COMPOUNDS AND COMPOSITIONS AS MODULATORS OF TLR SIGNALING

Abstract

The present disclosure relates to compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.

Claims

1. A compound of Formula (A): ##STR00597## or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R.sup.1 and R.sup.2 is OH and the other is selected from the group consisting of CN, halogen, C(O)R.sup.a, CHNR.sup.j, S(O)R.sup.b, S(O).sub.2R.sup.c, NHC(O)R.sup.d, NHS(O).sub.2R.sup.e, C.sub.1-C.sub.6alkyl-R.sup.f, C.sub.2-C.sub.6alkenyl-R.sup.g, unsubstituted or substituted C.sub.3-C.sub.8 cycloalkyl, unsubstituted or substituted C.sub.3-C.sub.8 cycloalkenyl, and unsubstituted or substituted heterocycloalkyl; R.sup.a, R.sup.b, R.sup.c, and R.sup.e are each independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl, or styryl; R.sup.d is H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl; R.sup.f and R.sup.g are each independently OH, unsubstituted heteroaryl, NR.sup.mR.sup.n, benzoyl, or styryl; R.sup.m and R.sup.n are each independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, or unsubstituted or substituted cycloalkyl; R.sup.j is unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl, OR.sup.k, NHR.sup.k, NHC(O)R.sup.k, NHS(O).sub.2R.sup.k, or NHC(NH)NHR.sup.aa; R.sup.aa is unsubstituted or substituted C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.3-C.sub.8cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted heteroaryl; R.sup.k is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, or aryl, wherein the C.sub.1-C.sub.6alkyl of R.sup.k is unsubstituted or substituted with heterocyclyl or heteroaryl; R.sup.3 is H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, or halogen, wherein the C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy of R.sup.3 are each independently unsubstituted or substituted with one or more halogen; wherein when R.sup.2 is Br, R.sup.3 is H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, Cl, F, or I; G.sub.1 and G.sub.2 are each independently CH or N, wherein when G.sub.1 is N, G.sub.2 is CH, and when G.sub.2 is N, G.sub.1 is CH; ##STR00598## indicates that the ring is aromatic; Y.sup.1 is C or N; Y.sup.2 is CH, N, NH, S, or O; Y.sup.3 is C or N; Y.sup.4 is CH, N, NH, S, or O; Y.sup.5 is CR.sup.7, N, NH, S, or O; wherein no more than one of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 is S or O and no more than four of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are N or NH; R.sup.7 is H or C.sub.1-C.sub.6alkyl; n is 0, 1, 2, or 3; R.sup.4 is alkoxy or ##STR00599## ##STR00600## indicates that the ring is saturated, partially unsaturated, or fully unsaturated; G.sub.3 is CH(X.sub.1R.sup.6a), C(X.sub.1R.sup.6a), N, N(X.sub.1R.sup.6a), S, or O; G.sub.4 is CH(X.sub.2R.sup.6b), C(X.sub.2R.sup.6b), N, N(X.sub.2R.sup.6b), S, or O; G.sub.5 is CH(X.sub.3R.sup.6c), C(X.sub.3R.sup.6c), N, N(X.sub.3R.sup.6c), S, or O; G.sub.6 is CH(X.sub.4R.sup.6d), C(X.sub.4R.sup.6d), N, N(X.sub.4R.sup.6d), S, or O; and G.sub.7 is N, C, or CH; X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are each independently absent, ##STR00601## m is 1-6; R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d are each independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, halo, OH, NR.sup.pR.sup.q, aryl, heterocyclyl, heteroaryl, C.sub.1-C.sub.6alkyl-heterocyclyl, OC(O)-heterocyclyl, C(O)R.sup.h, S(O).sub.2NR.sup.w1R.sup.w2, S(O).sub.2R.sup.y, or NR.sup.z1S(O).sub.2R.sup.z2, wherein the C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy of R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; the aryl and heteroaryl of R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.8cycloalkyl, OH, and C.sub.1-C.sub.6alkyl-OH; and the heterocyclyl, C.sub.1-C.sub.6alkyl-heterocyclyl, and OC(O)-heterocyclyl of R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, halo, OH, C.sub.1-C.sub.6alkyl-OH, O, and S; each R.sup.h is independently selected from the group consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and C.sub.3-C.sub.8cycloalkyl, and NR.sup.rR.sup.s; each R.sup.p is independently H or C.sub.1-C.sub.6alkyl; each R.sup.q is independently C.sub.2-C.sub.3alkyl, C(O)R.sup.t, C(O)OR.sup.u, C(O)NR.sup.v; each R.sup.r, R.sup.s, R.sup.w1, and R.sup.z1 is independently selected from H and C.sub.1-C.sub.6alkyl; and each R.sup.t, R.sup.u, R.sup.v, R.sup.w2, R.sup.y, and R.sup.z2 is independently selected from H, C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.3-C.sub.8cycloalkyl, and unsubstituted or substituted heterocyclyl; or G.sub.5 is CH(X.sub.3R.sup.6c) or C(X.sub.3R.sup.6c), G.sub.6 is CH(X.sub.4R.sup.6d) or C(X.sub.4R.sup.6d), and R.sup.6c and R.sup.6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, a 6-membered heterocyclyl, or a 6-membered heteroaryl ring; wherein the 6-membered aryl, 6-membered heterocyclyl, and 6-membered heteroaryl rings are each independently unsubstituted or substituted.

