

[0915] N-(5-bromo-1H-indol-3-yl)acetamide (2.0 g, 7.9 mmol, 1.0 equiv.) was dissolved in ACN (100 mL), then tert-butyl 4-ethenylpiperidine-1-carboxylate (2.5 g, 11.8 mmol, 1.5 equiv.), tri(o-tolyl)phosphine (962.0 mg, 3.2 mmol, 0.4 equiv.), Pd(AcO).sub.2 (177.4 mg, 0.8 mmol, 0.1 equiv.) and TEA (3.9 mL, 28.3 mmol, 3.6 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 10 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 4-[(E)-2-(3-acetamido-1H-indol-5-yl)ethenyl]piperidine-1-carboxylate (2.2 g) as a green solid. LCMS Method A: [M+H].sup.+=384.

Step 2: tert-butyl 4-[2-(3-acetamido-1H-indol-5-yl)ethyl]piperidine-1-carboxylate

[0916] tert-Butyl 4-[(E)-2-(3-acetamido-1H-indol-5-yl)ethenyl]piperidine-1-carboxylate (1.3 g, 3.5 mmol, 1.0 equiv.) was dissolved in MeOH (40 mL), then Pd/C (10% wt., 270.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 4-[2-(3-acetamido-1H-indol-5-yl)ethyl]piperidine-1-carboxylate (1.0 g) as a dark blue solid. LCMS Method A: [M+H].sup.+=386.

Step 3: N-[5-[2-(piperidin-4-yl)ethyl]-1H-indol-3-yl]acetamide

[0917] tert-Butyl 4-[2-(3-acetamido-1H-indol-5-yl)ethyl]piperidine-1-carboxylate (377.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in DCM (30 mL) and TFA (10 mL). The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum to afford N-[5-[2-(piperidin-4-yl)ethyl]-1H-indol-3-yl]acetamide (744.4 mg) as a brown oil, which was used in the next step directly without further purification. LCMS Method B: [M+H].sup.+=286.

Step 4: N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl]-1H-indol-3-yl)acetamide

[0918] N-[5-[2-(piperidin-4-yl)ethyl]-1H-indol-3-yl]acetamide (744.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in ACN (100 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (726.1 mg, 3.1 mmol, 1.2 equiv.) and TEA (1.5 mL, 10.5 mmol, 4.0 equiv.) were added. The resulting mixture was heated to 60° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with the following condition: Kinetex EVO C18 Column, 30*150, 5 um; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 70% B in 10 min; Wave Length: 220 nm. This resulted in N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl]-1H-indol-3-yl)acetamide (16.4 mg) as an off-white solid. LCMS Method E: [M+H].sup.+=368. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 9.72 (s, 1H), 7.65-7.63 (m, 1H), 7.56-7.54 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.94-6.92 (m, 1H), 3.15-3.07 (m, 2H), 2.91-2.88 (m, 2H), 2.68-2.64 (m, 2H), 2.30-2.24 (m, 2H), 2.08 (s, 3H), 1.71-1.68 (m, 2H), 1.58-1.53 (m, 2H), 1.26-1.21 (m, 3H).

Example 29: N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide (Compound 136)

[0919] ##STR00751##

[0920] 5-[2-[4-(trifluoromethyl)phenyl]ethoxy]-1H-indol-3-amine (350.0 mg, 1.1 mmol, 1.0 equiv.) and TEA (0.5 mL, 3.3 mmol, 3.0 equiv.) were dissolved in DCM (5 mL) and cooled to 0° C., then acetyl chloride (0.1 mL, 1.3 mmol, 1.2 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 30 min at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give material that was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42 B to 56 B in 8 min; 254/220 nm; RT1: 7.35 min. This resulted in N-(5-[2-[4-(trifluoromethyl)phenyl]ethoxy]-1H-indol-3-yl)acetamide (148.3 mg) as a white solid. LCMS Method F: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.68 (s, 1H), 7.71-7.65 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.55-7.52 (m, 2H), 7.32 (s, 1H), 7.22-7.19 (m, 1H), 6.73-6.70 (m, 1H), 4.20 (t, J=6.8 Hz, 2H), 3.18 (t, J=6.8 Hz, 2H), 2.07 (s, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 29.

TABLE-US-00035 Example Compound Starting LCMS # No. materials Used Structure data 30 123 [00752] embedded image [00753] Method E: MS-ESI: 336 [M + H].sup.+. 31 116 [00754] [00755] Method D: MS-ESI: 336 [M + H].sup.+. 32 122 [00756] [00757] Method E: MS-ESI: 384 [M + H].sup.+. 33 124 [00758] [00759] Method F: MS-ESI: 335 [M + H].sup.+.

Example 34: 2-methoxy-N-(5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-yl)acetamide (Compound 117)

[0921] ##STR00760##

[0922] 5-[2-[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-amine (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then TEA (0.2 mL, 1.2 mmol, 2.0 equiv.), methoxyacetic acid (105.6 mg, 1.2 mmol, 2.0 equiv.) and T.sub.3P (wt. 50% in ethyl acetate, 0.8 mL, 1.2 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 5% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 2-methoxy-N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)acetamide (88.5 mg) as a light yellow solid. LCMS Method D: [M+H].sup.+=414. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (s, 1H), 9.60 (s, 1H), 7.65 (d, J=6.4 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.23-7.21 (m, 1H), 6.75-6.72 (m, 1H), 4.07 (s, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.37 (s, 3H), 3.17-3.09 (m, 2H), 2.93-2.90 (m, 2H), 2.34-2.28 (m, 2H), 1.71-1.68 (m, 4H), 1.53-1.47 (m, 1H), 1.30-1.27 (m, 2H).

[0923] The analogs prepared in the following table were prepared using the same method described for Example 34.

TABLE-US-00036 Example # Compound No. Starting material A Starting material B Structure LCMS data 35 121 [00761] embedded image [00762] [00763] Method E: MS-ESI: 442 [M + H].sup.+. 36 118 [00764] [00765] [00766] Method E: MS-ESI: 442 [M + H].sup.+. 37 107 [00767] [00768] [00769] Method F: MS-ESI: 393 [M + H].sup.+.

Example 38: N-(5-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)ethyl)-1H-indol-3-yl)acetamide (Compound 126)

[0924] ##STR00770##

Step 1: tert-butyl 3-acetamido-5-(2-[[6-(trifluoromethyl)pyridin-3-yl]amino]ethyl)indole-1-carboxylate

[0925] tert-Butyl 3-acetamido-5-(2-oxoethyl)indole-1-carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then 6-(trifluoromethyl)pyridin-3-amine (230.6 mg, 1.4 mmol, 1.5 equiv.) and Ti(Oi-Pr).sub.4 (539.0 mg, 1.9 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 2 hours at 70° C., then cooled to ambient temperature. This was followed by the addition of NaBH.sub.4 (71.8 mg, 1.9 mmol, 2.0 equiv.). The resulting mixture was stirred for an additional 1 hour at ambient temperature, then quenched by the addition of MeOH and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl 3-acetamido-5-(2-[[6-(trifluoromethyl)pyridin-3-yl]amino]ethyl)indole-1-carboxylate (200.0 mg) as a light yellow solid. LCMS Method B: [M+H].sup.+=463.

Step 2: N-[5-(2-[[6-(trifluoromethyl)pyridin-3-yl]amino]ethyl)-1H-indol-3-yl]acetamide

[0926] tert-Butyl 3-acetamido-5-(2-[[6-(trifluoromethyl)pyridin-3-yl]amino]ethyl)indole-1-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and TFA (1 mL). The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25 B to 55 B in 8 min; 220 nm; RT1: 7.23 min. This resulted in N-[5-(2-[[6-(trifluoromethyl)pyridin-3-yl]amino]ethyl)-1H-indol-3-yl]acetamide (21.2 mg) as a light yellow solid. LCMS Method D: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.66 (s, 1H), 9.75 (s, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.66-7.65 (m, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.06-7.03 (m, 2H), 6.77 (t, J=5.6 Hz, 1H), 3.41-3.36 (m, 2H), 2.92 (t, J=7.2 Hz, 2H), 2.08 (s, 3H).

[0927] The analogs prepared in the following table were prepared using the same method described for Example 38.

TABLE-US-00037 Example # Compound No. Intermediate Structure LCMS data 39 125 [00771] embedded image [00772] Method D: MS-ESI: 349 [M + H].sup.+. 40 134 [00773] [00774] Method E: MS-ESI: 403 [M + H].sup.+.

Example 41/42: (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 135) and N-(5-(3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 139)

[0928] ##STR00775##

Step 1: (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclobutanecarboxamide

[0929] (E)-4,4,5,5-tetramethyl-2-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1,3,2-dioxaborolane (150.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), then N-(5-bromo-1H-indol-3-yl)cyclobutane carboxamide (169.1 mg, 0.6 mmol, 1.2 equiv.), K.sub.3PO.sub.4 (306.0 mg, 1.4 mmol, 3.0 equiv.) and Xphos Pd G.sub.3 (81.4 mg, 0.1 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give material that was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 80% B in 7 min; Wave Length: 220 nm; RT1: 6.02 min. This resulted in (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclobutanecarboxamide (19.0 mg) as a white solid. LCMS Method D: [M+H].sup.+=399. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 9.62 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.72-7.67 (m, 3H), 7.53-7.49 (m, 2H), 7.26-7.20 (m, 2H), 6.56-6.52 (m, 1H), 6.33-6.27 (m, 1H), 3.65 (d, J=7.2 Hz, 2H), 2.34-2.33 (m, 1H), 2.27-2.22 (m, 2H), 2.14-2.09 (m, 2H), 1.96-1.92 (m, 1H), 1.84-1.81 (m, 1H).

Step 2: N-(5-(3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)isobutyramide

[0930] (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclobutanecarboxamide (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then Pd/C (10% wt., 50.0 mg) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 10 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column, 30*50 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 55% B to 70% B in 8 min; Wave Length: 254/220 nm; RT1: 7.73 min. This resulted in N-(5-(3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)isobutyramide (30.0 mg) as a white solid. LCMS Method D: [M+H].sup.+=401. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.63 (s, 1H), 9.55 (s, 1H), 7.70-7.64 (m, 3H), 7.57 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.96-6.94 (m, 1H), 3.37-3.34 (m, 1H), 2.75-2.66 (m, 4H), 2.27-2.22 (m, 2H), 2.12-2.09 (m, 2H), 2.03-1.95 (m, 3H), 1.88-1.83 (m, 1H).

The analogs prepared in the following table were prepared using the same method described for Examples 41/42.

TABLE-US-00038 Intermediates Example # Compound No. Used Structure LCMS data 43 132 Intermediate 34 Intermediate 1 [00776] embedded image Method D: MS-ESI: 359 [M − H].sup.−. 44 143 (E)-2-(2- ethoxyvinyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane/ Intermediate 5 [00777] Method F: MS-ESI: 285 [M + H].sup.+.

Example 45: N-(5-(4-(trifluoromethyl)benzyl)-1H-indol-3-yl)acetamide (Compound 128)

[0931] ##STR00778##

[0932] N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl] acetamide (296.4 mg, 1.0 mmol, 2 equiv.) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (118.0 mg, 0.5 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (10 mL) and water (0.5 mL), then Cs.sub.2CO.sub.3 (402.1 mg, 1.2 mmol, 2.5 equiv.) and Pd(dppf)Cl.sub.2 CH.sub.2Cl.sub.2 (80.4 mg, 0.1 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 85° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give material that was further purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 mm*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 70% B in 7 min; 254/220 nm; RT1: 6.78 min. This resulted in N-(5-[[4-(trifluoromethyl)phenyl]methyl]-1H-indol-3-yl)acetamide (46.3 mg) as a white solid. LCMS Method E: [M+H].sup.+=333. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.69 (s, 1H), 9.76 (s, 1H), 7.66-7.63 (m, 4H), 7.44 (d, 2H), 7.26 (d, J=8.0 Hz, 1H), 6.99-6.96 (m, 1H), 4.10 (s, 2H), 2.07 (s, 3H).

Example 46: N-(5-(4-(4-(trifluoromethyl)phenyl)butan-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 131)

[0933] ##STR00779## ##STR00780##

Step 1: N-(5-bromo-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide

[0934] N-(5-bromo-1H-indol-3-yl)cyclobutanecarboxamide (3.0 g, 10.2 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then NaH (60% wt., 0.6 g, 15.9 mmol, 1.5 equiv.) was added, maintaining the solution at 0° C. This was followed by the dropwise addition of benzenesulfonyl chloride (1.5 mL, 12.3 mmol, 1.2 equiv.), maintaining the reaction mixture at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give N-(5-bromo-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g) as a yellow solid. LCMS Method A: [M+H].sup.+=433.

Step 2: N-(5-(1-ethoxyvinyl)-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide

[0935] N-(5-bromo-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g, 2.8 mmol, 1.0 equiv.) was dissolved in toluene (20 mL), then tributyl(1-ethoxyethenyl)stannane (3.0 g, 8.4 mmol, 3.0 equiv.) and Pd(PPh.sub.3).sub.2Cl.sub.2 (380.1 mg, 0.4 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 14 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give crude N-(5-(1-ethoxyvinyl)-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide (920.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=425.

Step 3: N-(5-acetyl-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide

[0936] N-[1-(benzenesulfonyl)-5-(1-ethoxyethenyl)indol-3-yl]cyclobutanecarboxamide (1.5 g, 3.5 mmol, 1.0 equiv.) was dissolved in aqueous HCl (2 N, 20 mL). The reaction mixture was stirred for 3 hours at ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-(5-acetyl-1-(phenylsulfonyl)-1H-indol-3-yl)cyclobutanecarboxamide (1.0 g) as a yellow solid. LCMS Method A: [M+H].sup.+=397.

Step 4: (Z)—N-(1-(phenylsulfonyl)-5-(3-(4-(trifluoromethyl)phenyl)acryloyl)-1H-indol-3-yl)cyclobutanecarboxamide

[0937] N-[5-acetyl-1-(benzenesulfonyl)indol-3-yl]cyclobutanecarboxamide (1.0 g, 2.5 mmol, 1.0 equiv.) and 4-(trifluoromethyl)benzaldehyde (527.0 mg, 3.0 mmol, 1.2 equiv.) were dissolved in EtOH (20 mL) and cooled to 0° C., then NaOH aqueous (2 M, 12 mL, 24.0 mmol, 10.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 5 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give (Z)—N-(1-(phenylsulfonyl)-5-(3-(4-(trifluoromethyl)phenyl)acryloyl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g) as a yellow solid. LCMS Method B: [M−H].sup.−=551. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H), 9.93 (s, 1H), 8.78 (s, 1H), 8.13-8.09 (m, 3H), 7.98-7.96 (m, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.87-7.83 (m, 3H), 7.46 (d, J=8.8 Hz, 1H), 3.46-3.42 (m, 1H), 2.30-2.26 (m, 2H), 2.16-2.14 (m, 2H), 2.02-1.98 (m, 1H), 1.88-1.85 (m, 1H).

Step 5: (Z)—N-(1-(phenylsulfonyl)-5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide

[0938] (E)-N-(1-(phenylsulfonyl)-5-(3-(4-(trifluoromethyl)phenyl)acryloyl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g, 2.2 mmol, 1.0 equiv.) was dissolved in THE (50 mL) and cooled to 0° C., then MeMgBr (3 M in THF, 2.2 mL, 6.6 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 18 hours at ambient temperature and then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (3:2) to give (Z)—N-(1-(phenylsulfonyl)-5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g) as a yellow solid. LCMS Method A: [M+H].sup.+=551.

Step 6: (E)-N-(5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide

[0939] (Z)—N-(1-(phenylsulfonyl)-5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (1.2 g, 2.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then K.sub.2CO.sub.3 (0.9 g, 6.3 mmol, 2.9 equiv.) was added. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give (E)-N-(5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (290.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=411.

Step 7: N-(5-(4-(4-(trifluoromethyl)phenyl)butan-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide

[0940] (E)-N-(5-(4-(4-(trifluoromethyl)phenyl)buta-1,3-dien-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (230.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt., 100.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 48 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give material that was further purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% to 85% in 8 min; 220 nm; RT1: 7.33 min. This resulted in N-(5-(4-(4-(trifluoromethyl)phenyl)butan-2-yl)-1H-indol-3-yl)cyclobutanecarboxamide (32.1 mg) as a white solid. LCMS Method D: [M+H].sup.+=415. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.63 (s, 1H), 9.58 (s, 1H), 7.71 (d, J=6.4 Hz, 1H), 7.63-7.61 (m, 3H), 7.39-7.37 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.00-6.97 (m, 1H), 3.39-3.33 (m, 2H), 2.76-2.74 (m, 1H), 2.60-2.54 (m, 1H), 2.28-2.23 (m, 2H), 2.13-2.10 (m, 2H), 1.97-1.90 (m, 3H), 1.88-1.83 (m, 1H), 1.29 (d, J=7.2 Hz, 3H).

Example 47: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (Compound 147)

[0941] ##STR00781## ##STR00782##

Step 1: tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate

[0942] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.1 mmol, 1.0 equiv.) was dissolved in THE (80.0 mL), then (BOc).sub.2O (4.2 g, 19.3 mmol, 1.2 equiv.), DMAP (0.2 g, 1.6 mmol, 0.1 equiv.) and TEA (4.6 mL, 32.1 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.5 g) as a white solid.

Step 2: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

[0943] tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.0 g, 14.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100.0 mL), then 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.6 g, 21.9 mmol, 1.5 equiv.), Pd(dppf)Cl.sub.2 (1.1 g, 1.5 mmol, 0.1 equiv.) and Cs.sub.2CO.sub.3 (9.5 g, 29.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C. under nitrogen, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g) as a white solid.

Step 3: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate

[0944] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g, 13.1 mmol, 1.0 equiv.) was dissolved in THE (80.0 mL) and cooled to 0° C. Then NaOH (1.6 g, 39.3 mmol, 3.0 equiv.) was added at 0° C., followed by the addition of H.sub.2O.sub.2 (3.0 g, 26.2 mmol, 2.0 equiv., 30%) dropwise, maintaining the reaction mixture at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of brine. The resulting resolution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (2.2 g) as a grey solid.

Step 4: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate

[0945] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.) and cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.2 g, 5.7 mmol, 2.0 equiv.) were dissolved in THE (20.0 mL) and cooled to 0° C., then n-Bu.sub.3P (1.7 g, 8.6 mmol, 3.0 equiv.) was added at 0° C. under an atmosphere of nitrogen. This was followed by the addition of ADDP (2.2 g, 8.6 mmol, 3.0 equiv.) dropwise, maintaining the solution at 0° C. The reaction mixture was heated to 50° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 45% phase B to 70% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.2 g) as an off-white solid.

Step 5: 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt

[0946] tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)-1H-indole-1-carboxylate (190.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DCM (2.0 mL), then TFA (2.0 mL) was added. The resulting mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum to give 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (120.0 mg) as a white solid.

Step 6: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide

[0947] 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THE (5.0 mL), then cyclopropanecarboxylic acid (29.8 mg, 0.3 mmol, 1.2 equiv.), HATU (131.7 mg, 0.3 mmol, 1.2 equiv.) and DIEA (0.1 mL, 0.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 30% to 60% gradient in 30 min; detector, UV 254 nm. The resulting material was further purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Aqueous (10 mmol/L NH.sub.4HCO.sub.3) and ACN (43% ACN up to 73% in 7 min). This resulted in N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (12.1 mg) as a white solid. [M+H].sup.+=415. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (d, J=1.6 Hz, 1H), 9.91 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.26-7.16 (m, 2H), 6.75-6.72 (m, 1H), 4.98-4.88 (m, 1H), 3.83-3.77 (m, 1H), 2.75-2.59 (m, 4H), 1.94-1.89 (m, 1H), 0.82-0.76 (m, 4H).

Example 48: N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (Compound 271)

[0948] ##STR00783##

[0949] tert-Butyl 3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in dioxane (5 mL), then tributyl(((4-(trifluoromethyl)benzyl)oxy)methyl)stannane (324.7 mg, 0.7 mmol, 1.2 equiv.), cataCXium A-Pd-G2 (37.8 mg, 0.1 mmol, 0.1 equiv.) and cataCXium A (40.5 mg, 0. mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 110° C. for 6 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give material which was further purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, Sum; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 52% B in 8 min; Wave Length: 254/220 nm. This gave N-(5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (24.0 mg) as a white solid. LCMS Method E: [M+H].sup.+=364. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.33 (s, 1H), 9.99 (s, 1H), 8.23-8.21 (m, 2H), 7.76 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 4.68-4.66 (m, 4H), 2.08 (s, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 48.

TABLE-US-00039 Example # Compound No. Starting materials Used Structure LCMS data 49 276 [00784] embedded image [00785] Method D: MS-ESI: 379 [M − H].sup.−. 50 272 [00786] [00787] Method F: MS-ESI: 375 [M − H].sup.−.

Example 51: N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)acetamide (Compound 283)

[0950] ##STR00788##

[0951] 2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in THE (8 mL), then N-(5-hydroxy-1H-indol-3-yl)acetamide (160.3 mg, 0.8 mmol, 1.0 equiv.), ADDP (422.0 mg, 1.7 mmol, 2.0 equiv.) and TBUP (340.5 mg, 1.7 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeOH in water, 1000 to 500% gradient in 10 min; detector, UV 254 nm. The resulting material was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30*150 mm 5 am, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21B to 35% B in 7 min; Wave Length: 254, 220 nm, RT1: 6.23 min. This gave N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)acetamide (25.8 mg) as a white solid. LCMS Method D: [M+H].sup.+=410. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 7.22-7.19 (m, 2H), 6.81-6.78 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.14-3.06 (m, 2H), 2.73-2.71 (m, 2H), 2.59-2.54 (m, 2H), 2.52-2.48 (m, 2H), 2.21 (s, 3H), 2.19-2.14 (m, 2H), 2.04-1.98 (m, 1H), 1.92-1.84 (m, 2H), 1.14-1.06 (in, 2H).

The analogs prepared in the following table were prepared using the same method described for Example 51.