2-6. (canceled)

7. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is OH and R.sup.2 is selected from the group consisting of F, Cl, Br, CN, C(O)H, ##STR00602##

8-11. (canceled)

12. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is OH and R.sup.1 is selected from the group consisting of F, Cl, Br, CN, C(O)H, ##STR00603##

13. (canceled)

14. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3 is selected from the group consisting of CH.sub.3, OCH.sub.3, Cl and F.

15. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ##STR00604## is selected from the group consisting of ##STR00605## ##STR00606##

16-19. (canceled)

20. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

21-24. (canceled)

25. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.4 is ##STR00607##

26. The compound of claim 25, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G.sub.3 is C(X.sub.1R.sup.6a); X.sub.1 is absent, ##STR00608## m is 1-6; R.sup.6a is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; G.sub.4 is C(X.sub.2R.sup.6b) or N; X.sub.2 is absent, ##STR00609## m is 1-6 and R.sup.6c is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; G.sub.5 is C(X.sub.3R.sup.6); X.sub.3 is absent ##STR00610## m is 1-6; and R.sup.6c is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocycyl, or 5- to 10-membered heteroaryl; G.sub.6 is C(X.sub.4R.sup.6d); X.sub.4 is absent, ##STR00611## m is 1-6; and R.sup.6d is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocycyl, or 5- to 10-membered heteroaryl; and G.sub.7 is C.

27-37. (canceled)

38. The compound of claim 25, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more of R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, halo, OH, NR.sup.pR.sup.q, aryl, heterocyclyl, heteroaryl, C.sub.1-C.sub.6alkyl-heterocyclyl, OC(O)-heterocyclyl, C(O)R.sup.h, S(O).sub.2NR.sup.w1R.sup.w2, S(O).sub.2R.sup.y, or NR.sup.z1S(O).sub.2R.sup.z2.

39-41. (canceled)

42. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G.sub.1 is CH and G.sub.2 is CH.

43. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G.sub.1 is N and G.sub.2 is CH.

44-45. (canceled)