TABLE-US-00040 Ex- Com- Starting ample pound materials LCMS # No. Used Structure Condition data 52 255 4- (trifluoro- methyl) phenol/ Intermediate 51 [00789] embedded image PPh.sub.3, DIAD, THF Method G MS-ESI: 364 [M + H].sup.+. 53 259 4- (trifluoro- methyl) phenol/ Intermediate 58 [00790] TBUP, ADDP, THF Method F: MS-ESI: 378 [M + H].sup.+. 54 264 4- (trifluoro- methyl) phenol/ Intermediate 50 [00791] TBUP, ADDP, THF Method F: MS-ESI: 377 [M + H].sup.+. 55 270 4- (trifluoro- methyl) phenol/ Intermediate 49 [00792] embedded image TBUP, ADDP, THF Method D: MS-ESI: 379 [M − H].sup.−. 56 277 Intermediate 45/ Intermediate 20 [00793] TBUP, ADDP, THF Method F: MS-ESI: 402 [M + H].sup.+. 57 278 Intermediate 7/ Intermediate 68 [00794] TBUP, ADDP, THF Method E: MS-ESI: 353 [M + H].sup.+. 58 289 Intermediate 7/ Intermediate 65 [00795] embedded image TBUP, ADDP, THF Method G: MS-ESI: 389 [M + H].sup.+. 59 167 Intermediate 54/6- (trifluoro- methyl) pyridin-3- ol [00796] TBUP, ADDP, THF Method F: MS-ESI: 390 [M + H].sup.+.

Example 60/61: N-(5-((1-(4-(trifluoromethyl)phenyl)propan-2-yl)oxy)-1H-indol-3-yl)acetamide (Compound 286) (Front Peak, Absolute Stereochemistry Unconfirmed) and (Compound 285) (Second Peak, Absolute Stereochemistry Unconfirmed)]

[0952] ##STR00797##

Step 1: N-[5-([1-[4-(trifluoromethyl)phenyl]propan-2-yl]oxy)-1H-indol-3-yl]acetamide

[0953] N-(5-hydroxy-1H-indol-3-yl)acetamide (500.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then 1-[4-(trifluoromethyl)phenyl]propan-2-ol (536.8 mg, 2.6 mmol, 1.0 equiv.), TBUP (1.1 g, 5.2 mmol, 2.0 equiv.) and ADDP (1.3 g, 5.3 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at ambient temperature under nitrogen, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-[5-([1-[4-(trifluoromethyl)phenyl]propan-2-yl]oxy)-1H-indol-3-yl]acetamide (33 mg) as a light yellow oil. LCMS Method A: [M+H].sup.+=377.

Step 2: Example 60 (Compound 286) (Front Peak, Absolute Stereochemistry Unconfirmed) and Example 61 (Compound 285) (Second Peak, Absolute Stereochemistry Unconfirmed)

[0954] The racemic N-[5-([1-[4-(trifluoromethyl)phenyl]propan-2-yl]oxy)-1H-indol-3-yl]acetamide (20.0 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2*25 cm, 5 m; Mobile Phase A: Hex (0.5% 2M NH.sub.3-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 13 min; Wave Length: 220/254 nm; RT1 (min): 9.03; RT2(min): 11.75. This gave Compound 286 (front peak, 1.3 mg) as a white solid and Compound 285 (second peak, 3.1 mg) as a white solid.

[0955] Example 60 (Compound 286): LCMS Method G: [M+H].sup.+=377. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.56 (s, 1H), 9.66 (s, 1H), 7.68-7.64 (m, 3H), 7.54 (d, J=8.0 Hz, 2H), 7.33 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.70-6.67 (m, 1H), 4.64-4.60 (m, 1H), 3.09-3.00 (m, 2H), 2.08 (s, 3H), 1.26 (d, J=6.0 Hz, 3H).

[0956] Example 61 (Compound 285): LCMS Method G: [M+H].sup.+=377. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.56 (s, 1H), 9.66 (s, 1H), 7.68-7.64 (m, 3H), 7.54 (d, J=8.0 Hz, 2H), 7.33 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.70-6.67 (m, 1H), 4.64-4.60 (m, 1H), 3.09-3.00 (m, 2H), 2.08 (s, 3H), 1.26 (d, J=6.0 Hz, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 60/61.

TABLE-US-00041 Starting Example # Compound No. materials Used Structure LCMS data 62 280 Intermediate 7/ Intermediate 67 [00798] embedded image Method G: MS-ESI: 384 [M + H].sup.+. front peak, absolute stereochemistry unconfirmed 63 279 Intermediate 7/ Intermediate 67 [00799] Method G: MS-ESI: 384 [M + H].sup.+. second peak, absolute stereochemistry unconfirmed

Example 64: N-(5-(2-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-1H-indol-3-yl)acetamide (Compound 171)

[0957] ##STR00800##

Step 1: tert-butyl 3-acetamido-5-{2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethoxy}indole-1-carboxylate

[0958] 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethanol (180.0 mg, 0.8 mmol, 1.0 equiv.) and tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate (234.1 mg, 0.8 mmol, 1.0 equiv.) were dissolved in THE (4 mL), then TBUP (326.3 mg, 1.6 mmol, 2.0 equiv.) and ADDP (403.7 mg, 1.6 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 70° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 100% gradient in 15 min; detector, UV 254 nm. This gave tert-butyl 3-acetamido-5-{2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethoxy}indole-1-carboxylate (220.0 mg) as a light yellow solid. LCMS Method A: [M+H].sup.+=496.

Step 2: N-(5-(2-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-1H-indol-3-yl)acetamide

[0959] tert-Butyl 3-acetamido-5-{2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethoxy}indole-1-carboxylate (200.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL), then K.sub.2CO.sub.3 (167.3 mg, 1.2 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 70° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.3.H.sub.2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 53% B in 8 min; Wave Length: 220 nm; RT1: 7.58 min. This gave N-(5-(2-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-1H-indol-3-yl)acetamide (110.0 mg) as a pale white solid. LCMS Method E: [M+H].sup.+=396. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.54 (s, 1H), 9.68 (s, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.71-6.89 (m, 1H), 3.87 (t, J=6.4 Hz, 2H), 3.35-3.33 (m, 2H), 3.24 (s, 2H), 3.14-3.06 (m, 2H), 2.33-2.24 (m, 3H), 2.08 (s, 3H), 1.81-1.79 (m, 4H).

The analogs prepared in following table were prepared using the same method described for Example 64.

TABLE-US-00042 Example Compound Starting # No. materials Used Structure Condition LCMS data 65 281 Intermediate 20/ Intermediate 46 [00801] embedded image TBUP, ADDP, THF Method F: MS-ESI: 398 [M + H].sup.+. 66 267 2-(4- (trifluoromethyl) phenyl) ethan-1-ol/ Intermediate 47 [00802] TBUP, ADDP, THF Method E: MS-ESI: 364 [M + H].sup.+. 67 262 Intermediate 69/ Intermediate 10 [00803] TBUP, ADDP, THF Method F: MS-ESI: 361 [M + H].sup.+. 68 257 Intermediate 70/ Intermediate 10 [00804] embedded image PPh.sub.3, DIAD, THF Method F: MS-ESI: 447 [M + H].sup.+. 69 254 Intermediate 71/ Intermediate 10 [00805] TBUP, ADDP, THF Method G: MS-ESI: 433 [M + H].sup.+. 70 247 (4- (trifluoromethyl) phenyl) methanol/ Intermediate 10 [00806] TBUP, ADDP, THF Method F: MS-ESI: 349 [M + H].sup.+. 71 232 Intermediate 11/6- (trifluoro- methyl)pyridin- 3-ol [00807] embedded image TBUP, ADDP, THF Method F: MS-ESI: 364 [M + H].sup.+. 72 230 Intermediate 11/4- cyclobutyl- phenol [00808] TBUP, ADDP, THF Method F: MS-ESI: 349 [M + H].sup.+. 73 231 Intermediate 11/3- (trifluoro- methyl)phenol [00809] TBUP, ADDP, THF Method F: MS-ESI: 363 [M + H].sup.+. 74 214 Intermediate 11/3,4- dichloro- phenol [00810] embedded image PPh.sub.3, DIAD, THF Method F: MS-ESI: 363 [M + H].sup.+. 75 228 Intermediate 11/4- methylphenol [00811] TBUP, ADDP, THF Method F: MS-ESI: 309 [M + H].sup.+. 76 229 Intermediate 11/4- chlorophenol [00812] TBUP, ADDP, THF Method F: MS-ESI: 329 [M + H].sup.+. 77 225 Intermediate 11/ Intermediate 73 [00813] embedded image TBUP, ADDP, THF Method E: MS-ESI: 385 [M + H].sup.+. 78 226 Intermediate 11/ Intermediate 74 [00814] CMPB, toluene Method F: MS-ESI: 379 [M + H].sup.+. 79 224 Intermediate 11/ Intermediate 75 [00815] TBUP, ADDP, THF Method F: MS-ESI: 413 [M + H].sup.+. 80 208 Intermediate 11/ Intermediate 77 [00816] embedded image TBUP, ADDP, THF Method F: MS-ESI: 474 [M + H].sup.+. 81 198 Intermediate 11/ Intermediate 78 [00817] TBUP, ADDP, THF Method F: MS-ESI: 474 [M + H]+. 82 197 Intermediate 79/ Intermediate 10 [00818] TBUP, ADDP, THF Method F: MS-ESI: 353 [M + H].sup.+. 83 196 Intermediate 80/ Intermediate A10 [00819] embedded image PPh.sub.3, DIAD, THF Method D: MS-ESI: 453 [M + H].sup.+. 84 184 Intermediate 11/2- (trifluoromethyl) pyrimidin- 5-ol [00820] TBUP, ADDP, THF Method E: MS-ESI: 365 [M + H].sup.+. 85 273 Intermediate 57/4- (trifluoro- methyl)phenol [00821] TBUP, ADDP, THF Method F: MS-ESI: 379 [M + H].sup.+. 86 253 Intermediate 72/ Intermediate 10 [00822] embedded image TBUP, ADDP, THF Method G: MS-ESI: 480 [M + H].sup.+. 87 168 Intermediate 55/p- methylphenol [00823] TBUP, ADDP, THF Method E: MS-ESI: 323 [M + H].sup.+. 88 169 Intermediate 62/ Intermediate 10 [00824] TBUP, ADDP, THF Method F: MS-ESI: 419 [M − H].sup.−. 89 170 Intermediate 11/ Intermediate 76 [00825] embedded image TBUP, ADDP, THF Method E: MS-ESI: 460 [M + H].sup.+.

Examples 90: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (Compound 147)

[0960] ##STR00826##

[0961] 5-(trans-3-(4-(Trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THE (5 mL), then cyclopropanecarboxylic acid (29.8 mg, 0.3 mmol, 1.2 equiv.), HATU (131.7 mg, 0.3 mmol, 1.2 equiv.) and DIEA (74.6 mg, 0.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 30% B to 60% B gradient in 30 min; detector, UV 254 nm. The resulting crude product was further purified by Prep-HPLC with the following conditions: Column, XBridgePrep OBD C18 Column, 30*150 mm, 5 m; mobile phase, Water (10 mM NH.sub.4HC.sub.3) and ACN (430 ACN up to 73% in 7 min). This gave N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (29.8 mg) as a white solid. LCMS Method 68: [M+H].sup.+=415. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (d, J=2.0 Hz, 1H), 9.91 (s, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.24-7.18 (m, 2H), 6.75-6.72 (m, 1H), 4.95-4.91 (m, 1H), 3.81-3.78 (m, 1H), 2.71-2.63 (m, 4H), 1.93-1.89 (m, 1H), 0.81-0.78 (in, 4H).

The analogs prepared in the following table were prepared using the same method described for Example 90.

TABLE-US-00043 Ex- Compound Starting ample # No. materials Used Structure LCMS data 91 258 Intermediate 85/ 2-methoxyacetic acid [00827] embedded image Method E: MS-ESI: 419 [M + H].sup.+. 92 260 Intermediate 86/ methoxyacetic acid [00828] Method E: MS-ESI: 419 [M + H].sup.+. 93 252 Intermediate 33/ cyclopropane- carboxylic acid [00829] Method F: MS-ESI: 387 [M + H].sup.+. 94 251 Intermediate 33/ 1- methylcyclo- propane-1- carboxylic acid [00830] embedded image Method F: MS-ESI: 403 [M + H].sup.+. 95 249 Intermediate 33/ 3,3- difluorocyclo- butane-1- carboxylic acid [00831] Method F: MS-ESI: 437 [M − H].sup.−. 96 241 Intermediate 85/ 3- methoxy- propanoic acid [00832] Method E: MS-ESI: 433 [M + H].sup.+. 97 244 Intermediate 85/ 1-(2,2,2- trifluoroethyl) azetidine-3- carboxylic acid [00833] embedded image Method D: MS-ESI: 512 [M + H].sup.+. 98 243 Intermediate 86/ 1-(2,2,2- trifluoroethyl) azetidine-3- carboxylic acid [00834] Method D: MS-ESI: 512 [M + H].sup.+. 99 227 Intermediate 85/ Intermediate 102 [00835] Method D: MS-ESI: 524 [M − H].sup.−. 100 221 Intermediate 92/ cis-3- methoxycyclo- butane-1- carboxylic acid [00836] embedded image Method F: MS-ESI: 433 [M + H].sup.+. 101 220 Intermediate 92/ trans-3- methoxycyclo- butane-1- carboxylic acid [00837] Method D: MS-ESI: 431 [M − H].sup.−. 102 222 Intermediate 33/ cis-3- methoxycyclo- butane-1- carboxylic acid [00838] Method F: MS-ESI: 433 [M + H].sup.+. 103 219 Intermediate 92/ 1-(2,2,2- trifluoroethyl) azetidine-3- carboxylic acid [00839] embedded image Method F: MS-ESI: 486 [M + H].sup.+. 104 211 Intermediate 33/ trans-3- methoxycyclo- butane-1- carboxylic acid [00840] Method D: MS-ESI: 431 [M − H].sup.−. 105 210 Intermediate 33/ 1-(2,2,2- trifluoroethyl) azetidine-3- carboxylic acid [00841] Method F: MS-ESI: 486 [M + H].sup.+. 106 195 Intermediate 88/ 1-(2,2,2- trifluoroethyl) azetidine-3- carboxylic acid [00842] embedded image Method E: MS-ESI: 487 [M + H].sup.+. 107 194 Intermediate 88/ trans-3- methoxycyclo- butane-1- carboxylic acid [00843] Method D: MS-ESI: 434 [M + H].sup.+. 108 183 Intermediate 89/ cyclopropane- carboxylic acid [00844] Method F: MS-ESI: 459 [M + H].sup.+. 109 182 Intermediate 90/ cyclopropane- carboxylic acid [00845] embedded image Method D: MS-ESI: 436 [M + H].sup.+. 110 148 Intermediate 85/ 3-methyloxetane- 3-carboxylic acid [00846] Method E: MS-ESI: 445 [M + H].sup.+. 111 163 Intermediate 33/ oxetane-3- carboxylic acid [00847] Method F: MS-ESI: 405 [M + H].sup.+. 112 165 Intermediate 92/ 3-methyloxetane- 3-carboxylic acid [00848] embedded image Method F: MS-ESI: 417 [M − H].sup.−. 113 164 Intermediate 92/ oxetane-3- carboxylic acid [00849] Method F: MS-ESI: 403 [M − H].sup.−.

Examples 114: N-(5-(cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (Compound 266)

[0962] ##STR00850##

[0963] 5-(cis-3-(4-(Trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THE (5 mL), then cyclopropanecarboxylic acid (29.8 mg, 0.3 mmol, 1.2 equiv.), HATU (131.7 mg, 0.3 mmol, 1.2 equiv.) and DIEA (74.6 mg, 0.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 30% B to 60% B gradient in 30 min; detector, UV 254 nm. The resulting material was further purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mM NH.sub.4HCO.sub.3) and ACN (43% ACN up to 73% in 7 min). This gave N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropanecarboxamide (30.1 mg) as a white solid. LCMS Method E: [M+H].sup.+=415. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (d, J=2.0 Hz, 1H), 9.95 (s, 1H), 7.70-7.66 (m, 3H), 7.54 (d, J=8.0 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.75-6.72 (m, 1H), 4.73-4.69 (m, 1H), 3.32-3.30 (m, 1H), 3.06-2.99 (m, 2H), 2.22-2.14 (m, 2H), 1.96-1.91 (m, 1H), 0.84-0.76 (m, 4H).

Example 115: 1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropane-1-carboxamide (Compound 261)

[0964] ##STR00851##

[0965] 5-(trans-3-(4-(Trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THE (5 mL), then 1-methylcyclopropane-1-carboxylic acid (34.5 mg, 0.3 mmol, 1.2 equiv.), HATU (131.7 mg, 0.3 mmol, 1.2 equiv.) and DIEA (74.6 mg, 0.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH.sub.4HCO.sub.3 in water; mobile phase B: Acetonitrile, 30% B to 60% B gradient in 30 min; detector, UV 254 nm. The resulting crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 M m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 75% B in 7 min; Wave Length: 220 nm. This gave 1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclopropane-1-carboxamide (19.9 mg) as a white solid. LCMS Method E: [M+H].sup.+=429. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.66 (s, 1H), 8.96 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.75-6.73 (m, 1H), 4.95-4.91 (m, 1H), 3.85-3.79 (m, 1H), 2.64-2.61 (m, 4H), 1.45 (s, 3H), 1.09-1.07 (m, 2H), 0.62-0.60 (m, 2H).

The analogs prepared in in the following table were prepared using the same method described for Example 115.

TABLE-US-00044 Example Compound LCMS # No. Starting materials Used Structure data 116 263 [00852] embedded image [00853] Method E: MS-ESI: 336 [M + H].sup.+.

Example 117: cis-3-methoxy-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 246)

[0966] ##STR00854##

[0967] 5-(trans-3-(4-(Trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (250 mg, 0.7 mmol, 1.5 equiv.) was dissolved in DCM (5 mL), then cis-3-methoxycyclobutane-1-carboxylic acid (62.6 mg, 0.4 mmol, 1.0 equiv.), HATU (274.4 mg, 0.7 mmol, 1.5 equiv.) and DIEA (310.9 mg, 2.4 mmol, 5.0 equiv.) were added. The reaction mixture was stirred for 0.5 hour at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 69% B in 8 min; Wave Length: 220 nm. This gave cis-3-methoxy-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (53.9 mg) as a white solid. LCMS Method F: [M+H].sup.+=459. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.60 (s, 1H), 9.64 (s, 1H), 7.76-7.71 (m, 3H), 7.60 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.75-6.72 (m, 1H), 4.93-4.89 (m, 1H), 3.82-3.78 (m, 2H), 3.15 (s, 3H), 2.84-2.81 (m, 1H), 2.68-2.63 (m, 4H), 2.42-2.37 (m, 2H), 2.07-2.02 (m, 2H).

The analogs prepared in the following table were prepared using the same method described for Example 117.

TABLE-US-00045 Example Compound Starting LCMS # No. materials Used Structure data 118 242 Intermediate 85/ trans-3- methoxy- cyclobutane- 1-carboxylic acid [00855] embedded image Method E: MS-ESI: 459 [M + H].sup.+. 119 245 Intermediate 86/ cis-3- methoxycyclo- butane-1- carboxylic acid [00856] Method E: MS-ESI: 459 [M + H].sup.+.

Example 120: N-(5-(2-(4-(trifluoromethyl)phenoxy)propyl)-1H-indol-3-yl)acetamide (Compound 287)

[0968] ##STR00857##

[0969] 5-[2-[4-(Trifluoromethyl)phenoxy]propyl]-1H-indol-3-amine (100.0 mg, 0.2 mmol, 1.0 equiv.) and TEA (90.8 mg, 0.8 mmol, 3.0 equiv.) were dissolved in ACN (10 mL) and cooled to 0° C., then and AcCl (70.4 mg, 0.8 mmol, 3.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 67% B in 8 min; Wave Length: 220 nm; RT1: 7.7 min. This gave N-(5-[2-[4-(trifluoromethyl)phenoxy]propyl]-1H-indol-3-yl)acetamide (10.5 mg) as a white solid. LCMS Method E: [M−H].sup.−=375. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=1.2 Hz, 1H), 9.78 (s, 1H), 7.66-7.62 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.06-7.04 (m, 1H), 4.82-4.76 (m, 1H), 3.14-3.09 (m, 1H), 2.92-2.87 (m, 1H), 2.09 (s, 3H), 1.27 (d, J=6.0 Hz, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 120.

TABLE-US-00046 Example Com- LCMS pound # No. Starting materials Used Structure data 121 250 [00858] embedded image [00859] Method F: MS-ESI: 378 [M + H].sup.+. 122 248 [00860] [00861] Method D: MS-ESI: 364 [M + H].sup.+. 123 233 [00862] [00863] Method F: MS-ESI: 390 [M + H].sup.+. 124 223 [00864] [00865] Method F: MS-ESI: 381 [M + H].sup.+. 125 213 [00866] [00867] Method E: MS-ESI: 379 [M − H].sup.−. 126 212 [00868] embedded image [00869] Method E: MS-ESI: 351 [M + H].sup.+.

Example 127/128: N-(5-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide (Compound 240) and N-(5-(1-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide (Compound 209)

[0970] ##STR00870##

Step 1: (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclopropanecarboxamide

[0971] N-(5-Bromo-1H-indol-3-yl)cyclopropanecarboxamide (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (15 mL) and water (1.5 mL), then 4,4,5,5-tetramethyl-2-[(1E)-3-[4-(trifluoromethyl)phenyl]prop-1-en-1-yl]-1,3,2-dioxaborolane (559.1 mg, 1.7 mmol, 1.0 equiv.), Cs.sub.2CO.sub.3 (1167.2 mg, 3.5 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (145.9 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. for 12 hours under nitrogen, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclopropanecarboxamide (400.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=385.

Step 2: N-(5-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide and N-(5-(1-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide

[0972] (E)-N-(5-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1H-indol-3-yl)cyclopropanecarboxamide (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then BH.sub.3-THF (1M, 1.6 mL, 1.6 mmol, 4.0 equiv.) was added dropwise. After 1 hour at ambient temperature, NaOH (31.2 mg, 0.8 mmol, 2.0 equiv.) in water (0.5 mL) and H.sub.2O.sub.2 (26.6 mg, 0.8 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (0.5% NH.sub.4HCO.sub.3), 0% ACN to 100% gradient in 15 min; detector, UV 254 nm. The resulting material was further purified by Prep-HPLC with the following conditions: Column: Kinetex EVO prep C18, 30*150, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: MeOH-HPLC; Flow rate: 60 mL/min; Gradient: 50% B to 70% B in 7 min; Wave Length: 220 nm. This gave N-(5-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide (38.1 mg, Peak 1, RT=7.65 min) as a white solid and N-(5-(1-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide (3.8 mg, Peak 2, RT=8.00 min) as a white solid.

[0973] Peak 1: Compound 240: LCMS Method F: [M−H].sup.−=401. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.62 (s, 1H), 10.01 (s, 1H), 7.63-7.61 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.00-6.98 (m, 1H), 4.74 (d, J=6.4 Hz, 1H), 3.98-3.95 (m, 1H), 2.86-2.66 (m, 4H), 1.99-1.93 (m, 1H), 0.80-0.76 (m, 4H).

[0974] Peak 2: Compound 209: LCMS Method F: [M−H].sup.−=401. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.64 (d, J=2.0 Hz, 1H), 10.06 (s, 1H), 7.79 (s, 1H), 7.67-7.63 (m, 3H), 7.44 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.4 Hz, 1H), 7.11-7.09 (m, 1H), 5.23 (d, J=4.0 Hz, 1H), 4.62-4.58 (m, 1H), 2.73-2.68 (m, 2H), 2.03-1.94 (m, 3H), 0.80-0.75 (m, 4H).

The analogs prepared in the following table were prepared using the same method described for Example 127/128.

TABLE-US-00047 Starting Example # Compound No. materials Used Structure LCMS data 129 284 Intermediate 34/ Intermediate 1 [00871] embedded image Method F: MS-ESI: 377 [M + H].sup.+. 130 282 Intermediate 34/ Intermediate 1 [00872] Method F: MS-ESI: 377 [M + H].sup.+. 131 174 Intermediate 34/ Intermediate 38 [00873] Method F: MS-ESI: 417 [M + H].sup.+. 132 172 Intermediate 34/ Intermediate 38 [00874] Method F: MS-ESI: 417 [M + H].sup.+.

Example 133/134: N-(5-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide [(Compound 201) (Front Peak, Absolute Stereochemistry Unconfirmed) and (Compound 200) (Second Peak, Absolute Stereochemistry Unconfirmed)]

[0975] ##STR00875##

[0976] The racemic N-(5-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-1H-indol-3-yl)cyclopropanecarboxamide (28.0 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2*25 cm, 5 m; Mobile Phase A: Hex (0.5% 2M NH.sub.3-MeOH)-HPLC, Mobile Phase B: EtOH:DCM=1:1-HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 17 min; Wave Length: 220/254 nm; RT1(min): 11.732; RT2(min): 14.323. This gave (Compound 201) (front peak, 4.9 mg) as a white solid and (Compound 200) (second peak, 5.8 mg) as a white solid.

[0977] Example 133 (Compound 201) (Peak 1): LCMS Method D: [M−H].sup.−=401. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.61 (s, 1H), 10.00 (s, 1H), 7.63-7.61 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.00-6.98 (m, 1H), 4.74 (d, J=6.4 Hz, 1H), 3.98-3.95 (m, 1H), 2.86-2.66 (m, 4H), 1.99-1.93 (m, 1H), 0.80-0.74 (m, 4H).

[0978] Example 134 (Compound 200) (Peak 2): LCMS Method D: [M−H].sup.−=401. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.61 (s, 1H), 10.00 (s, 1H), 7.63-7.61 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.00-6.98 (m, 1H), 4.74 (d, J=6.4 Hz, 1H), 3.98-3.95 (m, 1H), 2.86-2.66 (m, 4H), 1.99-1.93 (m, 1H), 0.80-0.74 (m, 4H).

Example 135: N-(5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)butyl)-1H-indol-3-yl)acetamide (Compound 275)

[0979] ##STR00876##

Step 1: tert-butyl (E)-3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)but-1-en-1-yl)-1H-indole-1-carboxylate

[0980] 4-(2-Methylbut-3-en-2-yl)-1-(2,2,2-trifluoroethyl)piperidine (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3 mL), then TEA (0.2 mL, 1.3 mmol, 2.0 equiv.), tert-butyl 5-bromo-3-acetamidoindole-1-carboxylate (225.2 mg, 0.6 mmol, 1.0 equiv.) and Pd(DtBPF)Cl.sub.2 (41.6 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 120° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give tert-butyl (E)-3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)but-1-en-1-yl)-1H-indole-1-carboxylate (110.0 mg) as a pale yellow solid. LCMS Method A: [M+H]+=508.

Step 2: tert-butyl 3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)butyl)-1H-indole-1-carboxylate

[0981] tert-Butyl (E)-3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)but-1-en-1-yl)-1H-indole-1-carboxylate (110.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (9.2 mg, 0.1 mmol, 0.4 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 3 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl 3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)butyl)-1H-indole-1-carboxylate (105.0 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=510.

Step 3: N-(5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)butyl)-1H-indol-3-yl)acetamide

[0982] tert-Butyl 3-acetamido-5-(3-methyl-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)butyl)-1H-indole-1-carboxylate (80.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL), then K.sub.2CO.sub.3 (43.4 mg, 0.3 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 70° C. for 50 min, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 65% B in 8 min; Wave Length: 220 nm; RT1: 7.67 min. This gave N-(5-[3-methyl-3-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]butyl]-1H-indol-3-yl)acetamide (15.9 mg) as an off-white solid. LCMS Method F: [M+H].sup.+=410. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.71 (s, 1H), 7.64 (s, 1H), 7.59-7.55 (m, 1H), 7.24-7.19 (m, 1H), 6.91 (d, J=8.4 Hz, 1H), 3.15-3.05 (m, 2H), 3.00-2.96 (m, 2H), 2.59-2.56 (m, 2H), 2.31-2.23 (m, 2H), 2.08 (s, 3H), 1.63-1.59 (m, 2H), 1.53-1.47 (m, 2H), 1.34-1.11 (m, 3H), 0.90 (s, 6H).

The analogs prepared in the following table were prepared using the same method described for Example 135.

TABLE-US-00048 Starting Example Compound materials # No. Used Structure LCMS data 136 288 Intermediate 100/ Intermediate 2 [00877] embedded image Method F: MS-ESI: 384 [M+H].sup.+.

Example 137: N-(5-((((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)methyl)-1H-indol-3-yl)acetamide (Compound 274)

[0983] ##STR00878##

Step 1: (1R,5S,6S)-6-{[(tert-butyldimethylsilyl)oxy]methyl}-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane

[0984] [(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methanol (2.2 g, 11.2 mmol, 1.0 equiv.) was dissolved in DCM (100 mL), then imidazole (1.5 g, 22.5 mmol, 2.0 equiv.) and TBSCl (3.4 g, 22.5 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with DCM, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give (1R,5S,6S)-6-{[(tert-butyldimethylsilyl)oxy]methyl}-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane (2.4 g) as an off-white oil. LCMS Method A: [M+H].sup.+=310.

Step 2: tert-butyl 3-acetamido-5-([[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]methyl)indole-1-carboxylate

[0985] (1R,5S,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane (200.0 mg, 0.6 mmol, 1.0 equiv.) and tert-butyl 5-formylindole-1-carboxylate (237.8 mg, 0.9 mmol, 1.5 equiv.) were dissolved in DCM (10 mL) and cooled to 0° C., then Et.sub.3SiH (165.0 mg, 1.4 mmol, 2.2 equiv.) and TMSOTf (215.0 mg, 0.9 mmol, 1.5 equiv.) were added. The reaction mixture was stirred overnight at 0° C. and then quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 3-acetamido-5-([[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]methyl)indole-1-carboxylate (100.0 mg) as a grey solid. LCMS Method A: [M+H].sup.+=482.

Step 3: N-[5-([[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]methyl)-1H-indol-3-yl]acetamide

[0986] tert-Butyl 3-acetamido-5-([[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo [3.1.0]hexan-6-yl]methoxy]methyl)indole-1-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in ethyl acetate (2 mL), then HCl/1,4-dioxane (4 M, 1 mL) was added. The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 35% B in 7 min; Wave Length: 254; 220 nm; RT1: 6.47 min. This gave N-[5-([[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]methyl)-1H-indol-3-yl]acetamide (1.4 mg) as a grey solid. LCMS Method E: [M+H].sup.+=382. LCMS Method F: [M+H].sup.+=410. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.73 (s, 1H), 9.83 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.69-4.65 (m, 2H), 3.46-3.27 (m, 2H), 3.07-3.02 (m, 2H), 2.68-2.61 (m, 4H), 2.08 (s, 3H), 1.51-1.23 (m, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 137.

TABLE-US-00049 Starting Example Compound materials LCMS # No. Used Structure data 138 268 Intermediate 21/ Intermediate 17 [00879] embedded image Method D: MS-ESI: 382 [M-H].sup.+.

Example 139: N-(5-(2-((5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)-1H-indol-3-yl)acetamide (Compound 199)

[0987] ##STR00880##

Step 1: tert-butyl 3-acetamido-5-(2-{[5-(trifluoromethyl) pyridin-2-yl]amino}ethyl)indole-1-carboxylate

[0988] tert-Butyl 5-(2-aminoethyl)-3-acetamidoindole-1-carboxylate (270.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in ACN (3 mL), then 2-fluoro-5-(trifluoromethyl)pyridine (168.5 mg, 1.0 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (235.1 mg, 1.7 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 80° C. for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl 3-acetamido-5-(2-{[5-(trifluoromethyl)pyridin-2-yl]amino}ethyl)indole-1-carboxylate (126.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=463.

Step 2: N-[5-(2-{[5-(trifluoromethyl) pyridin-2-yl]amino}ethyl)-1H-indol-3-yl]acetamide

[0989] tert-Butyl 3-acetamido-5-(2-{[5-(trifluoromethyl) pyridin-2-yl]amino}ethyl)indole-1-carboxylate (120.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in methanol (2 mL), then K.sub.2CO.sub.3 (143.5 mg, 1.0 mmol, 4.0 equiv.) was added. The reaction mixture was heated to 70° C. for 3 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 47% B in 8 min; Wave Length: 254/220 nm; RT1: 7.63 min. This gave N-[5-(2-{[5-(trifluoromethyl)pyridin-2-yl]amino}ethyl)-1H-indol-3-yl]acetamide (25.5 mg) as a white solid. LCMS Method D: [M+H].sup.+=363. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.65 (s, 1H), 9.79 (s, 1H), 8.33 (s, 1H), 7.66-7.64 (m, 3H), 7.44 (t, J=5.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.01-6.99 (m, 1H), 6.60 (d, J=8.8 Hz, 1H), 3.59-3.55 (m, 2H), 2.92-2.89 (m, 2H), 2.08 (s, 3H).

The analogs prepared in the following table were prepared using the same method described for Example 139.

TABLE-US-00050 Example Compound Starting LCMS # No. materials Used Structure data 140 215 Intermediate 11 [00881] embedded image Method E: MS-ESI: 364 [M+H].sup.+.

Example 141: N-(5-(((4-(trifluoromethyl)phenyl)sulfonamido)methyl)-1H-indol-3-yl)acetamide (Compound 265)

[0990] ##STR00882##

[0991] N-[5-(aminomethyl)-1H-indol-3-yl]acetamide (50.0 mg, 0.2 mmol, 1.0 equiv.) and TEA (0.1 mL, mg, 0.5 mmol, 2.0 equiv.) were dissolved in THE (5 mL), then 4-(trifluoromethyl)benzenesulfonyl chloride (60.1 mg, 0.2 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 53% B in 7 min; Wave Length: 220 nm. This gave N-(5-[[4-(trifluoromethyl)benzenesulfonamido]methyl]-1H-indol-3-yl)acetamide (24.5 mg) as an off-white solid. LCMS Method G: [M+H].sup.+=412. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.72 (s, 1H), 9.82 (s, 1H), 8.32 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.67-7.65 (m, 2H), 7.19 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.06 (d, J=6.0 Hz, 2H), 2.08 (s, 3H).

Example 142: N-(5-(2-((4-(trifluoromethyl)phenyl)thio)ethyl)-1H-indol-3-yl)acetamide (Compound 256)

[0992] ##STR00883##

[0993] N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide (254.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in THE (5 ml), then 4-(trifluoromethyl)benzenethiol (663.5 mg, 3.7 mmol, 3.2 equiv.) and TBUP (941.8 mg, 4.7 mmol, 4.0 equiv.) were added. This was followed by the addition of ADDP (582.7 mg, 2.3 mmol, 2.0 equiv.) at 0° C. under an atmosphere of nitrogen. The reaction mixture was heated to 70° C. for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 65% B in 8 min; Wave Length: 220 nm; RT1: 7.68 min. LCMS Method F: [M+H].sup.+=379. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.69 (s, 1H), 9.76 (s, 1H), 7.67-7.64 (m, 4H), 7.53 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.05-7.03 (m, 1H), 3.38-3.34 (m, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.08 (s, 3H).

Example 143: N-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide (Compound 173)

[0994] ##STR00884##

Step 1: 1-bromo-4-methyl-5-nitro-2-(4-(trifluoromethyl)phenethoxy)benzene

[0995] 1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (3.0 g, 12.8 mmol, 1.0 equiv.) and 2-(4-(trifluoromethyl)phenyl)ethan-1-ol (2.93 g, 15.4 mmol, 1.2 equiv.) were dissolved in ACN (30 mL) and cooled to 0° C., then KOH (1.1 g, 19.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at 0° C. then quenched by the addition of water.

[0996] The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:6) to give 1-bromo-4-methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}benzene (4.7 g) as a yellow solid. LCMS Method A: [M+H].sup.+=404.

Step 2: (E)-2-(4-bromo-2-nitro-5-(4-(trifluoromethyl)phenethoxy) phenyl)-N,N-dimethylethen-1-amine

[0997] 1-Bromo-4-methyl-5-nitro-2-(4-(trifluoromethyl)phenethoxy)benzene (2.7 g, 6.6 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), then DMF-DMA (10.0 mL, 75.4 mmol, 11.4 equiv.) was added. The reaction mixture was heated to 140° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum to give (E)-2-(4-bromo-2-nitro-5-(4-(trifluoromethyl)phenethoxy) phenyl)-N,N-dimethylethen-1-amine (2.5 g), which was used in the next step directly without further purification. LCMS Method A: [M+H].sup.+=459.

Step 3: 6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indole

[0998] (E)-2-(4-bromo-2-nitro-5-(4-(trifluoromethyl)phenethoxy)phenyl)-N,N-dimethylethen-1-amine (2.5 g, 5.4 mmol, 1.0 equiv.) was dissolved in EtOH (30 mL) and AcOH (30 mL), then Fe (5.5 g, 98.0 mmol, 18.0 equiv.) was added. The reaction mixture was heated to 90° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting mixture was adjusted to pH 7 with aqueous NaOH (5% wt./wt.), extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indole (850.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=384.

Step 4: 1-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one

[0999] 6-Bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indole (850.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0° C., then diethylaluminum chloride in hexane (1M, 3.3 mL, 3.3 mmol, 1.5 equiv.) was added dropwise. After 30 min at 0° C., AcCl (0.2 mL, 3.2 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred for additional 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 1-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one (740.0 mg) as a red solid. LCMS Method B: [M−H].sup.+=424.

Step 5: (Z)-1-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one oxime

[1000] 1-(6-Bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one (740.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), then NaOAc (284.8 mg, 3.5 mmol, 2.0 equiv.) and hydroxylamine hydrochloride (180.9 mg, 2.6 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 60° C. for 5 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give (Z)-1-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one oxime (620.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=441.

Step 6: N-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide

[1001] (Z)-1-(6-Bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)ethan-1-one oxime (300.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in ACN (5 mL) and cooled to 0° C., then concentrated H.sub.2SO.sub.4 (1 mL) was added dropwise. After 2 hours at ambient temperature, the reaction was quenched by the addition of water and adjusted to pH 7 with saturated aqueous NaHCO.sub.3. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 48% B to 63% B in 8 min; Wave Length: 220 nm; RT1: 7.03 min. This gave N-(6-bromo-5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide (10.7 mg) as an orange solid. LCMS Method F: [M−H].sup.−=439. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=1.6 Hz, 1H), 9.75 (s, 1H), 7.71-7.69 (m, 3H), 7.65 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.48 (s, 1H), 4.23 (t, J=6.8 Hz, 2H), 3.24 (t, J=6.8 Hz, 2H), 2.07 (s, 3H).

Example 144: 1-(2,2-difluoroethyl)-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)azetidine-3-carboxamide (Compound 149)

[1002] ##STR00885##

[1003] 5-{2-[4-(Trifluoromethyl)phenyl]ethoxy}-1H-indol-3-amine hydrochloride (178.4 mg, 0.5 mmol, 1.0 equiv.) was dissolved in ACN (5 mL), then potassium 1-(2,2-difluoroethyl)azetidine-3-carboxylate (101.5 mg, 0.5 mmol, 1.0 equiv.), TCFH (210.2 mg, 0.8 mmol, 1.5 equiv.) and NMI (123.0 mg, 1.5 mmol, 3.0 equiv.) were added. The reaction mixture was stirred for 8 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (0.5% NH.sub.4HCO.sub.3), 10% ACN to 50% gradient in 15 min; detector, UV 254 nm. The resulting material was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 M m; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 62% B in 8 min; Wave Length: 220 nm; RT1: 7.15 min. This gave 1-(2,2-difluoroethyl)-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)azetidine-3-carboxamide (93.5 mg) as a white solid. LCMS Method F: [M−H].sup.−=466. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.62 (s, 1H), 9.69 (s, 1H), 7.72-7.69 (m, 3H), 7.60 (d, J=8.0 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.74-6.72 (m, 1H), 6.11-5.81 (t, J.sub.1=56.0 Hz, J.sub.2=4.4 Hz, 1H), 4.20 (t, J=6.8 Hz, 2H), 3.57-3.50 (m, 3H), 3.38-3.34 (m, 2H), 3.20-3.16 (m, 2H), 2.86-2.81 (m, 2H).

Example 145: 3-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)oxetane-3-carboxamide (Compound 166)

[1004] ##STR00886##

[1005] 3-Methyloxetane-3-carboxylic acid (139.0 mg, 1.2 mmol, 1.0 equiv.) and HATU (682.7 mg, 1.8 mmol, 1.5 equiv.) were dissolved in DCM (5 mL), then DIEA (1.1 mL, 6.0 mmol, 5 equiv.) was added. After 2 min, 5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-amine TFA salt (754.9 mg, 1.8 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give 3-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)oxetane-3-carboxamide (91.0 mg) as a white solid. LCMS Method F: [M−H].sup.−=403. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.73 (s, 1H), 9.49 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.88-6.86 (m, 1H), 5.21 (s, 2H), 4.88 (d, J=6.0 Hz, 2H), 4.40 (d, J=6.0 Hz, 2H), 1.65 (s, 3H).

Example 146: 3-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)oxetane-3-carboxamide (Compound 238)

[1006] ##STR00887##

[1007] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indole-1-carboxylate (83.2 mg, 0.16 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), and TFA (500 μl) was added in the mixture. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. The residue and 3-methyloxetane-3-carboxylic acid (37.1 mg, 0.32 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (116 μl, 0.8 mmol, 5.0 equiv.) and HATU (63.8 mg, 0.168 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give 3-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)oxetane-3-carboxamide (14.5 mg, 0.035 mmol) as a powder. MS-ESI, 419.2 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.67 (br s, 1H), 9.46 (s, 1H), 7.71-7.64 (m, 3H), 7.63-7.56 (m, 2H), 7.27-7.24 (m, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.74 (dd, J=8.8 Hz, 1H), 4.85 (d, J=6.0 Hz, 2H), 4.38 (d, J=6.0 Hz, 2H), 4.21 (t, J=6.7 Hz, 2H), 3.23-3.10 (m, 2H), 1.63 (s, 3H).

Example 147: 1-(methoxymethyl)-N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)cyclopropane-1-carboxamide (Compound 176)

[1008] ##STR00888##

[1009] tert-butyl (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)carbamate (83.2 mg, 0.16 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. The residue and 1-(methoxymethyl)cyclopropane-1-carboxylic acid (41.6 mg, 0.32 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (116 μl, 0.8 mmol, 5.0 equiv.) and HATU (63.8 mg, 0.168 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give 1-(methoxymethyl)-N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)cyclopropanecarboxamide (14.5 mg, 0.035 mmol) as a powder. MS-ESI, 433.2 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.76 (br s, 1H), 9.20 (s, 1H), 7.68-7.55 (m, 3H), 7.40 (s, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.17-7.07 (m, 3H), 4.30 (t, J=6.9 Hz, 2H), 3.64 (s, 2H), 3.40 (s, 3H), 3.14 (br t, J=6.9 Hz, 2H), 1.15-1.06 (m, 2H), 0.86-0.71 (m, 2H).

Example 148: N-(5-{2-[(3aR,5S,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-1H-indol-3-yl)oxane-4-carboxamide (Compound 152)

[1010] ##STR00889##

[1011] tert-butyl 5-{2-[(3aR,5R,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-3-{[(tert-butoxy)carbonyl]amino}-1H-indole-1-carboxylate (85.1 mg, 0.15 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. Then the residue and tetrahydro-2H-pyran-4-carboxylic acid (39.0 mg, 0.30 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (109 μl, 0.75 mmol, 5.0 equiv.) and HATU (59.9 mg, 0.158 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give N-(5-{2-[(3aR,5S,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-1H-indol-3-yl)oxane-4-carboxamide (14.0 mg, 0.029 mmol) as a powder. MS-ESI, 480.1 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.55 (d, J=2.0 Hz, 1H), 9.64 (s, 1H), 7.68 (d, J=2.5 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.71 (dd, J=8.8, 2.4 Hz, 1H), 4.01-3.86 (m, 4H), 3.42-3.35 (m, 2H), 3.18 (q, J=10.3 Hz, 2H), 2.76-2.68 (m, 1H), 2.64 (d, J=8.4 Hz, 2H), 2.52 (d, J=1.9 Hz, 2H), 2.44-2.39 (m, 2H), 2.11-2.03 (m, 2H), 1.94-1.84 (m, 1H), 1.78 (q, J=6.5 Hz, 2H), 1.74-1.66 (m, 4H), 1.02-0.91 (m, 2H).

Example 149: 3-methoxy-N-{5-[(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}cyclobutane-1-carboxamide (Compound 159)

[1012] ##STR00890##

[1013] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-[(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indole-1-carboxylate (81.9 mg, 0.15 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. The residue and 3-methoxycyclobutane-1-carboxylic acid (39.0 mg, 0.30 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (109 μl, 0.75 mmol, 5.0 equiv.) and HATU (59.9 mg, 0.158 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give 3-methoxy-N-{5-[(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}cyclobutane-1-carboxamide (32.8 mg, 0.071 mmol) as a powder. MS-ESI, 459.3 [M+H+]0.1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br s, 1H), 9.68 (s, 1H), 7.74-7.65 (m, 3H), 7.53 (d, J=8.1 Hz, 2H), 7.28-7.18 (m, 2H), 6.71 (dd, J=8.7, 2.2 Hz, 1H), 4.68 (q, J=7.2 Hz, 1H), 3.93-3.68 (m, 1H), 3.31-3.26 (m, 1H), 3.18-3.12 (m, 3H), 3.05-2.96 (m, 2H), 2.92-2.76 (m, 1H), 2.43-2.37 (m, 2H), 2.20-2.03 (m, 4H).