46. A compound of Table 1A, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

47. A compound of Formula (B): ##STR00612## or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is selected from the group consisting of CC, *NHC(O), *C(O)NH, NHC(O)NH, *NHS(O).sub.2, *NHS(O)(NH), *S(O).sub.2NH, *S(O)NHNH, *NHNHS(O), *C(O)NHNH, *NHNHC(O), *NHC(O)O, and *OC(O)NH, wherein * represents the point of attachment to Y.sub.7; Y.sub.1 and Y.sub.2 are each independently CR.sup.x or N; R.sup.x is hydrogen or halogen; when L is CC, one of R.sup.1A and R.sup.2A is OH and the other is selected from the group consisting of C(O)R.sup.a1, CHNR.sup.j1, S(O)R.sup.b1, S(O).sub.2R.sup.c1, NHC(O)R.sup.d1, NHS(O).sub.2R.sup.e1, C.sub.1-C.sub.6alkyl-R.sup.n, C.sub.2-C.sub.6alkenyl-R.sup.g1, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, and 5- or 6-membered heterocycloalkyl, wherein the C.sub.3-C.sub.8 cycloalkyl and C.sub.3-C.sub.8 cycloalkenyl are each independently unsubstituted or substituted with one or more O, and the 5- or 6-membered heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, O, and C(O)OC.sub.1-C.sub.6alkyl; when L is *NHC(O), *C(O)NH, NHC(O)NH, *NHS(O).sub.2, *S(O).sub.2NH, *S(O)NHNH, *C(O)NHNH, or *NHC(O)O, one of R.sup.1A and R.sup.2A is OH and the other is selected from the group consisting of C(O)H, CHNR.sup.j1, and ##STR00613## R.sup.a1 is H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, or benzoyl, wherein the 3- to 10-membered heterocyclyl of R.sup.a1 is unsubstituted or substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8 cycloalkyl, O, and C(O)OC.sub.1-C.sub.6alkyl, and the 5- to 10-membered heteroaryl of R.sup.a1 is unsubstituted or substituted with one or more groups independently selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and C(O)OC.sub.1-C.sub.6alkyl; R.sup.b1, R.sup.c1, R.sup.d1, and R.sup.e1 are each independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, benzoyl, or styryl, wherein the 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl of R.sup.b1, R.sup.c1, R.sup.d1, and R.sup.e1 are each independently selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and C(O)OC.sub.1-C.sub.6alkyl; R.sup.f1 and R.sup.g1 are each independently OH, unsubstituted 5- to 6-membered heteroaryl, NR.sup.m1R.sup.n1, benzoyl, or styryl; R.sup.m1 is C.sub.3-C.sub.8 cycloalkyl, unsubstituted or substituted with one or more groups selected from C.sub.1-C.sub.6alkyl and halo; R.sup.n1 is H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or C.sub.2-C.sub.6alkynyl; R.sup.j1 is C.sub.1-C.sub.6alkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 6- to 12-membered aryl, OR.sup.k1, NHR.sup.k1, N(C.sub.1-C.sub.6alkyl)R.sup.k1, NHC(O)R.sup.k1, NHS(O).sub.2R.sup.k1, or NHC(NH)NHR.sup.bb, wherein the 5- to 6-membered heterocyclyl of R.sup.j1 is unsubstituted or substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, O, C(O)NHC.sub.1-C.sub.6alkyl, and C(O)OC.sub.1-C.sub.6alkyl, and the 5- to 6-membered heteroaryl and 6- to 12-membered aryl of R.sup.j1 are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and C(O)OC.sub.1-C.sub.6alkyl; R.sup.bb is unsubstituted or substituted C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.3-C.sub.8cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted heteroaryl; each R.sup.k1 is independently C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, or 6- to 12-membered aryl, wherein the C.sub.1-C.sub.6alkyl of R.sup.k1 is unsubstituted or substituted with a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R.sup.3A is H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, or halogen, wherein the C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy of R.sup.3A are each independently unsubstituted or substituted with one or more halogen; ##STR00614## indicates that the ring is saturated, partially unsaturated, or fully unsaturated; Y.sub.3 is CH(X.sub.1AR.sup.6a1), C(X.sub.1AR.sup.6a1), N, N(X.sub.1AR.sup.6a1), S, or O; Y.sub.4 is CH(X.sub.2AR.sup.6b1), C(X.sub.2AR.sup.6b1), N, N(X.sub.2AR.sup.6b1), S, or O; Y.sub.5 is CH(X.sub.3AR.sup.6c1), C(X.sub.3AR.sup.6c1), N, N(X.sub.3AR.sup.6c1), S, or O; Y.sub.6 is CH(X.sub.4AR.sup.6d1), C(X.sub.4AR.sup.6d1), N, N(X.sub.4AR.sup.6d1), S, or O; Y.sub.7 is N, C, or CH; and Y.sub.8 is N, NH, C, or CH; X.sub.1A, X.sub.2A, X.sub.3A, and X.sub.4A are each independently absent, ##STR00615## m1 is 1-6; R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 are each independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, halo, OH, NR.sup.p1R.sup.q1, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, C.sub.1-C.sub.6alkyl-5- to 6-membered heterocyclyl, OC(O)5- to 6-membered heterocyclyl, C(O)R.sup.h1, S(O).sub.2NR.sup.w1aR.sup.w2a, S(O).sub.2R.sup.y1, NR.sup.z1aS(O).sub.2R.sup.z2a, or N(CH.sub.3)CH.sub.2C(CH.sub.3).sub.3, wherein the C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy of R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.3-C.sub.8 cycloalkyl and halogen; the C.sub.6-C.sub.12 aryl and 5- to 10-membered heteroaryl of R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, OH, and C.sub.1-C.sub.6alkyl-OH; and the 3- to 10-membered heterocyclyl, C.sub.1-C.sub.6alkyl-5- to 6-membered heterocyclyl, and OC(O)5- to 6-membered heterocyclyl of R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, OH, C.sub.1-C.sub.6alkyl-OH, O, S, , halo, C.sub.3-C.sub.8cycloalkyl, C(O)NHC.sub.3-C.sub.8cycloalkyl, C.sub.6-C.sub.12 aryl, and 5- to 6-membered heterocyclyl; each R.sup.h1 is independently selected from the group consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.8cycloalkyl, and NR.sup.r1R.sup.s1; each R.sup.p1 is independently H or C.sub.1-C.sub.6alkyl; each R.sup.q1 is independently C.sub.2-C.sub.3alkyl, C(O)R.sup.t1, C(O)OR.sup.u1, or C(O)NR.sup.v1; each R.sup.r1, R.sup.s1, R.sup.w1a, and R.sup.z1a is independently selected from H and C.sub.1-C.sub.6alkyl; and each R.sup.t1, R.sup.u1, R.sup.v1, R.sup.w2a, R.sup.y1, and R.sup.z2a is independently selected from H, C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.3-C.sub.8cycloalkyl, and unsubstituted or substituted heterocyclyl; or Y.sub.5 is CH(X.sub.3AR.sup.6c1) or C(X.sub.3AR.sup.6c1), Y.sub.6 is CH(X.sub.4AR.sup.6d1) or C(X.sub.4AR.sup.6d1), and R.sup.6c1 and R.sup.6d1 are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, a 6-membered heterocyclyl, or a 6-membered heteroaryl ring; wherein the 6-membered aryl, 6-membered heterocyclyl, and 6-membered heteroaryl rings are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C.sub.1-C.sub.6alkyl and C(O)OC.sub.1-C.sub.6alkyl; wherein no more than one of R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 is C.sub.1-C.sub.6alkoxy or OH; and (1) when L is CC, Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is C(O)H, CH.sub.2OH, C(O)CH.sub.3 or NHC(O)CH.sub.3, and R.sup.3A is H, ##STR00616## is other than cyclohexyl, phenyl, pyridyl, or naphthyl, and R.sup.6c1 is hydrogen, C.sub.2-C.sub.3alkyl, C.sub.2-C.sub.5alkoxy, Br, Cl, I, NR.sup.p1R.sup.q1, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, C.sub.1-C.sub.6alkyl-5- to 6-membered heterocyclyl, OC(O)5- to 6-membered heterocyclyl, C(O)R.sup.h1, S(O).sub.2NR.sup.w1aR.sup.w2a, S(O).sub.2R.sup.y1, or NR.sup.z1aS(O).sub.2R.sup.z2a and each R.sup.h1 is independently selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.8cycloalkyl, and NR.sup.r1R.sup.s1; (2) when L is CC, Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is C(O)H, and R.sup.3A is CH.sub.3, t-Bu, or C.sub.2-C.sub.3alkoxy, ##STR00617## is other than phenyl and pyridyl, R.sup.b1 and R.sup.d1 are other than ##STR00618## and R.sup.6c1 is other than OH; (3) when L is CC, Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is piperidinyl, pyrrolidinyl, pyrrolidinone, piperazinyl, morpholinyl, or thiadiazolidinone 1,1-dioxide, and R.sup.3A is H, ##STR00619## is other than naphthyl, and R.sup.6c1 is other than fluoro; (4) when L is *NHS(O).sub.2 or *S(O).sub.2NH, Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is C(O)H, CHNR.sup.j1, or ##STR00620## and R.sup.3A is H or Br, ##STR00621## is other than phenyl, and R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 are each independently hydrogen, C.sub.2-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, OH, NR.sup.p1R.sup.q1, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, C.sub.1-C.sub.6alkyl-5- to 6-membered heterocyclyl, OC(O)5- to 6-membered heterocyclyl, C(O)R.sup.h1, S(O).sub.2NR.sup.w1aR.sup.w2a, S(O).sub.2R.sup.y1, or NR.sup.z1aS(O).sub.2R.sup.z2a; (5) when L is *C(O)NH or *NHC(O), Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is C(O)H, and R.sup.3A is H or Cl, ##STR00622## is other than phenyl, and R.sup.6a1 is other than CF.sub.3; and (6) when L is NHC(O)NH, Y.sub.1 and Y.sub.2 are each CH, one of R.sup.1A and R.sup.2A is C(O)H or ##STR00623## and R.sup.3A is H or Cl, ##STR00624## is other than cyclohexyl, and R.sup.6c1 is other than chloro.