Example 150: 3-methoxy-N-{5-[(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}cyclobutane-1-carboxamide (Compound 156)

[1014] ##STR00891##

[1015] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-{[4-(trifluoromethyl)phenyl]methoxy}-1H-indole-1-carboxylate (86.0 mg, 0.17 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give the residue. Then the residue and tetrahydro-2H-pyran-4-carboxylic acid (44.2 mg, 0.34 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (123 μl, 0.85 mmol, 5.0 equiv.) and HATU (68.0 mg, 0.179 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give N-(5-{[4-(trifluoromethyl)phenyl]methoxy}-1H-indol-3-yl)oxane-4-carboxamide (33.16 mg, 0.079 mmol) as a powder. MS-ESI, 419.3 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.67-10.60 (m, 1H), 9.68 (s, 1H), 7.80-7.75 (m, 2H), 7.73-7.68 (m, 3H), 7.45 (d, J=2.3 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.84 (dd, J=8.8, 2.3 Hz, 1H), 5.21 (s, 2H), 3.97-3.89 (m, 2H) 3.42-3.35 (m, 2H), 2.78-2.68 (m, 1H), 1.77-1.63 (in, 4H).

[1016] The analogs prepared in the following table were prepared using the above procedures with the appropriate starting material.

TABLE-US-00051 LC-MS, Example Compound MS-ESI, - # No. Structure - [M + H.sup.+]. 151 239 [00892] embedded image 433.2 152 218 [00893] 407.2 153 181 [00894] 425.2 154 180 [00895] 419.2 155 238 [00896] 419.2 156 237 [00897] 447.2 157 251 [00898] 403.2 158 193 [00899] 414.2 159 236 [00900] 431.2 160 235 [00901] 417.2 161 234 [00902] 433.2 162 192 [00903] 417.1 163 207 [00904] 421.2 164 191 [00905] embedded image 433.2 165 189 [00906] 433.2 166 217 [00907] 437.1 167 204 [00908] 433.2 168 187 [00909] 428.1 169 252 [00910] 389.3 170 186 [00911] 405.1 171 249 [00912] 439.2 172 185 [00913] 457.1 173 202 [00914] 419.2 174 178 [00915] 433.3 175 177 [00916] 437.2 176 176 [00917] 433.2 177 175 [00918] embedded image 441.1 178 161 [00919] 494.4 179 160 [00920] 480.3 180 151 [00921] 482.1 181 158 [00922] 459.3 182 157 [00923] 445.4 183 155 [00924] 403.3 184 154 [00925] 419.3 185 153 [00926] 419.3

Example 186: (1S,3S)-3-hydroxy-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 190)

[1017] ##STR00927##

[1018] tert-butyl 3-{[(tert-butoxy)carbonyl] amino}1-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indole-1-carboxylate (83.2 mg, 0.16 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), and TFA (500 μl) was added in the mixture. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. Then the residue and (1S,3S)-3-hydroxycyclobutane-1-carboxylic acid (37.1 mg, 0.32 mmol, 2.0 equiv.) were dissolved in ACN (2 mL), then NMI (0.5 mL) and TCFH (53.8 mg, 0.19 mmol, 1.2 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give (1S, 3S)-3-hydroxy-N-(5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indol-3-yl)cyclobutane-1-carboxamide (27.0 mg, 0.064 mmol) as a powder. MS-ESI, 419.1 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.61-10.52 (m, 1H), 9.57 (s, 1H), 7.69 (dd, J=5.2, 2.6 Hz, 3H), 7.59 (d, J=8.0 Hz, 2H), 7.31 (d, J=2.2 Hz, 1H), 7.19 (d, 1H), 6.71 (dd, J=8.8, 2.3 Hz, 1H), 5.14 (br d, J=6.4 Hz, 1H), 4.19 (t, J=6.7 Hz, 2H), 4.04-3.92 (m, 1H), 3.25-3.09 (m, 2H), 2.73-2.63 (m, 1H), 2.39-2.25 (m, 2H), 2.15-1.97 (m, 2H).

Example 187: (1S,3S)-3-hydroxy-N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 179)

[1019] ##STR00928##

[1020] tert-butyl (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)carbamate (83.2 mg, 0.16 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to a residue. Then the residue and (1S,3S)-3-hydroxycyclobutane-1-carboxylic acid (37.1 mg, 0.32 mmol, 2.0 equiv.) were dissolved in ACN (2 mL), then NMI (0.5 mL) and TCFH (53.8 mg, 0.192 mmol, 1.2 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give (1S,3S)-3-hydroxy-N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)cyclobutane-1-carboxamide (14.52 mg, 0.035 mmol) as a powder. MS-ESI, 419.2 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.72-10.65 (m, 1H), 9.68 (s, 1H), 7.72-7.60 (m, 4H), 7.26 (d, J=8.3 Hz, 1H), 7.16-7.05 (m, 3H), 5.14 (d, J=7.0 Hz, 1H), 4.29 (t, J=7.0 Hz, 2H), 4.04-3.92 (m, 1H), 3.16-3.07 (m, 2H), 2.78-2.68 (m, 1H), 2.39-2.27 (m, 2H), 2.15-1.95 (m, 2H).

Example 188: (1R,3S)—N-(5-{2-[(3aR,5S,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-1H-indol-3-yl)-3-methylcyclobutane-1-carboxamide (Compound 150)

[1021] ##STR00929##

[1022] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-[(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indole-1-carboxylate (81.9 mg, 0.15 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), then TFA (500 μl) was added to the mixture. The reaction mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. Then the residue and (1R,3S)-3-methylcyclobutane-1-carboxylic acid (34.2 mg, 0.30 mmol, 2.0 equiv.) were dissolved in ACN (2 mL), then NMI (0.5 mL) and TCFH (50.4 mg, 0.18 mmol, 1.2 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC to give (1R,3S)—N-(5-{2-[(3aR,5S,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-1H-indol-3-yl)-3-methylcyclobutane-1-carboxamide (30.5 mg, 0.066 mmol) as a powder. MS-ESI, 464.4 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.57-10.51 (m, 1H), 9.51 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.70 (dd, J=8.8, 2.3 Hz, 1H), 3.95 (t, J=6.5 Hz, 2H), 3.22-3.09 (m, 3H), 2.68-2.61 (m, 2H), 2.46-2.39 (m, 3H), 2.39-2.16 (m, 4H), 2.11-2.02 (m, 2H), 1.94-1.74 (m, 5H), 1.04 (d, J=6.3 Hz, 3H), 0.96 (td, J=11.7, 8.4 Hz, 2H).

[1023] The analogs prepared in the following table were prepared using the above procedures with the appropriate starting material.

TABLE-US-00052 LC-MS, Example Compound MS-ESI, -- # No. Structure [M+H.sup.+]. 189 190 [00930] embedded image 419.1 190 206 [00931] 403.2 191 162 [00932] 417.3 192 205 [00933] 417.3 193 203 [00934] 414.2 194 188 [00935] 414.2 195 179 [00936] 419.2

Example 196: N-(5-(2-(cis-4-hydroxy-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (compound 501)

[1024] ##STR00937##

Step 1: tert-butyl 3-acetamido-5-{2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]ethoxy}indole-1-carboxylate

[1025] 4-(2-hydroxyethyl)-1-(trifluoromethyl)cyclohexan-1-ol (132.0 mg, 0.6 mmol, 1.2 equiv.) and tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate (150.0 mg, 0.5 mmol, 1.0 equiv.) were dissolved in THE (10 mL), then TBUP (209.0 mg, 1.0 mmol, 2.0 equiv.) and ADDP (259.0 mg, 1.0 mmol, 2.0 equiv.) were added at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at rt and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (5:1) to afford tert-butyl 3-acetamido-5-{2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]ethoxy}indole-1-carboxylate (200.0 mg) as a pale white solid. LCMS Method A: [M+H].sup.+=485.1.

Step 2: N-(5-(2-(cis-4-hydroxy-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide

[1026] tert-Butyl 3-acetamido-5-{2-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]ethoxy}indole-1-carboxylate (200.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then K.sub.2CO.sub.3 (115.4 mg, 0.8 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60° C. for 16 hours, then cooled t rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 46% B in 8 min; Wave Length: 254; 220 nm; RT1: 6.83 min. This gave N-(5-(2-(cis-4-hydroxy-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (37.5 mg) as a pale white solid. LCMS Method D: [M+H].sup.+=385.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.55 (s, 1H), 9.67 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.73-6.71 (m, 1H), 5.66 (s, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.08 (s, 3H), 1.90-1.70 (m, 7H), 1.54-1.45 (m, 4H).

The Analogs Prepared in the Following Table were Prepared Using the Same Method Described for Example 196.

TABLE-US-00053 Com- example pound Starting LCMS # # materials Used Structure Condition data 197 498 Intermediate 67/ Intermediate 104 [00938] embedded image TBUP, ADDP, THF Method F: MS-ESI: 410.2 [M + H].sup.+. 198 497 1-(4- (trifluoromethyl) phenyl)ethan- 1-01/ Intermediate 10 [00939] TBUP, ADDP, THF Method E: MS-ESI: 361.1 [M − H].sup.+. 199 494 Intermediate 111/ Intermediate 10 [00940] PPh.sub.3, DEAD, THF Method F: MS-ESI: 404.0 [M + H].sup.+. 200 485 Intermediate 112/ Intermediate 104 [00941] embedded image TBUP, ADDP, THF Method F: MS-ESI: 452.1[M + H].sup.+. 201 484 Intermediate 113/ Intermediate 10 [00942] PPh.sub.3, DIAD, Py, THF Method D: MS-ESI: 382.1[M − H].sup.+. 202 479 Intermediate 64/ Intermediate 104 [00943] TBUP, ADDP, THF Method F: MS-ESI: 452.2 [M + H].sup.+. 203 474 Intermediate 116/ Intermediate 10 [00944] embedded image TBUP, ADDP, THF Method F: MS-ESI: 353.2 [M + H].sup.+. 204 473 Intermediate 118/ Intermediate 10 [00945] CMPB, toluene Method F: MS-ESI: 375.3[M + H].sup.+. 205 472 Intermediate 117/ Intermediate 10 [00946] TBUP, ADDP, THF Method F: MS-ESI: 355.3 [M + H].sup.+. 206 458 2- (bicyclo[1.1.1] pentan-1- yl)ethan-1-ol/ Intermediate 10 [00947] embedded image TBUP, ADDP, THF Method F: MS-ESI: 285.2[M + H].sup.+. 207 437 Intermediate 121/ Intermediate 10 [00948] TBUP, ADDP, THF Method F: MS-ESI: 401.1[M − H].sup.+. 208 436 Intermediate 119/ Intermediate 10 [00949] DBAD, PPh.sub.3, THF Method F: MS-ESI: 389.1[M + H].sup.+. 209 435 Intermediate 122/ Intermediate 10 [00950] embedded image TBUP, ADDP, THF Method E: MS-ESI: 403.2[M + H].sup.+.

Examples 210/211: N-(5-(2-(trans-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide [(compound 456) and N-(5-(2-(cis-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (compound 454)

[1027] ##STR00951##

Step 1: tert-butyl 3-acetamido-5-(2-(4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indole-1-carboxylate

[1028] tert-Butyl 3-acetamido-5-hydroxy-1H-indole-1-carboxylate (488.2 mg, 1.7 mmol, 1.0 equiv.) and 2-(4-(trifluoromethyl)cyclohexyl)ethan-1-ol (330.0 mg, 1.7 mmol, 1.0 equiv.) were dissolved in THE (5 mL) and cooled to 0° C., then TBUP (1.4 g, 6.7 mmol, 4.0 equiv.) and ADDP (842.1 mg, 3.3 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to afford tert-butyl 3-acetamido-5-(2-(4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indole-1-carboxylate (500.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=469.2.

Step 2: N-(5-(2-(trans-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (Front Peak) and N-(5-(2-(cis-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (Second Peak)

[1029] tert-Butyl 3-acetamido-5-(2-(4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indole-1-carboxylate (480 mg, 1.0 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then K.sub.2CO.sub.3 (283.2 mg, 2.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 1 hour at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30*150 mm 5 m, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 9 min, 57% B; Wave Length: 254; 220 nm; RT1: 7.75 min, RT2: 8.15 min. This resulted in N-(5-(2-(trans-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (front peak, absolute stereochemistry unconfirmed, assigned as Compound 456 (14.2 mg, 3.7%) as a white solid and N-(5-(2-(cis-4-(trifluoromethyl)cyclohexyl)ethoxy)-1H-indol-3-yl)acetamide (second peak, absolute stereochemistry unconfirmed, assigned as Compound 454 (16.3 mg, 4.1%) as a white solid.

[1030] Compound 456: LCMS Method E: [M+H].sup.+=369.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.70 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.73-6.71 (m, 1H), 3.99 (t, J=6.4 Hz, 2H), 2.31-2.29 (m, 1H), 2.08 (s, 3H), 1.92-1.90 (m, 1H), 1.81-1.76 (m, 2H), 1.67-1.60 (m, 8H).

[1031] Compound 454: LCMS Method E: [M+H].sup.+=369.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.70 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.73-6.71 (m, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24-2.18 (m, 1H), 2.09 (s, 3H), 1.90-1.87 (m, 4H), 1.70-1.65 (m, 2H), 1.55-1.41 (m, 2H), 1.31-1.19 (m, 2H), 1.11-1.02 (m, 2H).

The Analogs Prepared in Following Table were Prepared Using the Same Method Described for Example 210/211.

TABLE-US-00054 Compound Starting Compound # materials Used Structure LCMS data 212 448 Intermediate 120 /Intermediate 10 [00952] embedded image Method F: MS-ESI: 401.0 [M-H].sup.+. 213 596 Intermediate 120 /Intermediate 10 [00953] Method E: MS-ESI: 401.1 [M-H].sup.+.

Examples 214/215: N-(5-((2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide (compound 447) and N-(5-((1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide (compound 444)

[1032] ##STR00954## ##STR00955##

Step 1: mixture of tert-butyl 3-acetamido-5-{[2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methoxy}indole-1-carboxylate and tert-butyl 3-acetamido-5-{[1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methoxy}indole-1-carboxylate

[1033] A mixture of [2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol and [1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methanol (200.0 mg, 0.9 mmol, 1.0 equiv.) and tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate (264.0 mg, 0.9 mmol, 1.0 equiv.) were dissolved in THE (8 mL) and cooled to 0° C., then TBUP (368.0 mg, 1.8 mmol, 2.0 equiv.) and ADDP (455.0 mg, 1.8 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at rt and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (5:1) to give a mixture of tert-butyl 3-acetamido-5-{[2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methoxy}indole-1-carboxylate and tert-butyl 3-acetamido-5-{[1-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methoxy}indole-1-carboxylate (150.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=493.2.

Step 2: N-(5-((2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide and N-(5-((1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide

[1034] tert-Butyl 3-acetamido-5-{[2-(2,2,2-trifluoroethyl)-4H,5H,6H-cyclopenta[c]pyrazol-5-yl]methoxy}indole-1-carboxylate (169.7 mg, 0.3 mmol, 1.0 equiv) was dissolved in MeOH (8 mL), K.sub.2CO.sub.3 (97 mg, 0.915 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 5 hours at 60° C., then cooled to rt and removed the solid by filtration. The filter cake was washed with MeOH, and the combined filtrate was concentrated under vacuum. The resulting mixture was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH.sub.3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 15 min; Wave Length: 220/254 nm; RT1: 10.14 min, RT2: 14.00 min. This resulted in N-(5-((2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide (34.3 mg) as an off-white solid and N-(5-((1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-5-yl)methoxy)-1H-indol-3-yl)acetamide (11.0 mg) as an off-white solid.

[1035] Compound 447: LCMS Method E: [M+H].sup.+=393.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.70 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.77-6.75 (m, 1H), 5.00 (q, J=9.2 Hz, 2H), 4.00 (d, J=6.8 Hz, 2H), 3.27-3.22 (m, 1H), 2.92-2.82 (m, 2H), 2.60-2.54 (m, 2H), 2.08 (s, 3H).

[1036] Compound 444: LCMS Method E: [M+H].sup.+=393.4. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 9.69 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.77-6.74 (m, 1H), 5.02 (q, J=9.2 Hz, 2H), 4.99-4.00 (m, 2H), 3.46-3.43 (m, 1H), 3.02-2.96 (m, 1H), 2.86-2.80 (m, 1H), 2.72-2.67 (m, 1H), 2.52-2.50 (m, 1H), 2.08 (s, 3H).

Example 216: N-(5-(2-(5-(2,2,2-trifluoroethyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide (compound 478)

[1037] ##STR00956##

Step 1: tert-butyl 3-acetamido-5-(2-(5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indole-1-carboxylate

[1038] tert-Butyl 3-acetamido-5-hydroxy-1H-indole-1-carboxylate (150.0 mg, 0.5 mmol, 1.0 equiv.) and tert-butyl 7-(2-hydroxyethyl)-5-azaspiro[2.4]heptane-5-carboxylate (249.4 mg, 1.0 mmol, 2.0 equiv.) were dissolved in THE (5 mL) and cooled to 0° C., then TBUP (209.1 mg, 1.0 mmol, 2.0 equiv.) and ADDP (258.7 mg, 1.0 mmol, 2.0 equiv.) were added, maintaining the solution at 0° C. The reaction mixture was stirred for 4 hours at rt and then concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 30% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 3-acetamido-5-(2-(5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indole-1-carboxylate (120.0 mg) as an off-white solid. LCMS Method A: [M+H].sup.+=514.2.

Step 2: N-(5-(2-(5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide

[1039] tert-Butyl 3-acetamido-5-(2-(5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indole-1-carboxylate (110.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (3.0 mL), then TFA (0.6 mL) was added. The reaction mixture was stirred for 2 hours at rt and then concentrated under vacuum to give N-(5-(2-(5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide (60.0 mg) as a colorless oil. LCMS Method A: [M+H].sup.+=314.2.

Step 3: N-(5-(2-(5-(2,2,2-trifluoroethyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide

[1040] N-(5-(2-(5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide (60.0 mg, 0.2 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.7 mg, 0.3 mmol, 1.5 equiv.) were dissolved in ACN (5.0 mL), then K.sub.2CO.sub.3 (79.4 mg, 0.6 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 60° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase, Water (10 mmol/L NH.sub.4HCO.sub.3+0.1% NH.sub.3.H.sub.2O) and ACN (33% ACN up to 57% in 7 min). This resulted in N-(5-(2-(5-(2,2,2-trifluoroethyl)-5-azaspiro[2.4]heptan-7-yl)ethoxy)-1H-indol-3-yl)acetamide (15.0 mg) as a white solid. LCMS Method F: [M+H].sup.+=396.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.56 (d, J=1.6 Hz, 1H), 9.68 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.72-6.69 (m, 1H), 3.93-3.89 (m, 2H), 3.25-3.21 (m, 3H), 2.74 (d, J=8.8 Hz, 1H), 2.69 (d, J=8.8 Hz, 1H), 2.62-2.57 (m, 1H), 2.15-2.13 (m, 1H), 2.08 (s, 3H), 1.65-1.52 (m, 2H), 0.72-0.69 (m, 1H), 0.61-0.59 (m, 1H), 0.48-0.46 (m, 1H), 0.40-0.36 (m, 1H).

Example 217/218: trans-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl) benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (compound 415) and cis-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 414)

[1041] ##STR00957## ##STR00958##

Step 1: 1-methyl-3-oxo-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide

[1042] 5-((4-(Trifluoromethyl)benzyl)oxy)-1H-indol-3-amine TFA salt (500.0 mg, 1.6 mmol, 1.0 equiv.) and 1-methyl-3-oxocyclobutane-1-carboxylic acid (209.1 mg, 1.6 mmol, 1.0 equiv.) were added in DCM (10 mL), then DIEA (0.5 mL, 3.2 mmol, 2.0 equiv.) and HATU (931.1 mg, 2.4 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 1 hour at rt and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (3:1) to afford 1-methyl-3-oxo-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (500.0 mg) as a black solid. LCMS Method A: [M+H].sup.+=417.2.

Step 2: 3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide

[1043] 1-Methyl-3-oxo-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (500.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and cooled to 0° C., then NaBH.sub.4 (181.7 mg, 4.8 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 1 hour at rt and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 10% to 50% gradient in 10 min; detector, UV 254 nm.). This resulted in 3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (410.0 mg) as a with solid. LCMS Method A: [M+H].sup.+=419.2.

Step 3: trans-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide and cis-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide

[1044] The racemic 3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (400.0 mg) was separated by Chiral-HPLC with the following conditions: Column: JW-CHIRALPAK-ID, 2*25 cm; Sum; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 11.5 min; Wave Length: 220/254 nm; RT1: 6.942 min, RT2: 7.015 min. This resulted in trans-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (125.5 mg) as an off-white solid and cis-3-hydroxy-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (92.4 mg) as an off-white solid.

[1045] Compound 415: LCMS Method E: [M+H].sup.+=419.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=1.6 Hz, 1H), 9.20 (s, 1H), 7.78-7.70 (m, 4H), 7.60 (d, J=2.4 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.85-6.83 (m, 1H), 5.20 (s, 2H), 5.03 (d, J=6.0 Hz, 1H), 4.03-3.89 (m, 1H), 2.84-2.79 (m, 2H), 1.82-1.77 (m, 2H), 1.49 (s, 3H).

[1046] Compound 414: LCMS Method E: [M+H].sup.+=419.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=2.0 Hz, 1H), 9.03 (s, 1H), 7.80-7.70 (m, 4H), 7.58 (d, J=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 6.86-6.83 (m, 1H), 5.20 (s, 2H), 4.99 (d, J=6.8 Hz, 1H), 4.18-4.13 (m, 1H), 2.27-2.19 (m, 4H), 1.41 (s, 3H).

The Analogs Prepared in the Following Table were Prepared Using the Same Method Described for Example 217/218.

TABLE-US-00055 Example Compound LCMS # # Starting materials Used Structure data 219 446 [00959] embedded image [00960] Method F: MS-ESI: 433.1 [M+H].sup.+. Intermediate 33 220 445 [00961] [00962] Method D: MS-ESI: 433.1 [M+H].sup.+. Intermediate 33

Example 221/222: cis-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (compound 426) and trans-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (Compound 425)

[1047] ##STR00963## ##STR00964##

Step 1: 1-methyl-4-oxo-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide

[1048] 5-[trans-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-amine TFA salt (300.0 mg, 0.9 mmol, 1.0 equiv.) and 1-methyl-4-oxocyclohexane-1-carboxylic acid (135.3 mg, 0.9 mmol, 1.0 equiv.) were dissolved in ACN (5 mL), then TCFH (1.5 g, 5.2 mmol, 6.0 equiv.) and NMI (87.6 mg, 0.9 mmol, 1.0 equiv.) were added at 0° C. The reaction mixture was stirred for 2 hours at rt and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 1-methyl-4-oxo-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (140.0 mg) as a yellow green solid. LCMS Method B: [M+H].sup.+=485.2.