48. (canceled)

49. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sub.1 and Y.sub.2 are each CH.

50-57. (canceled)

58. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1A is OH and R.sup.2A is selected from the group consisting of C(O)H, ##STR00625## ##STR00626##

59-63. (canceled)

64. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2A is OH and R.sup.1A is selected from the group consisting of C(O)H, ##STR00627## ##STR00628##

65. (canceled)

66. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is CC, *NHC(O), or *C(O)NH.

67-71. (canceled)

72. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3A is OCH.sub.3 or F.

73-74. (canceled)

75. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sub.3 is C(X.sub.1AR.sup.6a1); X.sub.1A is absent, ##STR00629## m1 is 1-6; R.sup.6a1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; Y.sub.4 is C(X.sub.2AR.sup.6b1); X.sub.2A is absent, ##STR00630## m1 is 1-6; and R.sup.6b1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocycyl, or 5- to 10-membered heteroaryl; Y.sub.5 is C(X.sub.3AR.sup.6c1); X.sub.3A is absent, ##STR00631## m1 is 1-6; and R.sup.6c1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; Y.sub.6 is C(X.sub.4AR.sup.6d1); X.sub.4A is absent, ##STR00632## m1 is 1-6; and R.sup.6d1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, halo, C.sub.6-C.sub.12 aryl, 3- to 10-membered heterocycyl, or 5- to 10-membered heteroaryl; Y.sub.7 is C; and Y.sub.8 is CH.

76-88. (canceled)

89. The compound of claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R.sup.6a1, R.sup.6b1, R.sup.6c1, and R.sup.6d1 is selected from the group consisting of methyl, ethyl, F, Cl, CF.sub.3, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, and triazolyl.

90. (canceled)

91. A compound of Table 1B, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

92. A pharmaceutical composition comprising at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally further comprising a pharmaceutically acceptable excipient.

93. A method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

94. The method of claim 93, wherein the disease or condition is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, Progressive Supranuclear Palsy (PSP), Niemann-Pick disease type C, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, irritable bowel disease, tuberculosis, rheumatoid arthritis, osteoarthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy), stroke, ischemic heart disease, atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatisis, corneal wounds, corneal disorders, corneal HSV, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions.

95-98. (canceled)

99. A method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, or inhibiting TLR2 activation in a cell, comprising contacting the cell with an effective amount of at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the contacting is in vitro, ex vivo, or in vivo.

100. (canceled)

101. A method of treating a disease or condition associated with inhibition of TLR9, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

102. (canceled)

103. The method of claim 101, wherein the disease or condition is Parkinson's disease, Amyotrophic lateral sclerosis, Guillain-Barre syndrome, spinal cord injury, multiple sclerosis, multiple forms of tissue injury, chronic pain, or psoriasis.

104-109. (canceled)

110. A method of inhibiting TLR9 in a cell, comprising contacting the cell with an effective amount of at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the contacting is in vitro, ex vivo, or in vivo.

111. A pharmaceutical composition comprising at least one compound according to claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally further comprising a pharmaceutically acceptable excipient.

112. A method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

113. The method of claim 112, wherein the disease or condition is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, Progressive Supranuclear Palsy (PSP), Niemann-Pick disease type C, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, irritable bowel disease, tuberculosis, rheumatoid arthritis, osteoarthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy), stroke, ischemic heart disease, atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatisis, corneal wounds, corneal disorders, corneal HSV, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions.

114. A method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, or inhibiting TLR2 activation in a cell, comprising contacting the cell with an effective amount of at least one compound according to claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the contacting is in vitro, ex vivo, or in vivo.

115. A method of treating a disease or condition associated with inhibition of TLR9, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

116. The method of claim 115, wherein the disease or condition is Parkinson's disease, Amyotrophic lateral sclerosis, Guillain-Barre syndrome, spinal cord injury, multiple sclerosis, multiple forms of tissue injury, chronic pain, or psoriasis.

117. A method of inhibiting TLR9 in a cell, comprising contacting the cell with an effective amount of at least one compound according to claim 47, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the contacting is in vitro, ex vivo, or in vivo.

Description

EXAMPLES

[0380] The following examples are offered to illustrate but not to limit the present disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (A) and Formula (B). The compounds are prepared using the general methods described above.

[0381] The following abbreviations are used throughout the Examples: BuLi (butyl lithium), DCM (dichloromethane), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), EA or EtOAc (Ethyl acetate), MeOH (methanol), PdCl.sub.2(dppf) ((1,1-bis(diphenylphosphino)ferrocene))palladium(II) dichloride), dppf (1,1-bis(diphenylphosphino)ferrocene), Pd(PPh.sub.3).sub.2Cl.sub.2 (bis(triphenylphosphine)palladium(II) dichloride), Pd(PPh.sub.3).sub.4 (tetrakis(triphenylphosphine)palladium(0)), PMB (4-methoxybenzyl), PPh.sub.3 (triphenylphosphane), Ruphos (2-Dicyclohexylphosphino-2,6-diisopropoxybiphenyl), RuPhos Pd G3 ((2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate ), TBAF (tetrabutylammonium fluoride), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMS-diazomethane (tetramethylsilyldiazomethane), TLC (thin layer chromatography), XantPhos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), XantPhos Pd G3 ([(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate), Xphos (2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl), and XPhos Pd G3 ((2-Dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate).