Step 2: cis-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (front peak, stereochemistry unconfirmed) and trans-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (Second Peak, Stereochemistry Unconfirmed)

[1049] 1-Methyl-4-oxo-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (200.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and cooled to 0° C., then NaBH.sub.4 (31.2 mg, 0.8 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: SunFire C18 OBD Prep Column, 19*250 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 65% B in 6 min; Wave Length: 254/210 nm; RT1: 6.1 min, RT2: 6.7 min. This resulted in cis-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (front peak, absolute stereochemistry unconfirmed, assigned as compound 426) (20.1 mg) as a white solid and trans-4-hydroxy-1-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)cyclohexane-1-carboxamide (second peak, absolute stereochemistry unconfirmed, assigned as compound 425) (48.5 mg) as a white solid.

[1050] Compound 426: LCMS Method F: [M+H].sup.+=487.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.65 (s, 1H), 8.86 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.44 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.74-6.72 (m, 1H), 4.92-4.87 (m, 1H), 4.41 (d, J=4.0 Hz, 1H), 3.82-3.78 (m, 1H), 3.57-3.55 (m, 1H), 2.61 (t, J=6.8 Hz, 4H), 1.88-1.81 (m, 2H), 1.70-1.65 (m, 4H), 1.49-1.42 (m, 2H), 1.24 (s, 3H).

[1051] Compound 425: LCMS Method F: [M+H].sup.+=487.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.68 (s, 1H), 8.94 (s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.42 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.74-6.72 (m, 1H), 4.92-4.86 (m, 1H), 4.46 (d, J=4.4 Hz, 1H), 3.84-3.78 (m, 1H), 3.45-3.41 (m, 1H), 2.61 (t, J=6.8 Hz, 4H), 2.32-2.29 (m, 2H), 1.72-1.68 (m, 4H), 1.36-1.30 (m, 2H), 1.27-1.16 (m, 5H).

[1052] The Analogs Prepared in the Following Table were Prepared Using the Same Method Described for Examples 221/222.

TABLE-US-00056 Example Compound LCMS # # Starting materials Used Structure data 223 419 [00965] embedded image [00966] Method F: MS-ESI: 447.3 [M+H].sup.+. Intermediate 91 224 418 [00967] [00968] Method F: MS-ESI: 447.3 [M+H].sup.+. Intermediate 91

Example 225/226: trans-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 417) and cis-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 416)

[1053] ##STR00969##

Step 1: 1-methyl-3-methylene-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide

[1054] 1-Methyl-3-methylenecyclobutane-1-carboxylic acid (350.1 mg, 2.8 mmol, 1.0 equiv.), 5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-amine TFA salt (850.0 mg, 2.8 mmol, 1.0 equiv.) and DIEA (2.3 mL, 13.9 mmol, 5.0 equiv.) were dissolved in DCM (10 mL), then HATU (1582.8 mg, 4.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to give 1-methyl-3-methylene-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (660.0 mg) as a green solid. LCMS Method A: [M+H].sup.+=415.2.

Step 2: 3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide

[1055] 1-Methyl-3-methylene-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (600.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then BH.sub.3-THF (5.8 mL, 1M, 5.8 mmol, 4.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 1 hour at 0° C., then to the above mixture were added aqueous NaOH (30% wt., 3.0 mL, 6.7 mmol, 4.6 equiv,) and H.sub.2O.sub.2 (30% wt., 1.3 mL, 3.3 mmol, 2.3 equiv,) were added dropwise at 0° C. The reaction mixture was stirred for additional 2 hours at rt and then quenched by the addition of saturated aqueous NH.sub.4Cl. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with dichloromethane/methanol (10:1) to give the crude product, that was further purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 60% B to 80% B in 5.5 min; Wave Length: 210/254 nm; RT1: 5.30 min. This resulted in 3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl) cyclobutane-1-carboxamide (150 mg). LCMS Method A: [M+H].sup.+=433.3.

Step 3: trans-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 417) and cis-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (Compound 416)

[1056] 3-(Hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl) cyclobutane-1-carboxamide (150 mg) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: JW-CHIRALPAK IA-3, 4.6*50 mm, 3 m; Mobile Phase A: Hex (0.1% DEA): IPA=70: 30; Flow rate: 1 mL/min; Gradient: 0% B to 0% B. This resulted in trans-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (compound 417, 98.2 mg) as a white solid and cis-3-(hydroxymethyl)-1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (compound 416), 38.3 mg) as a white solid.

[1057] compound 417: LCMS Method D: [M+H].sup.+=433.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.66 (s, 1H), 9.19 (s, 1H), 7.78-7.71 (m, 4H), 7.61 (d, J=2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.86-6.83 (m, 1H), 5.21 (s, 2H), 4.49 (t, J=5.6 Hz, 1H), 3.41-3.35 (m, 2H), 2.59-2.56 (m, 2H), 2.24-2.20 (m, 1H), 1.74-1.69 (m, 2H), 1.48 (s, 3H).

[1058] compound 416: LCMS Method D: [M+H].sup.+=433.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.65 (d, J=2.0 Hz, 1H), 9.08 (s, 1H), 7.81-7.71 (m, 4H), 7.60 (d, J=2.4 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 6.86-6.84 (m, 1H), 5.21 (s, 2H), 4.58 (t, J=5.2 Hz, 1H), 3.37-3.33 (m, 2H), 2.40-2.34 (m, 1H), 2.21-2.15 (m, 2H), 1.94-1.89 (m, 2H), 1.48 (s, 3H).

Example 227/228: (2R,3R)-2-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)oxetane-3-carboxamide (Compound 424) and (2S,3R)-2-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)oxetane-3-carboxamide (Compound 423)

[1059] ##STR00970##

[1060] 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (100.0 mg, 0.3 mmol, 1.0 equiv.) and 2-methyloxetane-3-carboxylic acid (50.3 mg, 0.4 mmol, 1.5 equiv.) were dissolved in THE (5 mL), then HATU (164.7 mg, 0.4 mmol, 1.5 equiv.) and DIEA (0.15 mL, 0.9 mmol, 3.0 equiv.) were added. The reaction mixture was stirred for 1 hour at rt and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 30% to 70% gradient in 30 min; detector, UV 254 nm. The crude product was further purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 60% B to 90% B in 5.5 min; Wave Length: 210/254 nm; RT1: 5.1 min, RT2: 5.4 min. This resulted in cis-2-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)oxetane-3-carboxamide (compound 424) (6.2 mg) as an off-white solid and trans-2-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)oxetane-3-carboxamide (compound 423) (5.6 mg) as an off-white solid.

[1061] compound 424: LCMS Method F: [M+H].sup.+=445.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=2.4 Hz, 1H), 9.62 (s, 1H), 7.73-7.70 (m, 3H), 7.61-7.59 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.76-6.73 (m, 1H), 5.15-5.10 (m, 1H), 4.94-4.89 (m, 1H), 4.74 (t, J=6.0 Hz, 1H), 4.55-4.52 (m, 1H), 4.02-3.97 (m, 1H), 3.84-3.79 (m, 1H), 2.65-2.60 (m, 4H), 1.23 (d, J=7.2 Hz, 3H).

[1062] compound 423: LCMS Method F: [M+H].sup.+=445.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.67 (d, J=1.2 Hz, 1H), 9.71 (s, 1H), 7.76-7.71 (m, 3H), 7.60 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.76-6.73 (m, 1H), 4.96-4.90 (m, 2H), 4.60-4.51 (m, 2H), 3.83-3.79 (m, 1H), 3.69-3.63 (m, 1H), 2.69-2.61 (m, 4H), 1.42 (d, J=6.0 Hz, 3H).

Example 229: (R)-2-hydroxy-N-(5-(trans-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)-1H-indol-3-yl)butanamide (compound 429)

[1063] ##STR00971##

[1064] 5-[trans-3-[4-(trifluoromethyl) phenyl] cyclobutoxy]-1H-indol-3-amine TFA salt (120.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), (R)-2-hydroxybutyric acid (72.1 mg, 0.7 mmol, 2.0 equiv.), NMM (210.3 mg, 2.1 mmol, 6.0 equiv.) and PyBOP (180.3 mg, 0.3 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 5 hours at rt and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 70% gradient in 25 min; detector, UV 254 nm. The resulting crude product was further purified by Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 55% B to 80% B in 5.3 min; Wave Length: 210/254 nm; RT1: 5.3 min. This resulted in (2R)-2-hydroxy-N-{5-[trans-3-[4-(trifluoromethyl) phenyl] cyclobutoxy]-1H-indol-3-yl} butanamide (28.0 mg) as a white solid. LCMS Method E: [M+H].sup.+=433.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.68 (d, J=2.6 Hz, 1H), 9.38 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.64-7.58 (m, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.76-6.73 (m, 1H), 5.46 (d, J=5.6 Hz, 1H), 4.94-4.91 (m, 1H), 4.06-4.02 (m, 1H), 3.83-3.79 (m, 1H), 2.67-2.62 (m, 4H), 1.77-1.72 (m, 1H), 1.66-1.59 (m, 1H), 0.92 (t, J=7.6 Hz, 3H).

The Analogs Prepared in the Following Table were Prepared Using the Same Method Described for Example 229.

TABLE-US-00057 Example # Compound # Starting materials Used Structure condition LCMS data 230 496 Intermediate 91 /Tetramethyloxet ane-3-carboxylic acid [00972] embedded image HATU, DIEA, DCM Method E: MS- ESI: 4475.2 [M-H].sup.+. 231 464 Intermediate 107 /l- methylcycloprop ane-1-carboxylic acid [00973] T.sub.3P, TEA, DMF Method F: MS- ESI: 402.1[M+H].sup.+. 232 455 Intermediate 106 /AcCl [00974] TEA, DCM Method F: MS- ESI: 390.1[M+H].sup.+. 233 434 Intermediate 90 /2-(2,2,2- trifluoroethoxy)a cetic acid [00975] embedded image HATU, DIEA, DCM Method F: MS- ESI: 508.2[M+H].sup.+. 234 433 Intermediate 90 /4,4,4-trifluoro-3- hydroxybntanoic acid [00976] HATU, DIEA, DCM Method F: MS- ESI: 508.2[M+H].sup.+. 235 431 Intermediate 33 /(R)-2- hydroxybutanoic acid [00977] HATU, DIEA, DCM Method F: MS- ESI: 407.2[M+H].sup.+. 236 430 Intermediate 33 /(S)-2- hydroxybutanoic acid [00978] embedded image HATU, DIEA, DCM Method F: MS- ESI: 407.2[M+H].sup.+. 237 428 Intermediate 90 /2,4- dimethyloxetane- 3-carboxylic acid [00979] T.sub.3P, TEA, ACN Method E: MS- ESI: 419.2[M+H].sup.+. 238 422 Intermediate 86 /Intermediate 131 [00980] HATU, DIEA, DCM Method F: MS- ESI: 502.2[M+H].sup.+. 239 421 Intermediate 91 /Intermediate 132 [00981] embedded image HATU, DIEA, DCM Method F: MS- ESI: 468.1[M+H].sup.+. 240 420 Intermediate 91 /l- (hydroxymethyl) cyclobutane-1- carboxylic acid [00982] HATU, DIEA, DCM Method F: MS- ESI: 459.2[M+H].sup.+. 241 413 Intermediate 86 /Intermediate 133 [00983] T.sub.3P, TEA, THF Method F: MS- ESI: 500.2[M+H].sup.+. 242 412 Intermediate 86 /Intermediate 134 [00984] embedded image T.sub.3P, TEA, THF Method F: MS- ESI: 500.2[M+H].sup.+. 243 409 Intermediate 91 /2,2- dimethyloxetane- 3-carboxylic acid [00985] HATU, DIEA, DCM Method F: MS- ESI: 419.2[M+H].sup.+.

Example 244: 1-(2,2-difluoroethyl)-3-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)azetidine-3-carboxamide (Compound 483)

[1065] ##STR00986##

Step 1: tert-butyl 3-methyl-3-((5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)carbamoyl)azetidine-1-carboxylate

[1066] 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine (300.0 mg, 0.9 mmol, 1.0 equiv.) and 1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (223.7 mg, 1.0 mmol, 1.2 equiv.) were dissolved in THE (15 mL), then HATU (395.2 mg, 1.0 mmol, 1.2 equiv.) and DIEA (0.3 mL, 1.7 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at rt and then concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 30% to 90% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 3-methyl-3-((5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)carbamoyl)azetidine-1-carboxylate (274.0 mg) as a brown yellow oil. LCMS Method A: [M+H].sup.+=544.2.

Step 2: 3-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)azetidine-3-carboxamide

[1067] tert-Butyl 3-methyl-3-((5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)carbamoyl)azetidine-1-carboxylate (200.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DCM (4 mL), then TFA (1 mL) was added. The reaction mixture was stirred for 4 hours at rt and concentrated under vacuum to give the crude product, which was used in the next step directly without further purification. LCMS Method A: [M+H].sup.+=444.2.

Step 3: 1-(2,2-difluoroethyl)-3-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)-1H-indol-3-yl)azetidine-3-carboxamide

[1068] 3-Methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)azetidine-3-carboxamide (100.0 mg, 0.2 mmol, 1.0 equiv.) and 2,2-difluoroethyl trifluoromethanesulfonate (72.4 mg, 0.3 mmol, 1.5 equiv.) were dissolved in ACN (5 mL), K.sub.2CO.sub.3 (62.3 mg, 0.5 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 4 hours at 80° C., then cooled to rt and diluted with water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, Xselect CSH C18 OBD Column 30*150 mm Sum; mobile phase, Water (0.1% FA) and ACN (31% ACN up to 45% in 7 min). This resulted in 1-(2,2-difluoroethyl)-3-methyl-N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)azetidine-3-carboxamide (33.0 mg) as a white solid. LCMS Method E: [M+H].sup.+=508.2. 1H NMR (400 MHz, DMSO-d.sub.6) δ 10.67 (d, J=1.6 Hz, 1H), 9.36 (s, 1H), 8.15 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 3H), 7.26-7.23 (m, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.76-6.74 (m, 1H), 6.10-5.82 (m, 1H), 4.94-4.91 (m, 1H), 3.83-3.79 (m, 2H), 3.64-3.60 (m, 2H), 3.22 (d, J=7.2 Hz, 2H), 2.86-2.81 (m, 2H), 2.65-2.61 (m, 4H), 1.53 (s, 3H).

Example 245: trans-3-methoxy-1-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (compound 427)

[1069] ##STR00987##

[1070] 3-Methoxy-1-methylcyclobutane-1-carboxylic acid (627.8 mg, 4.3 mmol, 2.0 equiv.) and DIEA (1.8 mL mg, 10.9 mmol, 5.0 equiv.) were dissolved in DCM (10 mL), then HATU (1241.9 mg, 3.3 mmol, 1.5 equiv.) and 5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-amine (800.0 mg, 2.2 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 2 hours at rt and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether/EtOAc=1:1) to afford racemate, that was purified by Prep-CHIRAL-HPLC with the following conditions: Column: JW-CHIRALPAK-IF, 20*250 mm, Sum; Mobile Phase A: EtOH-HPLC, Mobile Phase B: Hex:DCM=3:1 (0.1% FA)-HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 10 min; Wave Length: 220/254 nm; RT1(min): 5.6. This resulted in trans-3-methoxy-1-methyl-N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)cyclobutane-1-carboxamide (87.3 mg) as a green solid. LCMS Method F: [M+H].sup.+=494.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.61 (s, 1H), 9.24 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.74-6.71 (m, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.73-3.70 (m, 1H), 3.22-3.17 (m, 2H), 3.14 (s, 3H), 2.85-2.80 (m, 2H), 2.64 (d, J=8.4 Hz, 2H), 2.44-2.40 (m, 4H), 2.10-2.06 (m, 2H), 1.95-1.76 (m, 5H), 1.51 (s, 3H), 0.98-0.95 (m, 2H).

Example 246: N-(5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indol-3-yl)acetamide (Compound 495)

[1071] ##STR00988##

Step 1: tert-butyl 3-acetamido-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indole-1-carboxylate

[1072] tert-Butyl 3-acetamido-5-bromo-1H-indole-1-carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) and 1-ethynyl-4-(trifluoromethyl)benzene (289.0 mg, 1.6 mmol, 1.2 equiv.) were dissolved in TEA (4 mL) and ACN (4 mL), then Pd(PPh.sub.3).sub.4 (327.1 mg, 0.2 mmol, 0.2 equiv.) and CuI (26.9 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at 90° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to give tert-butyl 3-acetamido-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indole-1-carboxylate (700.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=443.2.

Step 2: N-(5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indol-3-yl)acetamide

[1073] tert-Butyl 3-acetamido-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indole-1-carboxylate (600.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in DCM (4 mL), then TFA (2 mL) was added. The reaction mixture was stirred for 30 min at rt and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 44% B to 61% B in 8 min; Wave Length: 254 nm; RT1(min): 7.55. This resulted in N-(5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indol-3-yl)acetamide (35.7 mg) as a pale brown solid. LCMS Method E: [M−H].sup.−=341.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.08 (s, 1H), 9.92 (s, 1H), 8.16 (s, 1H), 7.80-7.74 (m, 5H), 7.39 (d, J=8.4 Hz, 1H), 7.32-7.29 (m, 1H), 2.10 (s, 3H).

Example 247: N-(5-(2-((2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide (compound 499)

[1074] ##STR00989##

Step 1: tert-butyl 3-(2-(2-bromoethoxy) propan-2-yl) pyrrolidine-1-carboxylate

[1075] tert-Butyl 3-(2-(2-bromoethoxy)propan-2-yl)pyrrolidine-1-carboxylate (800.0 mg, 1.7 mmol, 1.0 equiv.) and 8-(2-bromoethoxy)-1,4-dioxaspiro[4.5]decane (900.8 mg, 3.4 mmol, 2.0 equiv.) were dissolved in DME (10 mL), then tris(trimethylsilyl)silane (633.6 mg, 2.5 mmol, 1.5 equiv.), Na.sub.2CO.sub.3 (360.1 mg, 3.4 mmol, 2.0 equiv.), Ir[DF(CF.sub.3)PPY].sub.2(DTBPY)PF.sub.6 (190.6 mg, 0.2 mmol, 0.1 equiv.), DTBPY (45.6 mg, 0.2 mmol, 0.1 equiv.) and 1,2-dimethoxyethane dihydrochloride nickel (37.3 mg, 0.2 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at rt under nitrogen atmosphere and the Blue LED light. The resulting mixture was concentrated under vacuum and the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 30% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 3-acetamido-5-(2-((2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indole-1-carboxylate (200.0 mg) as a brown oil. LCMS Method A: [M+H].sup.+=530.2.

Step 2: N-(5-(2-((2-(pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide

[1076] tert-Butyl 5-[2-({2-[1-(tert-butoxycarbonyl) pyrrolidin-3-yl] propan-2-yl} oxy) ethyl]-3-acetamidoindole-1-carboxylate (200.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), then TFA (1 mL) was added at 0° C. The reaction mixture was stirred overnight at rt and concentrated under vacuum to give crude N-(5-(2-((2-(pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide, that was used in the next step directly without further purification.

Step 3: N-(5-(2-((2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide

[1077] N-(5-(2-((2-(pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide (60.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in ACN (2 mL), then K.sub.2CO.sub.3 (50.3 mg, 0.4 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (42.3 mg, 0.2 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 1 hour at 60° C., then cooled to rt and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane/MeOH=10:1) to give the crude product, that was further purified by Prep-HPLC with the following conditions: Column, Xselect CSH C18 OBD Column 30*150 mm 5 um; mobile phase, Water (0.1% FA) and ACN (15% ACN up to 30% in 7 min); Detector, UV 220/254 nm. This resulted in N-(5-(2-((2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)propan-2-yl)oxy)ethyl)-1H-indol-3-yl)acetamide (12.6 mg) as a white solid. LCMS Method F: [M+H].sup.+=412.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.61 (s, 1H), 9.73 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 3.51 (t, J=7.2 Hz, 2H), 3.25-3.07 (m, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.73-2.63 (m, 2H), 2.58-2.54 (m, 2H), 2.33-2.25 (m, 1H), 2.08 (s, 3H), 1.64-1.51 (m, 2H), 1.04 (s, 6H).

Example 248: N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide (compound 457)

[1078] ##STR00990##

Step 1: tert-butyl 3-acetamido-5-((E)-2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)vinyl)-1H-indole-1-carboxylate

[1079] tert-Butyl (3aR,5r,6aS)-5-vinylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (380.0 mg, 1.6 mmol, 1.0 equiv.) and tert-butyl 3-acetamido-5-bromo-1H-indole-1-carboxylate (735.2 mg, 2.1 mmol, 1.3 equiv.) were dissolved in ACN (5 mL), then Pd(OAc).sub.2 (71.9 mg, 0.3 mmol, 0.2 equiv.), P(o-Tol).sub.3 (194.9 mg, 0.6 mmol, 0.4 equiv.) and TEA (0.7 mL, 4.8 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 16 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (15:1) to give tert-butyl 3-acetamido-5-((E)-2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)vinyl)-1H-indole-1-carboxylate (760.0 mg) as an orange solid. LCMS Method A: [M+H].sup.+=510.2.

Step 2: tert-butyl 3-acetamido-5-(2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl) octahydrocyclopenta [c]pyrrol-5-yl)ethyl)-1H-indole-1-carboxylate

[1080] tert-Butyl 3-acetamido-5-((E)-2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c] pyrrol-5-yl)vinyl)-1H-indole-1-carboxylate (660.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (137.8 mg, 10% wt.) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at rt. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl 3-acetamido-5-(2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-1-carboxylate (340.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=512.

Step 3: N-(5-(2-((3aR,5r,6aS)-octahydrocyclopenta [c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide

[1081] tert-Butyl 3-acetamido-5-(2-((3aR,5r,6aS)-2-(tert-butoxycarbonyl) octahydro cyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-1-carboxylate (300.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), then TFA (5 mL) was added. The reaction mixture was stirred for 2 hours at rt and then concentrated under vacuum to give crude N-(5-(2-((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide TFA salt (320.0 mg) as a grey solid. LCMS Method A: [M+H].sup.+=512.1.