Example A1: 2-hydroxy-3-methoxy-5-(1-phenyl-1H-pyrazol-4-yl)benzaldehyde (Compound No. A1)

[0382] ##STR00455##

[0383] In a 30 mL sealed cap glass vial, 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) and Na.sub.2CO.sub.3 (666 mg, 6.0 mmol) were suspended in DMF-water (10 mL). Then bubbled Argon gas for one minute and added Pd(PPh.sub.3).sub.4 (63 mg, 0.05 mmol) to the reaction vial and closed with sealed cap and continued at 105 C. for 16 hours on a stirrer plate with metallic beads contained dish. Then cooled to room temperature and diluted with water (10 mL) and transferred into a separating funnel using dichloromethane. Acidified the aqueous layer with 1.0 N HCl to pH-3.0-4.0 and extracted with additional dichloromethane (250 mL). The combined organic layer washed with brine, dried over sodium sulfate and evaporated. The resulted crude product purified using silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a light yellow solid (63 mg, 21% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.01 (s, 1H), 9.99 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.78-7.70 (m, 2H), 7.49 (t, J=7.9 Hz, 2H), 7.39-7.30 (m, 2H), 7.27 (m, 1H) 4.01 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.14N.sub.2O.sub.3, 295; found, 295.

Example A2: 2-hydroxy-3-methoxy-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A2)

[0384] ##STR00456##

[0385] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (369 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow gummy solid (108 mg, 33% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.95 (s, 1H), 9.95 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 4.27 (m, 2H), 3.97 (s, 3H), 3.69 (m, 6H), 2.81 (m, 2H), 2.48-2.41 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.21N.sub.3O.sub.4, 332; found, 332.

Example A3: 5-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-2-hydroxy-3-methoxybenzaldehyde (Compound No. A3)

[0386] ##STR00457##

[0387] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(3-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (267 mg, 1.2 mmol) as described in Example A1 to give the title compound cis/trans mixture as a yellow solid (53 mg, 16% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.01 (s, 1H), 9.99 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.79 (t, J=2.1 Hz, 1H), 7.64 (dd, J=8.3, 2.1 Hz, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.35 (d, J=1.9 Hz, 1H), 7.33-7.28 (m, 1H), 7.25 (d, J=1.9 Hz, 1H), 4.01 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.13ClN.sub.2O.sub.3, 330; found, 330.

Example A4: 5-(1-benzyl-1H-pyrazol-4-yl)-2-hydroxy-3-methoxybenzaldehyde (Compound No. A4)

[0388] ##STR00458##

[0389] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (341 mg, 1.2 mmol) as described in Example A1 to give the title compound as a brown solid (115 mg, 37% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.94 (s, 1H), 9.93 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=3.9 Hz, 1H), 7.43-7.31 (m, 3H), 7.30-7.26 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.16 (d, J=1.9 Hz, 1H), 5.32 (s, 2H), 3.95 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.16N.sub.2O.sub.3, 309; found, 309.

Example A5: 2-hydroxy-3-methoxy-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A5)

[0390] ##STR00459##

[0391] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (334 mg, 1.2 mmol) as described in Example A1 to give the title compound as a brown solid (68 mg, 23% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.95 (s, 1H), 9.95 (s, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 4.39 (tt, J=10.4, 4.9 Hz, 1H), 4.21-4.08 (m, 2H), 3.97 (s, 3H), 3.57 (td, J=11.6, 2.9 Hz, 2H), 2.22-2.01 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.18N.sub.2O.sub.4, 303; found, 303.

Example A6: 5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-hydroxy-3-methoxybenzaldehyde (Compound No. A6)

[0392] ##STR00460##

[0393] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (247 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (52 mg, 17% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.00 (s, 1H), 9.99 (s, 1H), 8.07 (d, J=0.7 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.73-7.68 (m, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.21-7.16 (m, 2H), 4.00 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.13FN.sub.2O.sub.3, 313; found, 313.

Example A7: 2-hydroxy-3-methoxy-5-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A7)

[0394] ##STR00461##

[0395] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (319 mg, 1.2 mmol) as described in Example A1 to give the title compound as a black gummy solid (132 mg, 45% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.95 (s, 1H), 9.95 (s, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.62 (d, J=0.9 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 4.26 (t, J=6.9 Hz, 2H), 3.97 (s, 3H), 3.37 (t, J=5.9 Hz, 2H), 3.35 (s, 3H), 2.16 (ddd, J=12.8, 7.0, 5.9 Hz, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.18N.sub.2O.sub.4, 291; found, 291.