Step 4: N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide

[1082] N-(5-(2-((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide (250.0 mg, 0.8 mmol, 1.0 equiv.) and K.sub.2CO.sub.3 (443.8 mg, 3.2 mmol, 4.0 equiv.) were dissolved in ACN (5 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (242.2 mg, 1.0 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 1 hour at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give the crude product, that was further purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 75% B in 7.5 min; Wave Length: 220 nm; RT1: 7.5 min. This resulted in N-(5-(2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indol-3-yl)acetamide (20.8 mg) as a white solid. LCMS Method D: [M+H].sup.+=394.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.60 (s, 1H), 9.74 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.58 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.21-3.16 (m, 2H), 2.64-2.60 (m, 4H), 2.46-2.41 (m, 4H), 2.08-2.05 (m, 5H), 2.08 (s, 5H), 1.66-1.63 (m, 3H), 0.92-0.88 (m, 2H).

Example 249: N-(5-((cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H-indol-3-yl)acetamide (Compound 500)

[1083] ##STR00991##

Step 1: tert-butyl 3-acetamido-5-((cis-3-(4-(trifluoromethyl)phenyl) cyclobutoxy)methyl)-1H-indole-1-carboxylate

[1084] tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (431.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL), then bis(adamantan-1-yl)(butyl)phosphane (87.5 mg, 0.2 mmol, 0.2 equiv.), Chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II) (81.6 mg, 0.1 mmol, 0.1 equiv.) and tributyl({[(1s,3s)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]methyl})stannane (697.0 mg, 1.3 mmol, 1.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at 100° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/EtOAc (1:1) to give tert-butyl 3-acetamido-5-((cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H-indole-1-carboxylate (190.0 mg) as a white solid. LCMS Method A: [M+H].sup.+=503.2.

Step 2: N-(5-((cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H-indol-3-yl)acetamide

[1085] tert-Butyl 3-acetamido-5-((cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H-indole-1-carboxylate (170.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then K.sub.2CO.sub.3 (93.5 mg, 0.7 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 1 hour at 70° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 61% B in 8 min; Wave Length: 220 nm; RT1(min): 7.48. This resulted in N-(5-((cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)methyl)-1H-indol-3-yl)acetamide (61.9 mg) as a white solid. LCMS Method E: [M−H].sup.−=401.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.74 (s, 1H), 9.83 (s, 1H), 7.77 (s, 1H), 7.70-7.65 (m, 3H), 7.46 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.09-7.07 (m, 1H), 4.49 (s, 2H), 4.09-4.02 (m, 1H), 3.14-3.10 (m, 1H), 2.71-2.65 (m, 2H), 2.09 (s, 3H), 2.01-1.93 (m, 2H).

The Analog-s Prepared in the Following Table were Prepared Using the Same Method Described for Examples 249.

TABLE-US-00058 Example # Compound # Starting materials Used Structure LCMS data 250 492 [00992] embedded image Intermediate 128 [00993] Method F: MS- ESI:382.1 [M+H].sup.+. 251 482 [00994] Intermediate 127 [00995] Method F: MS- ESI: 401.1 [M-H].sup.+.

Example 252: N-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl) phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide (Compound 432)

[1086] ##STR00996## ##STR00997##

Step 1: 2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one

[1087] N,N-dimethylisobutyramide (1.6 g, 13.9 mmol, 1.2 equiv.) was dissolved in DCE (20 mL) and cooled to 0° C., Tf.sub.2O (4.6 g, 16.3 mmol, 1.4 equiv.) was added under an atmosphere of nitrogen. The reaction mixture was stirred for 30 min at 0° C., then to the above mixture were added 1-(trifluoromethyl)-4-vinylbenzene (2.0 g, 11.6 mmol, 1.0 equiv.) and 2,4,6-trimethylpyridine (2.0 g, 16.3 mmol, 1.4 equiv.) dropwise, maintaining the solution at 0° C. The resulting mixture was stirred for additional 2 hours at 80° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (10:1) to give 2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (1.9 g) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 3.69 (dd, J=17.2, 8.4 Hz, 1H), 3.55 (t, J=8.8 Hz, 1H), 3.30 (dd, J=17.2, 8.4 Hz, 1H), 1.28 (s, 3H), 0.68 (s, 3H).

Step 2: cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol

[1088] 2,2-Dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (1.9 g, 7.9 mmol, 1.0 equiv.) was dissolved in THE (30 mL) and cooled to 0° C., then NaBH.sub.4 (299.8 mg, 7.9 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 30 min at 0° C. and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (2:1) to give cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.5 g) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3-d.sub.1) δ 7.58 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 4.02 (dd, J=8.4, 7.2 Hz, 1H), 2.88 (dd, J=11.2, 7.6 Hz, 1H), 2.60-2.56 (m, 1H), 2.20-2.16 (m, 1H), 1.30 (s, 3H), 0.68 (s, 3H).

Step 3: 4-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-methyl-1-nitrobenzene

[1089] cis-2,2-Dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.5 g, 6.1 mmol, 1.0 equiv.) was dissolved in DMF (20 mL) and cooled to 0° C., then NaH (60% wt., 368.4 mg, 9.2 mmol, 1.5 equiv.) was added under an atmosphere of nitrogen. After stirred for 30 min, 4-fluoro-2-methyl-1-nitrobenzene (1.4 g, 9.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for additional 2 hours at rt and then quenched by the addition of water at 0° C. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (5:1) to give 4-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-methyl-1-nitrobenzene (1.0 g) as a yellow oil. LCMS Method A: [M+H].sup.+=380.2.

Step 4: (E)-2-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-nitrophenyl)-N,N-dimethylethen-1-amine

[1090] 4-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-methyl-1-nitrobenzene (1.2 g, 3.2 mmol, 1.0 equiv.) and DMF-DMA (1.9 g, 16.0 mmol, 5.0 equiv.) were dissolved in DMF (15 mL). The reaction mixture was heated to 120° C. for 16 hours, then cooled to rt and concentrated under vacuum to give (E)-2-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-nitrophenyl)-N,N-dimethylethen-1-amine (1.4 g, crude) as a red oil. LCMS Method A: [M+H].sup.+=435.2.

Step 5: 5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole

[1091] (E)-2-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-2-nitrophenyl)-N,N-dimethylethen-1-amine (1.4 g, 3.2 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then Pd/C (685.8 mg, 10% wt.) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 16 hours at rt. The solids were removed by filtration and the filter cake was washed with MeOH. The combined filtrate was concentrated under vacuum to give 5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole (605.0 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=360.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.94 (s, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.43 (d, J=7.6 Hz, 2H), 7.31-7.29 (m, 2H), 7.06 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.34 (s, 1H), 4.52 (t, J=8.0 Hz, 1H), 3.07 (t, J=9.6 Hz, 1H), 2.70-2.63 (m, 1H), 2.45-2.37 (m, 1H), 1.38 (s, 3H), 0.68 (s, 3H).

Step 6: 1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one

[1092] 5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole (450.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to −30° C., then Et.sub.2AlCl (1M in DCM, 1.9 mL, 1.9 mmol, 1.5 equiv.) and acetyl chloride (147.4 mg, 1.9 mmol, 1.5 equiv.) were added dropwise, maintaining the solution at −30° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours at −30° C. and then quenched by the addition of ice-water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to give 1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one (428.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=402.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.82 (s, 1H), 8.25 (d, J=3.2 Hz, 1H), 7.76 (d, J=2.8 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.6 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 6.86-6.83 (m, 1H), 4.54 (t, J=7.6 Hz, 1H), 3.14-3.10 (m, 1H), 2.68-2.58 (m, 1H), 2.45-2.41 (m, 1H), 2.43 (s, 3H), 1.43 (s, 3H), 0.66 (s, 3H).

Step 7: (Z)-1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one oxime

[1093] 1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one (428.0 mg, 1.1 mmol, 1.0 equiv.) and NaOAc (174.9 mg, 2.1 mmol, 2.0 equiv.) were dissolved in EtOH (5 mL), then NH.sub.2OH.HCl (111.1 mg, 1.6 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 4 hours at 60° C., then cooled to rt and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to give (Z)-1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one oxime (340.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=417.0.

Step 8: N-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide

[1094] (Z)-1-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)ethan-1-one oxime (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THE (4 mL), then T.sub.3P (305.6 mg, 0.9 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 1 hour at 70° C. and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 65% B to 77% B in 6 min; Wave Length: 254 nm; RT1(min): 5.78. This resulted in N-(5-(cis-2,2-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide (74.7 mg) as a white solid. LCMS Method F: [M+H].sup.+=417.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.60 (s, 1H), 9.71 (s, 1H), 7.69-7.65 (m, 3H), 7.43 (d, J=6.0 Hz, 2H), 7.32 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 4.48 (t, J=7.2 Hz, 1H), 3.12-3.08 (s, 1H), 2.74-2.67 (m, 1H), 2.42-2.37 (m, 1H), 2.09 (s, 3H), 1.36 (s, 3H), 0.72 (s, 3H).

Example 253: Synthesis of N-{5-[(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}oxane-4-carboxamide (Compound 493)

[1095] ##STR00998##

[1096] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-[(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indole-1-carboxylate (98.3 mg, 0.18 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), then TFA (1 mL) was added to the solution. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. Then the residue and oxane-4-carboxylic acid (46.8 mg, 0.36 mmol, 2.0 equiv.) were dissolved in DMF (2 mL), then TEA (130 μl, 0.9 mmol, 5.0 equiv.) and HATU (71.8 mg, 0.189 mmol, 1.05 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC-1-1 to give N-{5-[(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}oxane-4-carboxamide (24.7 mg, 0.054 mmol) as a powder. MS-ESI, 459.3 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 10.89 (br s, 1H), 9.01 (s, 1H), 7.68 (br d, J=8.1 Hz, 2H), 7.58 (br d, J=8.00 Hz, 2H), 7.28-7.12 (m, 3H), 6.73 (dd, J=8.70 Hz, 1H), 4.19 (t, J=6.60 Hz, 2H), 3.22-3.09 (m, 2H), 2.92 (q, J=7.40 Hz, 2H), 1.22 (t, J=7.30 Hz, 3H).

[1097] The compounds in the following table were prepared using the above procedures (example 253) with the appropriate starting material.

TABLE-US-00059 LC-MS, MS-ESI, - Example # Compound # Structure IUPAC Name - [M+H+]. 253 493 [00999] embedded image N-{5-[(IR,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}oxane-4- carboxamide 459.3 254 489 [01000] l-fluoro-N-{5- [(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}cyclopropane-1- carboxamide 433.2 255 488 [01001] 4-methyl-N-{5- [(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}oxane-4- carboxamide 473.4 256 487 [01002] embedded image 2-methyl-N-{5- [(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}oxolane-2- carboxamide 459.3 257 469 [01003] 3-fluoro-3-methyl- N-{5-[(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}cyclobutane-1- carboxamide 461.3 258 468 [01004] l-(methoxymethyl)- N-{5-[(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}cyclopropane-1- carboxamide 459.3 259 467 [01005] embedded image 2-cyano-N-{5- [(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}cyclobutane-1- carboxamide 454.3 260 486 [01006] 2-(2- methoxyethoxy)-N- {5-[(1R,3R)-3-[4- (trifluoromethyl)phe nyl]cyclobutoxy]- 1H-indol-3- yl}acetamide 463.3

Example 261: Synthesis of N-{5-[(1R, 3R)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indol-3-yl}azetidine-3-carboxamide (Compound 459)

[1098] ##STR01007##

[1099] tert-butyl 3-{[(tert-butoxy)carbonyl]amino}-5-[(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclobutoxy]-1H-indole-1-carboxylate (136.5 mg, 0.25 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), then TFA (1 mL) was added to the solution. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue. Then the residue and 1-[(tert-butoxy)carbonyl] azetidine-3-carboxylic acid (100.5 mg, 0.5 mmol, 2.0 equiv.) were dissolved in ACN (1.5 mL), then NMI (500 μl) and TCFH (78.4 mg, 0.28 mmol, 1.1 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac to give a residue. The residue was diluted with H.sub.2O (1 mL) and extracted with 3*1 mL EtOAc. The combined organic layers were washed with H.sub.2O (1 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. After that DCM (3 mL) was added dropwise and TFA (1 mL) at 30° C. for 2 hrs. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC-1 to give N-{5-[(1R, 3R)-3-[4-(trifluoromethyl) phenyl] cyclobutoxy]-1H-indol-3-yl} azetidine-3-carboxamide (4.82 mg, 0.011 mmol) as a powder. MS-ESI, 430.3 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 11.03-10.95 (m, 1H), 9.07 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.14-7.06 (m, 3H), 4.27 (t, J=6.8 Hz, 2H), 3.17-3.07 (m, 2H), 2.93 (q, J=7.4 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H).

[1100] The compounds in the following table were prepared using the above procedure (example 261) with the appropriate starting material.

TABLE-US-00060 LC-MS, MS-ESI, - Example # Compound # Final compound IUPAC Name - [M+H+]. 262 460 [01008] embedded image 4-methyl-N-{5- [(1R,3R)-3-[4- (trifluoromethyl) phenyl]cyclobutoxy]- 1H-indol-3- yl}piperidine-4- carboxamide 472.3 263 459 [01009] N-{5-[(1R,3R)-3- [4- (trifluoromethyl) phenyl]cyclobutoxy]- 1H-indol-3- yl} azetidine-3 - carboxamide 430.3

[1101] The compound in the following table was prepared using steps 1) and 2) of the above procedure (example 261) with the appropriate starting material.

TABLE-US-00061 LC-MS, MS-ESI, - Example # Compound # Final compound IUPAC Name - [M+H+]. 264 466 [01010] embedded image tert-butyl 3-({5- [(1R,3R)-3-[4- (trifluoromethyl) phenyl] cyclobutoxy]- 1H-indol-3- yl}carbamoyl) azetidine-1- carboxylate 529.3

Example 265: Synthesis of N-(5-{2-[4-(2, 2, 2-trifluoroethyl)phenoxy]ethyl}-1H-indol-3-yl)acetamide (Compound 442)

[1102] ##STR01011##

[1103] tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate (66.8 mg, 0.21 mmol, 1.0 equiv.) and 4-(2,2,2-trifluoroethyl)phenol (73.9 mg, 0.42 mmol, 2.0 equiv.) were dissolved in DCM (2 mL), DIAD (127.3 mg, 0.63 mmol, 3.0 equiv.), pyridine (210 μl) and Triphenylphosphine resin (350 mg, 3.0 g/mol, 1.05 mmol, 5.0 equiv.) were added under N2 atmosphere. The mixture was heated at 30° C. for 24 hours under N2 atmosphere. The mixture was diluted with 3*1 mL DCM and extracted with H.sub.2O (1 mL). The combined organic layers were washed with H.sub.2O (1 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. After that the residue were dissolved in DCM (2 mL), then TFA (500 μl) was added. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC-1 to give N-(5-{2-[4-(2, 2, 2-trifluoroethyl)phenoxy]ethyl}-1H-indol-3-yl) acetamide (16.24 mg, 0.041 mmol) as a powder. MS-ESI, 400.3 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 10.67 (br s, 1H), 9.77 (s, 1H), 7.65 (d, J=9.88 Hz, 2H), 7.29-7.22 (m, 3H), 7.10-7.05 (m, 1H), 6.98-6.92 (m, 2H), 4.20 (t, J=7.03 Hz, 2H), 3.62-3.46 (m, 2H), 3.12-3.06 (m, 2H), 2.08 (s, 3H).

[1104] The compounds in the following table were prepared using the above procedure (example 265) with the appropriate starting material.

TABLE-US-00062 LC-MS, MS-ESI, - Example # Example # Final compound IUPAC Name - [M+H+]. 266 490 [01012] embedded image N-(5-[2-(5,6,7,8- tetrahydronaphtha len-2- yloxy)ethyl]-1H- indol-3- yl}acetamide 349.3 267 462 [01013] N-{5-[2-(4- cyanophenoxy)et hyl]-1H-indol-3- yl}acetamide 320.2 268 461 [01014] N-(5-{2-[4-(2- methoxyethyl)phe noxy]ethyl}-1H- indol-3- yl)acetamide 353.3 269 470 [01015] N-(5-{2-[4- fluoro-3- (trifluoromethyl)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 381.2 270 476 [01016] embedded image N-{5-[2-(3- chloro-5- cyanophenoxy)et hyl]-1H-indol-3- yl}acetamide 354.2 271 453 [01017] N-(5-{2-[3- (cyanomethyl)phe noxy]ethyl}-1H- indol-3- yl)acetamide 334.3 272 438 [01018] N-(5-{2-[3- fluoro-4- (trifluoromethoxy )phenoxy]ethyl}- 1H-indol-3- yl)acetamide 397.3 273 475 [01019] N-(5-{2-[4-(2- methyl-1,3- thiazol-4- yl)phenoxy]ethyl} -1H-indol-3- yl)acetamide 392.2 274 452 [01020] embedded image N-(5-{2-[4-(2,2,2- trifluoroethoxy)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 393.2 275 451 [01021] N-(5-{2-[4- (pyridin-4- yl)phenoxy]ethyl} -1H-indol-3- yl)acetamide 372.2 276 442 [01022] N-(5-{2-[4-(2,2,2- trifluoroethyl)phe noxy]ethyl}-1H- indol-3- yl)acetamide 400.3 277 441 [01023] embedded image N-(5-{2-[3-(2,2,2- trifluoroethyl)phe noxy]ethyl}-1H- indol-3- yl)acetamide 452.3 278 450 [01024] N-(5-{2-[4- chloro-2- (trifluoromethyl)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 397.2 279 449 [01025] N-{5-[2- (isoquinolin-7- yloxy)ethyl]-1H- indol-3- yl}acetamide 346.2 280 411 [01026] embedded image N-(5-{2-[2- chloro-4- (trifluoromethyl)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 397.1 281 440 [01027] N-(5-{2-[2- cyano-4- (trifluoromethyl)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 412.3 282 410 [01028] N-(5-{2-[3,5- difluoro-4- (trifluoromethyl)p henoxy]ethyl}- 1H-indol-3- yl)acetamide 399.2

Example 283: Synthesis of N-[5-(2-{[2-(difluoromethoxy)pyridin-4-yl]oxy}ethyl)-1H-indol-3-yl]acetamide (Compound 491)

[1105] ##STR01029##

[1106] tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate (66.8 mg, 0.21 mmol, 1.0 equiv.) and 2-(difluoromethoxy)pyridin-4-ol (67.6 mg, 0.42 mmol, 2.0 equiv.) were dissolved in DCM (2 mL), DIAD (127.3 mg, 0.63 mmol, 3.0 equiv.) and Triphenylphosphine resin (350 mg, 3.0 g/mol, 1.05 mmol, 5.0 equiv.) were added under N.sub.2 atmosphere. The mixture was heated at 30° C. for 24 hours under N2 atmosphere. The mixture was diluted with 3 *1 mL DCM and extracted with H.sub.2O (1 mL). The combined organic layers were washed with H.sub.2O (1 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. After that the residue were dissolved in DCM (2 mL), then TFA (500 l) was added. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC-1 to give N-[5-(2-{[2-(difluoromethoxy)pyridin-4-yl]oxy}ethyl)-1H-indol-3-yl]acetamide (20.03 mg, 0.055 mmol) as a powder. MS-ESI, 362.2 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 10.69 (s, 1H), 9.78 (s, 1H), 8.04 (d, J=5.77 Hz, 1H), 7.86 (s, 1H), 7.69-7.65 (m, 1H), 7.50 (s, 1H), 7.91-7.48 (m, 1H), 7.26 (d, J=8.53 Hz, 1H), 7.06 (dd, J=8.28, 1.25 Hz, 1H), 6.85 (dd, J=5.90, 2.13 Hz, 1H), 6.66 (d, J=2.01 Hz, 1H), 4.34 (t, J=6.90 Hz, 2H), 3.11 (t, J=6.90 Hz, 2H), 2.08 (s, 3H).

[1107] The compounds in the following table were prepared using the above procedures (example 283) with the appropriate starting material.

TABLE-US-00063 LC-MS, MS-ESI, -- Example # Compound # Final compound IUPAC Name [M+H+]. 283 491 [01030] embedded image N-[5-(2-(2- (difluoromethoxy )pyridin-4- yl]oxy}ethyl)-1H- indol-3- yl]acetamide 362.2 284 463 [01031] N-(5-(2-(2- cyclopropylpyridi n-4- yl)oxy]ethyl}-1H- indol-3- yl)acetamide 336.3 285 481 [01032] N-[5-(2-{[5- (trifluoromethyl)p yridin-3- yl]oxy}ethyl)-1H- indol-3- yl]acetamide 364.2 286 471 [01033] embedded image N-[5-(2-{[6- (trifluoromethoxy )pyridin-3- yl]oxy}ethyl)-1H- indol-3- yl]acetamide 380.2 287 477 [01034] N-[5-(2-{[8- (trifluoromethoxy )quinolin-3- yl]oxy}ethyl)-1H- indol-3- yl]acetamide 430.3 288 480 [01035] N-[5-(2-{[6- (trifluoromethoxy )quinolin-3- yl]oxy}ethyl)-1H- indol-3- yl]acetamide 430.3

Example 289: Synthesis of N-[5-(2-{[5-(difluoromethyl)pyridin-3-yl]oxy}ethyl)-1H-indol-3-yl]acetamide (compound 439)

[1108] ##STR01036##

[1109] tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate (66.8 mg, 0.21 mmol, 1.0 equiv.) and 3-bromo-5-(difluoromethyl)pyridine (86.5 mg, 0.42 mmol, 2.0 equiv.) were dissolved in t-AmOH (1 mL) and Tol (1 mL), Cs.sub.2CO.sub.3(204.8 mg, 0.63 mmol, 3.0 equiv.) and tBuBrettphos-Pd-G3 (89.7 mg, 0.105 mmol, 0.5 equiv.) were added under N2 atmosphere. The mixture was heated at 100° C. for 16 hours under N2 atmosphere. The reaction mixture was concentrated by Speedvac to give a residue. The residue was diluted with H.sub.2O (1 mL) and extracted with 3*1 mL DCM. The combined organic layers were washed with H.sub.2O (1 mL), dried over anhydrous sodium sulfate anhydrous, filtered and concentrated under reduced pressure to give a residue. After that the residue were dissolved in DCM (2 mL), then TFA (500 μl) was added. The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac to give a residue that was purified by prep HPLC-1 to give N-[5-(2-{[5-(difluoromethyl) pyridin-3-yl]oxy}ethyl)-1H-indol-3-yl]acetamide (13.71 mg, 0.040 mmol) as a powder. MS-ESI, 346.2 [M+H.sup.+].

[1110] The compounds in the following table were prepared using the above procedures (example 289) with the appropriate starting material.

TABLE-US-00064 LC-MS, MS- ESI, -- Example # Compound # Final compound IUPAC Name [M+H+]. 289 439 [01037] embedded image N-[5-(2-([5- (difluoromethyl) pyridin-3-yl] oxy}ethyl)- 1H-indol-3-yl] acetamide 346.2

Example 290. General Methods for the Synthesis of Compounds of Formula (I-a) and Formula (I-d)

[1111] ##STR01038## ##STR01039##

Biological Assays

[1112] STING pathway activation by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

[1113] THP1-Dual™ KO-IFNAR2 Cells (obtained from InvivoGen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017-100 μM. Cells were plated into the TC plates at 40 μL per well, 2×10E6 cells/mL. For activation with STING ligand, 2′3′cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.

[1114] The following solutions were prepared for each 1×384 plate: [1115] Solution A: 2 mL Optimem with one of the following stimuli: [1116] 60 μL of 10 mM 2′3′cGAMP.fwdarw.150 μM stock [1117] Solution B: 2 mL Optimem with 60 μL Lipofectamine 2000.fwdarw.Incubate 5 min at RT

[1118] 2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 μL of transfection solution (A+B) was added on top of the plated cells, with a final 2′3′cGAMP concentration of 15 μM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37° C., 5% CO.sub.2, >98% humidity for 24 h. Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.

[1119] Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells. One pouch of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC Stabilizer per 25 mL of QUANTI-Luc™ Plus solution was added. 50 μL of QUANTI-Luc™ Plus/QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)).

[1120] Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.

[1121] Table BA shows the activity of compounds in STING reporter assay: <0.008 μM=“++++++”; ≥0.008 and <0.04 μM=“+++++”; ≥0.04 and <0.2 μM=“++++”; ≥0.2 and <1 M=“+++”; ≥1 and <5 μM=“++”; ≥5 and <100 μM=“+”.

TABLE-US-00065 TABLE BA Pharmaron, THP1_IFNAR2 STING 24 h Luci Normalized: Compound GeoMean EC.sub.50 No. (μM) 101 +++ 102 ++++ 103 ++++ 104 +++ 105 ++ 106 +++ 107 ++++ 108 + 109 ++++ 110 +++ 111 ++++ 112 + 113 ++ 114 +++ 115 ++++ 116 + 117 +++ 118 +++ 119 + 120 + 121 +++ 122 +++ 123 + 124 ++ 125 +++ 126 ++ 127 ++++ 128 +++ 129 +++ 130 +++ 131 ++ 132 ++++ 133 +++ 134 +++ 135 +++ 136 ++++ 137 ++ 138 +++ 139 ++++ 140 +++ 141 ++ 142 +++ 143 ++ 144 + 145 +++ 146 ++++ 147 ++++ 148 +++ 149 ++++ 150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 ++++ 158 ++++ 159 ++++ 160 +++ 161 ++++ 162 ++++ 163 ++++ 164 +++ 165 ++++ 166 ++++ 167 +++ 168 +++ 169 ++++ 170 +++ 171 ++ 172 +++ 173 + 174 +++ 175 +++ 176 +++ 177 +++ 178 +++ 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 184 + 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 ++++ 193 +++ 194 +++ 195 +++ 196 + 197 + 198 +++ 199 ++ 200 +++ 201 +++ 202 ++++ 203 +++ 204 ++++ 205 ++++ 206 ++++ 207 ++++ 208 ++ 209 +++ 210 ++++ 211 ++++ 212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 ++++ 218 +++ 219 ++++ 220 ++++ 221 ++++ 222 ++++ 223 ++++ 224 ++++ 225 ++++ 226 ++ 227 ++++ 228 +++ 229 +++ 230 ++++ 231 +++ 232 ++ 233 ++++ 234 ++++ 235 ++++ 236 ++++ 237 ++++ 238 ++++ 239 ++++ 240 +++ 241 ++++ 242 ++++ 243 ++++ 244 ++++ 245 ++++ 246 ++++ 247 +++ 248 ++ 249 +++ 250 ++ 251 ++++ 252 ++++ 253 ++ 254 ++++ 255 ++ 256 +++ 257 +++ 258 ++++ 259 ++ 260 +++ 261 ++++ 262 ++++ 263 +++ 264 ++ 265 + 266 ++++ 267 ++ 268 ++ 270 ++ 271 ++ 272 ++ 273 ++++ 274 ++ 275 ++ 276 ++ 277 + 278 + 279 ++ 280 ++ 281 + 282 ++ 283 +++ 284 +++ 285 ++ 286 ++ 287 ++ 288 + 289 ++ 290 + 291 +++ 292 + 293 + 294 ++++ 295 ++++ 296 ++++ 297 +++ 298 +++ 299 +++ 300 ++++ 301 +++ 302 +++ 303 + 304 +++ 305 ++ 306 +++ 307 +++ 308 ++++ 309 ++++ 310 ++++ 311 ++ 312 ++++ 313 ++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319 +++ 320 +++ 321 +++ 322 +++ 323 +++ 324 +++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 +++ 331 ++ 332 +++ 333 ++ 334 ++++ 335 +++ 336 +++ 337 +++ 338 +++ 339 +++ 340 ++ 341 +++ 342 +++ 343 +++ 344 +++ 345 +++ 346 +++ 347 +++ 348 +++ 349 + 350 ++ 351 +++ 352 ++++ 353 +++ 354 +++ 355 +++ 356 +++ 357 +++ 358 ++ 359 ++++ 360 +++ 361 ++++ 362 +++ 363 +++ 364 ++++ 365 ++++ 366 +++ 367 +++ 368 +++ 369 +++ 370 +++ 371 +++ 372 ++ 373 ++ 374 + 375 ++ 376 +++ 377 + 378 +++ 379 +++ 380 ++++ 381 +++ 382 +++ 383 +++ 384 +++ 385 + 386 ++ 387 +++ 388 +++ 389 +++ 390 +++ 391 ++++ 392 +++ 393 +++ 394 ++++ 395 +++ 396 +++ 397 +++ 398 +++ 399 +++ 400 +++ 401 +++ 402 + 404 ++ 405 +++ 406 +++ 407 +++ 408 ++++ 412 ++ 413 ++ 414 +++ 415 ++ 416 +++ 417 +++ 418 +++ 419 +++ 420 +++ 421 +++ 422 ++ 423 +++ 424 +++ 425 +++ 426 ++++ 427 +++ 428 +++ 429 +++ 430 ++++ 431 ++++ 432 ++ 433 +++ 434 ++++ 435 ++++ 436 ++++ 437 +++ 438 ++++ 439 + 440 ++ 441 ++++ 442 ++++ 443 +++ 444 + 445 ++++ 446 ++++ 447 + 448 ++++ 449 ++ 450 +++ 451 ++ 452 ++++ 453 ++ 454 +++ 455 +++ 456 +++ 457 +++ 458 ++ 459 + 460 ++ 461 +++ 462 ++ 463 + 464 +++ 465 +++ 466 +++ 467 +++ 468 +++ 469 +++ 470 +++ 471 +++ 472 +++ 473 ++ 474 +++ 475 ++ 476 ++ 477 ++ 478 ++ 479 ++++ 480 +++ 481 ++ 482 ++++ 483 ++++ 484 ++ 485 ++ 486 ++++ 487 ++++ 488 ++++ 489 +++ 490 ++++ 491 +++ 492 + 493 ++++ 494 +++ 495 ++ 496 +++ 497 ++ 498 +++ 499 + 500 ++++ 501 ++ 504 +++ 505 +++ 506 + 507 + 508 + 509 ++ 510 +++ 511 +++ 512 +++ 513 +++ 514 +++ 515 ++ 516 + 517 + 518 +++ 519 ++++ 520 ++++ 521 +++ 522 ++++ 523 +++ 524 ++++ 525 +++ 526 + 527 ++ 528 + 529 + 530 ++++ 531 ++++ 532 + 533 ++++ 534 ++++ 535 +++ 536 + 537 + 538 ++ 539 ++ 540 ++ 541 + 542 +++ 543 +++ 544 +++ 545 ++++ 546 ++ 547 +++ 548 +++ 549 ++ 550 +++ 551 +++ 552 +++ 553 +++ 554 +++ 555 ++ 556 + 557 ++ 558 +++ 559 +++ 560 ++ 561 ++++ 562 +++ 563 ++++ 564 ++++ 565 +++ 566 ++++ 567 ++ 568 +++ 569 ++ 570 +++ 571 +++ 572 ++++ 573 ++++ 574 ++++ 575 +++ 576 ++++ 577 +++ 578 ++ 579 +++ 580 ++++ 581 + 582 ++++ 583 ++ 584 +++ 585 +++ 586 +++ 587 ++++ 588 ++++ 589 ++++ 590 ++ 591 +++ 592 +++ 593 ++++ 594 +++ 595 ++++

Numbered Clauses

[1122] The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:

[1123] 1. A compound of Formula (I):

##STR01040##

[1124] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[1125] L.sup.A is -(L.sup.1).sub.a1-(L.sup.2).sub.a2-(L.sup.3).sub.a3-(L.sup.4).sub.a4-(L.sup.5).sub.a5-*, wherein * represents the point of attachment to Q.sup.1;

[1126] a1, a2, a3, a4, and a5 are each independently 0 or 1,

[1127] provided that a1+a2+a3+a4+a5≥1, and

[1128] each of L.sup.1, L.sup.3, and L.sup.5 is independently selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, S(O).sub.0-2, and —C(═O)—;

[1129] provided that when one or both of a2 and a4 is 0, then the combinations of L.sup.1, L.sup.3, and L.sup.5 cannot form O—O, N—O, N—N, O—S, S—S, or N—S(O).sub.0 bonds, and

[1130] each of L.sup.2 and L.sup.4 is independently selected from the group consisting of: [1131] straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b; [1132] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c; and [1133] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c;

[1134] Q.sup.1 is —R.sup.g;

[1135] Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2;

[1136] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1;

[1137] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;

[1138] each custom-character is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl;

[1139] further provided that L.sup.A cannot include a cyclic group directly attached to the 6-membered ring containing Y.sup.1, Y.sup.2, and Y.sup.3;

[1140] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1141] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1142] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.g;

[1143] W is selected from the group consisting of: [1144] H; [1145] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [1146] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1147] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[1148] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom;

[1149] each occurrence of R.sup.a and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano;

[1150] each occurrence of R.sup.b and R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; —NR′C(═O)(C.sub.1-4 alkyl) and —SF.sub.5;

[1151] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[1152] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, halo, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;

[1153] each occurrence of R.sup.g is independently selected from the group consisting of: [1154] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [1155] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [1156] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; and [1157] C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h;

[1158] each occurrence of R.sup.h is independently selected from the group consisting of: [1159] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; [1160] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; [1161] heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and [1162] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.i;

[1163] each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo;

[1164] each occurrence of L.sup.g is independently selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a; each occurrence of bg is independently 1, 2, or 3; and

[1165] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.

[1166] 2. The compound of clause 1, wherein a2 is 1.

[1167] 3. The compound of clauses 1 or 2, wherein L.sup.2 is straight-chain C.sub.1-6 alkylene, straight-chain C.sub.2-6 alkenylene, or straight-chain C.sub.2-6 alkynylene, each of which is optionally substituted with 1-6 R.sup.b.

[1168] 4. The compound of any one of clauses 1-3, wherein L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b.

[1169] 5. The compound of any one of clauses 1-4, wherein L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1170] 6. The compound of any one of clauses 1-5, wherein L.sup.2 is selected from the group consisting of —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—.

[1171] 7. The compound of any one of clauses 1-6, wherein L.sup.2 is —CH.sub.2—.

[1172] 8. The compound of any one of clauses 1-4, wherein L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1173] 9. The compound of any one of clauses 1-4 or 8, wherein L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[1174] 10. The compound of any one of clauses 1-4 or 8-9, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[1175] 11. The compound of any one of clauses 1-4 or 8-10, wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1176] 12. The compound of any one of clauses 1-4 or 8, wherein L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1177] 13. The compound of any one of clauses 1-4, 8, or 12, wherein L.sup.2 is selected from the group consisting of:

##STR01041##

wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[1178] 14. The compound of any one of clauses 1-3, wherein L.sup.2 is straight-chain C.sub.2-6 alkenylene, which is optionally substituted with 1-6 R.sup.b.

[1179] 15. The compound of any one of clauses 1-3 or 14, wherein L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b.

[1180] 16. The compound of any one of clauses 1-3 or 14-15, wherein L.sup.2 is selected from the group consisting of:

##STR01042##

and wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[1181] 17. The compound of clauses 1 or 2, wherein L.sup.2 is selected from the group consisting of: [1182] C.sub.3-10 cycloalkylene or C.sub.3-10 cycloalkenylene, each of which is optionally substituted with 1-3 R.sup.c; and [1183] heterocyclylene or heterocycloalkenylene, each having 4-10 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-3 R.sup.c.

[1184] 18. The compound of any one of clauses 1-2 or 17, wherein L.sup.2 is selected from the group consisting of: [1185] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [1186] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[1187] 19. The compound of any one of clauses 1-2 or 17-18, wherein L.sup.2 is:

##STR01043##

[1188] 20. The compound of clause 19, wherein Q.sup.2 is CH.

[1189] 21. The compound of clauses 19 or 20, wherein n1 and n2 are each 0.

[1190] 22. The compound of any one of clauses 1-2 or 17-21, wherein L.sup.2 is

##STR01044##

wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[1191] 23. The compound of clause 1, wherein a2 is 0.

[1192] 24. The compound of any one of clauses 1-23, wherein a1 is 1.

[1193] 25. The compound of any one of clauses 1-24, wherein L.sup.1 is selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, and —S—.

[1194] 26. The compound of any one of clauses 1-25, wherein L.sup.1 is —O—.

[1195] 27. The compound of any one of clauses 1-23, wherein a1 is 0.

[1196] 28. The compound of any one of clauses 1-27, wherein a3 is 1.

[1197] 29. The compound of any one of clauses 1-28, wherein L.sup.3 is selected from the group consisting of: —O—, —N(H)—, —N(R.sup.d)—, and —S—

[1198] 30. The compound of any one of clauses 1-29, wherein L.sup.3 is —O—.

[1199] 31. The compound of any one of clauses 1-29, wherein L.sup.3 is —N(H)— or —N(R.sup.d)—optionally —N(H)—.

[1200] 32. The compound of any one of clauses 1-27, wherein a3 is 0.

[1201] 33. The compound of any one of clauses 1-32, wherein a4 is 1.

[1202] 34. The compound of any one of clauses 1-33, wherein L.sup.4 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1203] 35. The compound of any one of clauses 1-34, wherein L.sup.4 is —CH.sub.2—.

[1204] 36. The compound of any one of clauses 1-33, wherein L.sup.4 is selected from the group consisting of: [1205] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [1206] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[1207] 37. The compound of any one of clauses 1-33 or 36, wherein L.sup.4 is:

##STR01045##

[1208] 38. The compound of clause 37, wherein n3 and n4 are each 1.

[1209] 39. The compound of clauses 37 or 38, wherein Q.sup.3 is N.

[1210] 40. The compound of any one of clauses 1-33 or 36-39, wherein L.sup.4 is

##STR01046##

wherein the asterisk represents the point of attachment to -(L.sup.5).sub.a5-.

[1211] 41. The compound of any one of clauses 1-32, wherein a4 is 0.

[1212] 42. The compound of any one of clauses 1-41, wherein a5 is 0.

[1213] 43. The compound of clause 1, wherein one of a1, a3, and a5 is 1, and the other two are 0.

[1214] 44. The compound of clauses 1 or 43, wherein one of a2 and a4 is 1, and the other is 0 or 1.

[1215] 45. The compound of any one of clauses 1 or 43-44, wherein a1 and a2 are each 1.

[1216] 46. The compound of any one of clauses 1 or 43-45, wherein:

[1217] a1 and a2 are each 1;

[1218] L.sup.1 is —O—, —N(H)—, or —N(R.sup.d)—;

[1219] L.sup.2 is selected from the group consisting of: [1220] straight-chain CI-3 alkylene, which is optionally substituted with 1-3 R.sup.b; [1221] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [1222] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[1223] 47. The compound of any one of clauses 1 or 43-46, wherein:

[1224] a1 and a2 are each 1;

[1225] L.sup.1 is —O—; and

[1226] L.sup.2 is straight-chain CI-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1227] 48. The compound of any one of clauses 1 or 43-47, wherein:

[1228] a1 and a2 are each 1;

[1229] L.sup.1 is —O—; and

[1230] L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—.

[1231] 49. The compound of any one of clauses 1 or 43-47, wherein:

[1232] a1 and a2 are each 1;

[1233] L.sup.1 is —O—; and

[1234] L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1235] 50. The compound of clause 49, wherein L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[1236] 51. The compound of clauses 49 or 50, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[1237] 52. The compound of any one of clauses 49-51, wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1238] 53. The compound of any one of clauses 1 or 43-46, wherein:

[1239] a1 and a2 are each 1;

[1240] L.sup.1 is —O—;

[1241] L.sup.2 is selected from the group consisting of: [1242] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [1243] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[1244] 54. The compound of clause 53, wherein L.sup.2 is:

##STR01047##

[1245] 55. The compound of clause 54, wherein n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH; optionally wherein n1 and n2 are 0 and Q.sup.2 is CH; optionally wherein L.sup.2 is cyclobutane-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is cyclobutane-1,3-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is unsubstituted cyclobutane-diyl; optionally wherein L.sup.2 is unsubstituted cyclobutane-1,3-diyl.

[1246] 56. The compound of any one of clauses 43-55, wherein a3, a4 and a5 are each 0, optionally wherein L.sup.A is —O—CH.sub.2CH.sub.2—*, or

##STR01048##

(such as

##STR01049##

wherein * represents the point of attachment to Q.sup.1.

[1247] 57. The compound of any one of clauses 43-55, wherein a3 and a5 are 0; and a4 is 1.

[1248] 58. The compound of clause 57, wherein L.sup.4 is selected from the group consisting of: [1249] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.c; and [1250] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c.

[1251] 59. The compound of clauses 57 or 58, wherein L.sup.4 is:

##STR01050##

[1252] 60. The compound of clause 59, wherein n3 and n4 are independently 0 or 1; and Q.sup.3 is N.

[1253] 61. The compound of any one of clauses 1 or 43-44, wherein: a1 is 0; and a2 is 1.

[1254] 62. The compound of any one of clauses 1, 43-44, or 61, wherein a1 is 0; a2 is 1; and L.sup.2 is straight-chain C.sub.1-6 alkylene, which is optionally substituted with 1-6 R.sup.b.

[1255] 63. The compound of clauses 61 or 62, wherein L.sup.2 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1256] 64. The compound of any one of clauses 61-63, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R″).sub.2—.

[1257] 65. The compound of any one of clauses 61-64, wherein L.sup.2 is —CH.sub.2—.

[1258] 66. The compound of any one of clauses 61-63, wherein L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1259] 67. The compound of any one of clauses 61-63 or 66, wherein L.sup.2 is straight-chain C.sub.2 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1260] 68. The compound of any one of clauses 61-63 or 66-67, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R″)-*, and —CH.sub.2C(R″).sub.2-*, wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[1261] 69. The compound of any one of clauses 61-63 or 66-68, wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1262] 70. The compound of any one of clauses 61-63 or 66, wherein L.sup.2 is straight-chain C.sub.3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1263] 71. The compound of any one of clauses 61-63, 66, or 70, wherein L.sup.2 is selected from the group consisting of:

##STR01051##

wherein the asterisk represents point of attachment to -(L.sup.3).sub.a3-.

[1264] 72. The compound of any one of clauses 61-71, wherein a3 is 0; a4 is 0; and a5 is 0.

[1265] 73. The compound of any one of clauses 61-71, wherein a3 is 1.

[1266] 74. The compound of clause 73, wherein a3 is 1; and L.sup.3 is selected from the group consisting of: is —O—, —N(H)—, and —N(R.sup.d)—.

[1267] 75. The compound of clauses 73 or 74, wherein a3 is 1; and L.sup.3 is —O—.

[1268] 76. The compound of any one of clauses 61-71 or 73-74, wherein a3 is 1; and L.sup.3 is —N(H)— or —N(R.sup.d)—, optionally —N(H)—.

[1269] 77. The compounds of any one of clauses 61-71 or 73-76, wherein a4 is 1; and L.sup.4 is straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1270] 78. The compound of any one of clauses 61-71 or 73-77, wherein a4 is 1; and L.sup.4 is —CH.sub.2—.

[1271] 79. The compound of any one of clauses 61-71 or 73-77, wherein a4 is 0; and a5 is 0, optionally wherein L.sup.A is —CH.sub.2CH.sub.2—O—*, wherein * represents to point of attachment to Q.sup.1.

[1272] 80. The compound of clause 1, wherein a1 is 0; a2 is 1; L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b.

[1273] 81. The compound of clause 80, wherein L.sup.2 is selected from the group consisting of:

##STR01052##

wherein the asterisk represents the point of attachment to -(L.sup.3).sub.a3-.

[1274] 82. The compound of clauses 80 or 81, wherein a3 is 0; a4 is 0; and a5 is 0.

[1275] 83. The compound of any one of clauses 1-82, wherein Q.sup.1 is selected from the group consisting of: [1276] heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.c; and [1277] C.sub.6-10 aryl optionally substituted with 1-4 R.sup.c.

[1278] 84. The compound of any one of clauses 1-82, wherein Q.sup.1 is selected from the group consisting of: [1279] heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [1280] phenyl optionally substituted with 1-3 R.sup.c.

[1281] 85. The compound of any one of clauses 1-82, wherein Q.sup.1 is selected from the group consisting of: [1282] heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [1283] phenyl optionally substituted with 1-3 R.sup.c.

[1284] 86. The compound of any one of clauses 1-85, wherein Q.sup.1 is phenyl optionally substituted with 1-3 R.sup.c.

[1285] 87. The compound of any one of clauses 1-86, wherein Q.sup.1 is selected from the group consisting of:

##STR01053##

[1286] 88. The compound of any one of clauses 1-85, wherein Q.sup.1 is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c.

[1287] 89. The compound of any one of clauses 1-85 or 88, wherein Q.sup.1 is pyridyl, which is optionally substituted with 1-3 R.sup.c.

[1288] 90. The compound of any one of clauses 1-85 or 88-89, wherein Q.sup.1 is selected from the group consisting of:

##STR01054##

[1289] 91. The compound of any one of clauses 1-82, wherein Q.sup.1 is heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1290] 92. The compound of any one of clauses 1-82 or 91, wherein Q.sup.1 is heterocyclyl of 4-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1291] 93. The compound of any one of clauses 1-82 or 91-92, wherein Q.sup.1 is heterocyclyl of 4-8 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, provided that one ring atom is N(R.sup.d),

[1292] and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1293] 94. The compound of any one of clauses 1-82 or 91-93, wherein Q.sup.1 is

##STR01055##

wherein m1 and m2 are each independently 0, 1, or 2; and wherein Q.sup.1 is optionally substituted with 1-2 R.sup.c.