Example A8: 2-hydroxy-3-methoxy-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A8)

[0396] ##STR00462##

[0397] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (342 mg, 1.2 mmol) as described in Example A1 to give the title compound as an off-white solid (76 mg, 25% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.96 (s, 1H), 9.94 (s, 1H), 8.60 (dt, J=4.8, 1.4 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.67 (qd, J=7.5, 1.7 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.15 (dt, J=7.9, 1.1 Hz, 1H), 5.47 (s, 2H), 3.96 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.15N.sub.3O.sub.3, 310; found, 310.

Example A9: 2-hydroxy-3-methoxy-5-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A9)

[0398] ##STR00463##

[0399] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)boronic acid (307 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (97 mg, 27% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.01 (s, 1H), 9.99 (s, 1H), 8.19 (s, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (s, 1H), 7.96 (dt, J=7.9, 1.6 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.26 (s, 1H), 4.01 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.13F.sub.3N.sub.2O.sub.3, 363; found, 363.

Example A10: 2-hydroxy-3-methoxy-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A10)

[0400] ##STR00464##

[0401] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (90 mg, 27% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.94 (s, 1H), 9.93 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.26-7.22 (m, 3H), 7.15 (d, J=1.9 Hz, 1H), 6.94-6.89 (m, 2H), 5.28 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.18N.sub.2O.sub.4, 339; found, 339.

Example A11: 3-fluoro-2-hydroxy-5-(1-phenyl-1H-pyrazol-4-yl)benzaldehyde (Compound No. A11)

[0402] ##STR00465##

[0403] The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (86 mg, 30% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.89 (s, 1H), 10.00 (d, J=1.9 Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.76-7.70 (m, 2H), 7.58-7.52 (m, 2H), 7.49 (dt, J=8.4, 7.0 Hz, 2H), 7.38-7.29 (m, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.11FN.sub.2O.sub.2, 283; found, 283.

Example A12: 2-hydroxy-3-methyl-5-(1-phenyl-1H-pyrazol-4-yl)benzonitrile (Compound No. A12)

[0404] ##STR00466##

[0405] The title compound was prepared from 5-bromo-2-hydroxy-3-methylbenzonitrile (216 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as an off-white solid (98 mg, 36% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.10 (s, 1H), 7.92 (s, 1H), 7.74-7.69 (m, 2H), 7.55-7.52 (m, 1H), 7.52-7.49 (m, 1H), 7.49-7.45 (m, 2H), 7.33 (td, J=7.3, 1.0 Hz, 1H), 5.87 (s, 1H), 2.34 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.13N.sub.3O, 276; found, 276.

Example A13: 2,3-difluoro-5-(1-phenyl-1H-pyrazol-4-yl)phenol (Compound No. A13)

[0406] ##STR00467##

[0407] The title compound was prepared from 5-bromo-2,3-difluorophenol (209 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as an off-white solid (172 mg, 63% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.08 (s, 1H), 7.90 (s, 1H), 7.76-7.66 (m, 2H), 7.53-7.43 (m, 2H), 7.39-7.28 (m, 1H), 6.97 (dt, J=7.1, 2.0 Hz, 1H), 6.91 (ddd, J=10.7, 6.6, 2.2 Hz, 1H), 5.55 (s, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.10F.sub.2N.sub.2O, 273; found, 273.

Example A14: 2-fluoro-3-methyl-5-(1-phenyl-H-pyrazol-4-yl)phenol (Compound No. A14)

[0408] ##STR00468##

[0409] The title compound was prepared from 5-bromo-2-fluoro-3-methylphenol (205 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a white solid (102 mg, 38% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.07 (s, 1H), 7.91 (s, 1H), 7.77-7.64 (m, 2H), 7.51-7.40 (m, 2H), 7.36-7.29 (m, 1H), 7.02 (dd, J=7.9, 2.3 Hz, 1H), 6.90 (dd, J=6.5, 2.2 Hz, 1H), 5.40 (s, 1H), 2.32 (d, J=2.1 Hz, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.13FN.sub.2O, 269; found, 269.

Example A15: 2-chloro-6-fluoro-4-(1-phenyl-1H-pyrazol-4-yl)phenol (Compound No. A15)

[0410] ##STR00469##

[0411] The title compound was prepared from 4-bromo-2-chloro-6-fluorophenol (225 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as an off-white solid (196 mg, 68% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.08 (s, 1H), 7.89 (d, J=4.1 Hz, 1H), 7.79-7.65 (m, 2H), 7.51-7.44 (m, 2H), 7.36-7.30 (m, 2H), 7.20 (dd, J=11.0, 2.1 Hz, 1H), 5.90 (s, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.10ClFN.sub.2O, 290; found, 290.