[1294] 95. The compound of any one of clauses 1-82 or 91-94, wherein Q.sup.1 is

##STR01056##

[1295] 96. The compound of any one of clauses 1-82 or 91-94, wherein Q.sup.1 is

##STR01057##

[1296] 97. The compound any one of clauses 91-96, wherein each R.sup.d present in Q.sup.1 is independently selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a.

[1297] 98. The compound of any one of clauses 91-97, wherein each R.sup.d present in Q.sup.1 is C.sub.1-6 alkyl optionally substituted with 1-3 independently selected halo.

[1298] 99. The compound of any one of clauses 91-98, wherein each R.sup.d present in Q.sup.1 is:

[1299] i. C.sub.1-4 alkyl substituted with 1-3 —F;

[1300] ii. C.sub.2-3 alkyl substituted with 1-3 —F; or

[1301] iii. —CH.sub.2CF.sub.3.

[1302] 100. The compound of any one of clauses 83-99, wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.

[1303] 101. The compound of any one of clauses 83-100, wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and C.sub.1-6 alkyl which is optionally substituted with 1-6 independently selected halo.

[1304] 102. The compound of any one of clauses 83-101, wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo and C.sub.1-3 alkyl which is optionally substituted with 1-6 independently selected halo.

[1305] 103. The compound of any one of clauses 83-102, wherein each R.sup.c present in Q.sup.1 is:

[1306] i. C.sub.1-3 alkyl which is optionally substituted with 1-6 —F; or

[1307] ii. CF.sub.3.

[1308] 104. The compound of any one of clauses 83-102, wherein each R.sup.c present in Q.sup.1 is an independently selected halo, optionally —F or —Cl.

[1309] 105. The compound of any one of clauses 1-104, wherein Y.sup.1 is CR.sup.1.

[1310] 106. The compound of any one of clauses 1-105, wherein Y.sup.2 is CR.sup.1.

[1311] 107. The compound of any one of clauses 1-106, wherein Y.sup.3 is CR.sup.1.

[1312] 108. The compound of any one of clauses 1-107, wherein each occurrence of R.sup.1 is independently H or R.sup.c.

[1313] 109. The compound of any one of clauses 1-108, wherein each occurrence of R.sup.1 is H.

[1314] 110. The compound of any one of clauses 1-108, wherein 1-2 occurrence of R.sup.1 is R.sup.c; and each remaining occurrence of R.sup.1 is H.

[1315] 111. The compound of any one of clauses 1-108 or 110, wherein one occurrence of R.sup.1 is halo, optionally —F or —C.sub.1; and each remaining occurrence of R.sup.1 is H.

[1316] 112. The compound of any one of clauses 1-111, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected CR.sup.1.

[1317] 113. The compound of any one of clauses 1-107 or 112, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each CH.

[1318] 114. The compound of any one of clauses 1-107 or 112, wherein one of Y.sup.1, Y.sup.2, and Y.sup.3 is CR.sup.e, optionally C-halo; and each of the remaining two Y.sup.1, Y.sup.2, and Y.sup.3 is CH.

[1319] 115. The compound of any one of clauses 1-114, wherein X.sup.1 is NR.sup.2.

[1320] 116. The compound of any one of clauses 1-115, wherein X.sup.1 is NH.

[1321] 117. The compound of any one of clauses 1-116, wherein X.sup.2 is CR.sup.5.

[1322] 118. The compound of any one of clauses 1-117, wherein X.sup.2 is CH.

[1323] 119. The compound of any one of clauses 1-114, wherein X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5.

[1324] 120. The compound of any one of clauses 1-114 or 119, wherein X.sup.1 is NH; and X.sup.2 is CH.

[1325] 121. The compound of any one of clauses 1-104, wherein Y, Y.sup.2, and Y.sup.3 are each an independently selected CR.sup.1; X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5.

[1326] 122. The compound of any one of clauses 1-104 or 121, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each CH; X.sup.1 is NH; and X.sup.2 is CH.

[1327] 123. The compound of any one of clauses 1-122, wherein R.sup.6 is H.

[1328] 124. The compound of any one of clauses 1-123, wherein W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with 1-6 R.sup.a2.

[1329] 125. The compound of any one of clauses 1-124, wherein W is C.sub.1-10 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[1330] 126. The compound of any one of clauses 1-125, wherein W is C.sub.1-6 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[1331] 127. The compound of any one of clauses 1-126, wherein W is C.sub.1-4 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[1332] 128. The compound of any one of clauses 1-127, wherein W is unsubstituted C.sub.1-4 alkyl.

[1333] 129. The compound of any one of clauses 1-128, wherein W is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, and isobutyl

[1334] 130. The compound of any one of clauses 1-129, wherein W is methyl or ethyl.

[1335] 131. The compound of any one of clauses 1-126, wherein W is C.sub.1-4 alkyl, which is substituted with 1-6 R.sup.a2.

[1336] 132. The compound of any one of clauses 1-126 or 131, wherein each R.sup.a2 is independently selected from the group consisting of:

[1337] i. —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano; or

[1338] ii. halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy.

[1339] 133. The compound of any one of clauses 1-126 or 131-132, wherein W:

[1340] i. C.sub.1-4 alkyl which is substituted with 1-3 substituents each independently selected from the group consisting of: halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy; or

[1341] ii. selected from the group consisting of: W is

##STR01058##

[1342] 134. The compound of any one of clauses 1-123, wherein W is selected from the group consisting of: [1343] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1344] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1345] 135. The compound of any one of clauses 1-123 or 134, wherein W is monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1346] 136. The compound of any one of clauses 1-123 or 134-135, wherein W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1347] 137. The compound of any one of clauses 1-123 or 134-136, wherein W is unsubstituted C.sub.3-8 cycloalkyl.

[1348] 138. The compound of any one of clauses 1-123 or 134-137, wherein W is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[1349] 139. The compound of any one of clauses 1-123 or 134-138, wherein W is cyclobutyl.

[1350] 140. The compound of any one of clauses 1-123, wherein W is H.

[1351] 141. The compound of clause 1, wherein the compound is a compound of Formula (I-a):

##STR01059##

[1352] or a pharmaceutically acceptable salt thereof, wherein:

[1353] L.sup.1 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—;

[1354] L.sup.2 is selected from the group consisting of: [1355] straight-chain C.sub.1-3 alkylene, which is optionally substituted with 1-3 R.sup.b; [1356] C.sub.3-8 cycloalkylene, which is optionally substituted with 1-3 R.sup.e; and [1357] heterocyclylene having 4-8 ring atoms wherein 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of: N, N(H), N(R.sup.d), O, and S(O).sub.0-2, wherein the heterocyclylene is optionally substituted with 1-3 R.sup.c;

[1358] Q.sup.1 is —R.sup.g;

[1359] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1360] each occurrence of R.sup.2 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1361] W is selected from the group consisting of: [1362] H; [1363] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [1364] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1365] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[1366] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom.

[1367] 142. The compound of clause 141, wherein L.sup.1 is —O—.

[1368] 143. The compound of clauses 141 or 142, wherein L.sup.2 is straight-chain CI-3 alkylene, which is optionally substituted with 1-3 R.sup.b.

[1369] 144. The compound of any one of clauses 141-143, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2—, optionally wherein L.sup.2 is —CH.sub.2—.

[1370] 145. The compound of any one of clauses 141-143 wherein L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[1371] 146. The compound of any one of clauses 141-143 or 145, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R″)-*, and —CH.sub.2C(R″).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1.

[1372] 147. The compound of clause 146, wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1373] 148. The compound of any one of clauses 141-143, wherein L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1374] 149. The compound of clauses 141 or 142, wherein L.sup.2 is:

##STR01060##

which is optionally substituted with 1-2 R.sup.c, wherein n1 and n2 are independently 0, 1, or 2; Q.sup.2 is CH, CR.sup.c, or N; and the asterisk represents the point of attachment to Q.sup.1;

[1375] 150. The compound of clause 149, wherein n1 and n2 are independently 0 or 1, optionally 0; and Q.sup.2 is CH; optionally wherein n1 and n2 are 0 and Q.sup.2 is CH; optionally wherein L.sup.2 is cyclobutane-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is cyclobutane-1,3-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is cyclobutane-diyl optionally substituted with 1-2 R.sup.c; optionally wherein L.sup.2 is unsubstituted cyclobutane-diyl; optionally wherein L.sup.2 is unsubstituted cyclobutane-1,3-diyl.

[1376] 151. The compound of clause 141, wherein L.sup.1 is —O—; and L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1377] 152. The compound of clause 151, wherein L.sup.2 is:

[1378] i. straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b;

[1379] ii. selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R″)-*, and —CH.sub.2C(R″).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1; or

[1380] iii. —CH.sub.2CH.sub.2—.

[1381] 153. The compound of clause 141, wherein L.sup.1 is —O—; and L.sup.2 is:

[1382] i. selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2; or

[1383] ii. —CH.sub.2—.

[1384] 154. The compound of clause 1, wherein the compound is a compound of Formula (I-b):

##STR01061##

[1385] or a pharmaceutically acceptable salt thereof, wherein:

[1386] L.sup.2 is straight-chain C.sub.1-6 alkylene or straight-chain C.sub.2-6 alkenylene, each of which is optionally substituted with 1-6 R.sup.b;

[1387] Q.sup.1 is —R.sup.g;

[1388] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.e; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1389] each occurrence of R.sup.2 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g; and

[1390] W is selected from the group consisting of: [1391] H; [1392] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [1393] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1394] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[1395] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom.

[1396] 155. The compound of clause 154, wherein L.sup.2 is straight-chain C.sub.2-3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1397] 156. The compound of clauses 154 or 155, wherein L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[1398] 157. The compound of any one of clauses 154-156, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -Q.sup.1, optionally wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1399] 158. The compound of clauses 154-155, wherein L.sup.2 is straight-chain C.sub.3 alkylene which is optionally substituted with 1-3 R.sup.b.

[1400] 159. The compound of any one of clauses 154-155 or 158, wherein L.sup.2 is selected from the group consisting of:

##STR01062##

wherein the asterisk represents point of attachment to -Q.sup.1, optionally wherein L.sup.2 is

##STR01063##

[1401] 160. The compound of clause 154, wherein L.sup.2 is straight-chain C.sub.2-4 alkenylene, which is optionally substituted with 1-3 R.sup.b.

[1402] 161. The compound of clauses 154 or 160, wherein L.sup.2 is selected from the group consisting of:

##STR01064##

wherein the asterisk represents the point of attachment to -Q.sup.1.

[1403] 162. The compound of clause 1, wherein the compound is a compound of Formula (I-c):

##STR01065##

[1404] or a pharmaceutically acceptable salt thereof, wherein:

[1405] L.sup.2 and L.sup.4 are independently selected straight-chain C.sub.1-3 alkylene which is optionally substituted with 1-6 R.sup.b;

[1406] L.sup.3 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—;

[1407] Q.sup.1 is —R.sup.g;

[1408] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1409] each occurrence of R.sup.2 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g; and

[1410] W is selected from the group consisting of: [1411] H; [1412] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [1413] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1414] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[1415] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom.

[1416] 163. The compound of clause 162, wherein L.sup.2 and L.sup.4 are independently selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2.

[1417] 164. The compound of clauses 162 or 163, wherein L.sup.2 and L.sup.4 are each —CH.sub.2—.

[1418] 165. The compound of any one of clauses 162-164, wherein L.sup.3 is —O—.

[1419] 166. The compound of any one of clauses 162-164, wherein L.sup.3 is —N(H)— or —N(R.sup.d)—, optionally —N(H)—.

[1420] 167. The compound of clause 1, wherein the compound is a compound of Formula (I-d):

##STR01066##

[1421] or a pharmaceutically acceptable salt thereof, wherein:

[1422] L.sup.2 is straight-chain C.sub.1-3 alkylene which is optionally substituted with 1-6 R.sup.b; and

[1423] L.sup.3 is selected from the group consisting of: —O—, —N(H)—, and —N(R.sup.d)—;

[1424] Q.sup.1 is —R.sup.g;

[1425] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.e; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g;

[1426] each occurrence of R.sup.2 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.g).sub.bg-R.sup.g; and

[1427] W is selected from the group consisting of: [1428] H; [1429] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2, wherein one or more of the internal optionally substituted methylene group can be replaced by one or more heteroatom selected from O or S, wherein when W is alkenyl or alkynyl, the heteroatom is not directed connected to the sp.sup.2 or sp carbon; [1430] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1431] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c,

[1432] provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom.

[1433] 168. The compound of clause 167, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2—, —CHR.sup.b—, and —C(R.sup.b).sub.2.

[1434] 169. The compound of clause 167, wherein L.sup.2 is straight-chain C.sub.2 alkylene which is optionally substituted with 1-3 R.sup.b.

[1435] 170. The compound of clauses 167 or 169, wherein L.sup.2 is selected from the group consisting of: —CH.sub.2CH.sub.2—, —CH.sub.2CH(R.sup.b)-*, and —CH.sub.2C(R.sup.b).sub.2-*, wherein the asterisk represents point of attachment to -L.sup.3, optionally wherein L.sup.2 is —CH.sub.2CH.sub.2—.

[1436] 171. The compound of any one of clauses 167-170, wherein L.sup.3 is —O—.

[1437] 172. The compound of any one of clauses 167-170, wherein L.sup.3 is —N(H)— or —N(R.sup.d)—, optionally —N(H)—.

[1438] 173. The compound of any one of clauses 141-172, wherein Q.sup.1 is selected from the group consisting of: [1439] heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [1440] phenyl optionally substituted with 1-3 R.sup.c.

[1441] 174. The compound of any one of clauses 141-173, wherein Q.sup.1 is selected from the group consisting of: [1442] heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with 1-3 R.sup.c; and [1443] phenyl optionally substituted with 1-3 R.sup.c.

[1444] 175. The compound of any one of clauses 141-174, wherein Q.sup.1 is:

[1445] i. phenyl or pyridyl, each optionally substituted with 1-3 R.sup.c;

[1446] ii.

##STR01067##

[1447] iii. any groups of i or ii, wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: halo and CI-3 alkyl which is optionally substituted with 1-6 independently selected halo; or

[1448] iv. any groups of i or ii, wherein each R.sup.c present in Q.sup.1 is independently selected from the group consisting of: —F, —Cl, and —CF.sub.3.

[1449] 176. The compound of any one of clauses 141-172, wherein Q.sup.1 is heterocyclyl of 4-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1450] 177. The compound of any one of clauses 141-172 or 176, wherein Q.sup.1 is:

[1451] i.

##STR01068##

wherein m1 and m2 are each independently 0, 1, or 2;

[1452] ii.

##STR01069##

[1453] iii any groups of i or ii, wherein the R.sup.d present in Q.sup.1 is selected from the group consisting of: —C(O)O(C.sub.1-4 alkyl); and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; or

[1454] iv. any groups of i or ii, wherein the R.sup.d present in Q.sup.1 is C.sub.2-3 alkyl substituted with 1-3 —F.

[1455] 178. The compound of any one of clauses 141-177, wherein each R.sup.1 is H.

[1456] 179. The compound of any one of clauses 141-177, wherein one occurrence of R.sup.1 is R.sup.c; and each remaining R.sup.1 is H.

[1457] 180. The compound of any one of clauses 141-179, wherein R.sup.2 is H; and R.sup.5 is H.

[1458] 181. The compound of any one of clauses 141-180, wherein W is C.sub.1-6 alkyl, which is optionally substituted with 1-6 R.sup.a2.

[1459] 182. The compound of any one of clauses 141-181, wherein W is unsubstituted C.sub.1-4 alkyl.

[1460] 183. The compound of any one of clauses 141-182, wherein W is methyl or ethyl.

[1461] 184. The compound of any one of clauses 141-181, wherein W is C.sub.1-4 alkyl, which is substituted with 1-6 R.sup.a2.

[1462] 185. The compound of any one of clauses 141-181 or 184, wherein W:

[1463] i. C.sub.1-4 alkyl which is substituted with 1-3 substituents each independently selected from the group consisting of: halo; —OH; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy; or

[1464] ii. selected from the group consisting of: W is

##STR01070##

[1465] 186. The compound of any one of clauses 141-181, wherein W is selected from the group consisting of: [1466] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [1467] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1468] 187. The compound of any one of clauses 141-181 or 186, wherein W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.

[1469] 188. The compound of any one of clauses 141-181 or 186-187, wherein W is:

[1470] i. unsubstituted C.sub.3-8 cycloalkyl; or

[1471] ii. cyclobutyl.

[1472] 189. The compound of clause 1, wherein the compound is selected from the group consisting of compounds delineated in Table C.sub.1, and a pharmaceutically acceptable salt thereof, optionally wherein the compound is compound 101-147; or 148-408; or 409-596.

[1473] 190. A pharmaceutical composition comprising a compound of clauses 1-189 and one or more pharmaceutically acceptable excipients.

[1474] 191. A method for inhibiting STING activity, the method comprising contacting STING with a compound or a pharmaceutically acceptable salt thereof as defined in any one of clauses 1-189; or a pharmaceutical composition as defined in clause 190.

[1475] 192. The method of clause 191, wherein the inhibiting comprises antagonizing STING.

[1476] 193. The method of any one of clauses 191-192, which is carried out in vitro.

[1477] 194. The method of clauses 193, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

[1478] 195. The method of clauses 193 or 194, wherein the one or more cells are one or more cancer cells.

[1479] 196. The method of clauses 194 or 195, wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[1480] 197. The method of clauses 191 or 192, which is carried out in vivo.

[1481] 198. The method of clause 197, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.

[1482] 199. The method of clause 198, wherein the subject is a human.

[1483] 200. The method of clause 199, wherein the disease is cancer.

[1484] 201. The method of clause 200, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[1485] 202. The method of clauses 200 or 201, wherein the cancer is a refractory cancer.

[1486] 203. The method of clause 198, wherein the compound is administered in combination with one or more additional cancer therapies.

[1487] 204. The method of clause 203, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[1488] 205. The method of clause 204, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[1489] 206. The method of clause 205, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[1490] 207. The method of any one of clauses 198-206, wherein the compound is administered intratumorally.

[1491] 208. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190.

[1492] 209. The method of clause 208, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[1493] 210. The method of clause 208 or 209, wherein the cancer is a refractory cancer.

[1494] 211. The method of clause 208, wherein the compound is administered in combination with one or more additional cancer therapies.

[1495] 212. The method of clause 211, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[1496] 213. The method of clause 212, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[1497] 214. The method of clause 212, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[1498] 215. The method of any one of clauses 208-214, wherein the compound is administered intratumorally.

[1499] 216. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190.

[1500] 217. The method of clause 216, wherein the subject has cancer.

[1501] 218. The method of clause 217, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

[1502] 219. The method of clause 217, wherein the cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[1503] 220. The method of clause any one of clauses 217-219, wherein the cancer is a refractory cancer.

[1504] 221. The method of clause 219, wherein the immune response is an innate immune response.

[1505] 222. The method of clause 221, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[1506] 223. The method of clause 222, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[1507] 224. The method of clause 223, wherein the one or more additional chemotherapeutic agents is selected from alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[1508] 225. A method of treatment of a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190.

[1509] 226. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease an effective amount of a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190.

[1510] 227. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

[1511] 228. The method of any one of clauses 225-227, wherein the disease is cancer.

[1512] 229. The method of clause 228, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[1513] 230. The method of clause 228 or 229, wherein the cancer is a refractory cancer.

[1514] 231. The method of any one of clauses 228-230, wherein the compound is administered in combination with one or more additional cancer therapies.

[1515] 232. The method of clause 231, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[1516] 233. The method of clause 232, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[1517] 234. The method of clause 233, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[1518] 235. The method of any one of clauses 225-234, wherein the compound is administered intratumorally.

[1519] 236. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-189, or a pharmaceutical composition as defined in clause 190.

[1520] 237. The method of clause 236, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.

[1521] 238. The method of clause 237, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)).

[1522] 239. The method of clause 238, wherein the type I interferonopathy is STING-associated vasculopathy with onset in infancy (SAVI)).

[1523] 240. The method of clause 237, wherein the disease, disorder, or condition is Aicardi-Goutières Syndrome (AGS).

[1524] 241. The method of clause 237, wherein the disease, disorder, or condition is a genetic form of lupus.

[1525] 242. The method of clause 237, wherein the disease, disorder, or condition is inflammation-associated disorder.

[1526] 243. The method of clause 242, wherein the inflammation-associated disorder is systemic lupus erythematosus.

[1527] 244. The method of any one of clauses 191-243, wherein the method further comprises identifying the subject.

[1528] 245. A combination comprising a compounds defined in any one of clauses 1 to 189 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

[1529] 246. A compound defined in any one of clauses 1-189 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 190, for use as a medicament.

[1530] 247. A compound defined in any one of clauses 1-189 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 190, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

[1531] 248. A compound defined in any one of clauses 1-189 or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 190, for use in the treatment of a disease mentioned in any one of clauses 191-244.

[1532] 249. Use of a compound defined in any one of clauses 1-189 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 190, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 191-244.

COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY

Inventors

Cpc classification

Classification Explorer

C07D401/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/12

CHEMISTRY; METALLURGY

Classification Explorer

A61K45/06

HUMAN NECESSITIES

Classification Explorer

C07D403/06

CHEMISTRY; METALLURGY

Classification Explorer

C07D403/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D209/40

CHEMISTRY; METALLURGY

Classification Explorer

C07D471/04

CHEMISTRY; METALLURGY

Classification Explorer

C07D401/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D417/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/14

CHEMISTRY; METALLURGY

Classification Explorer

C07B2200/05

CHEMISTRY; METALLURGY

Classification Explorer

C07D451/02

CHEMISTRY; METALLURGY

Classification Explorer

C07D487/08

CHEMISTRY; METALLURGY

Classification Explorer

A61P35/00

HUMAN NECESSITIES

Classification Explorer

C07D407/12

CHEMISTRY; METALLURGY

International classification

Classification Explorer

C07D209/40

CHEMISTRY; METALLURGY

Classification Explorer

A61K45/06

HUMAN NECESSITIES

Classification Explorer

C07D401/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D401/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D403/06

CHEMISTRY; METALLURGY

Classification Explorer

C07D403/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D405/14

CHEMISTRY; METALLURGY

Classification Explorer

C07D417/12

CHEMISTRY; METALLURGY

Classification Explorer

C07D471/04

CHEMISTRY; METALLURGY

Classification Explorer