Example A16: 2-fluoro-3-methoxy-5-(1-phenyl-1H-pyrazol-4-yl)phenol (Compound No. A16)

[0412] ##STR00470##

[0413] The title compound was prepared from 5-bromo-2-fluoro-3-methoxyphenol (221 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a brown solid (205 mg, 72% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.09 (s, 1H), 7.92 (s, 1H), 7.82-7.67 (m, 2H), 7.56-7.42 (m, 2H), 7.36-7.28 (m, 1H), 6.82 (dd, J=7.2, 2.1 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz, 1H), 5.41 (d, J=3.9 Hz, 1H), 3.95 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.13FN.sub.2O.sub.2, 285; found, 285.

Example A17: 2-chloro-6-methyl-4-(1-phenyl-1H-pyrazol-4-yl)phenol (Compound No. A17)

[0414] ##STR00471##

[0415] The title compound was prepared from 4-bromo-2-chloro-6-methylphenol (222 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a brown solid (179 mg, 63% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.07 (s, 1H), 7.90 (s, 1H), 7.75-7.69 (m, 2H), 7.51-7.44 (m, 2H), 7.36 (d, J=2.1 Hz, 1H), 7.31 (td, J=7.4, 1.3 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 5.60 (s, 1H), 2.33 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.13ClN.sub.2O, 286; found, 286.

Example A18: 2,6-difluoro-4-(1-phenyl-1H-pyrazol-4-yl)phenol (Compound No. A18)

[0416] ##STR00472##

[0417] The title compound was prepared from 4-bromo-2,6-difluorophenol (209 mg, 1.0 mmol) and 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a white solid (195 mg, 72% yield). .sup.1H NMR (500 MHz, Chloroform-d) 8.08 (s, 1H), 7.89 (s, 1H), 7.76-7.66 (m, 2H), 7.55-7.41 (m, 2H), 7.39-7.29 (m, 1H), 7.17-7.03 (m, 2H), 5.34 (s, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.10F.sub.2N.sub.2O, 273; found, 273.

Example A19: 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A19)

[0418] ##STR00473##

Step 1. 4-Bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazole

[0419] A mixture of 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(4-bromophenyl)pyrrolidine (2.25 g, 10 mmol) potassium carbonate (4.14 g, 30 mmol), CuI (190 mg, 1.0 mmol), and (1S,2S)-N,N-dimethyl-1,2-cyclohexanediamine (284 mg, 2 mmol) in toluene (100 mL) was refluxed overnight under nitrogen protection. The mixture was cooled to room temperature and filtered. The cake was washed with ethyl acetate. The filtrate and wash were combined and concentrated. The residue was purified by silica gel column to give the desired title product (910 mg, 31% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3, 292; found, 292.

Step 2

[0420] A mixture of 4-Bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazole (292 mg, 1.0 mmol), 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol), potassium carbonate (414 mg, 3.0 mmol), PdCl.sub.2(dppf) (74 mg, 0.1 mmol) in dioxane/water (3:1) (12 mL) was heated at 95 C. for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The cake was washed with ethyl acetate. The filtrate and wash were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title product as a yellow solid (49 mg, 14% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.87 (br, 1H), 10.32 (s, 1H), 8.83 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=12.0 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.27 (m, 4H), 1.97 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2, 352; found, 352.

Example A20: 3-fluoro-2-hydroxy-5-(1-(4-(piperidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A20)

[0421] ##STR00474##

Step 1: 1-(4-(4-bromo-1H-pyrazol-1-yl)phenyl)piperidine

[0422] The title compound was prepared from 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(4-bromophenyl)piperidine (2.40 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (1.16 g, 38% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.16BrN.sub.3, 306; found, 306.

Step 2

[0423] The title compound was prepared from 1-(4-(4-bromo-1H-pyrazol-1-yl)phenyl)piperidine (306 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (128 mg, 35% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.88 (s, 1H), 10.32 (s, 1H), 8.90 (s, 1H), 8.15 (s, 1H), 7.92 (d, J=12.0 Hz, 1H), 7.80 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 3.18 (m, 4H), 1.63 (m, 4H), 1.55 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.20FN.sub.3O.sub.2, 366; found, 366.

Example A21: 3-fluoro-2-hydroxy-5-(1-(4-morpholinophenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A21)

[0424] ##STR00475##

Step 1. 4-(4-(4-bromo-1H-pyrazol-1-yl)phenyl)morpholine

[0425] The title compound was prepared from 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 4-(4-bromophenyl)morpholine (2.42 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (1.14 g, 37% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3O, 308; found, 308.

[0426] Step 2.

[0427] The title compound was prepared from 4-(4-(4-bromo-1H-pyrazol-1-yl)phenyl)morpholine (308 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (63 mg, 17% yield). . .sup.1H NMR (DMSO-d6, 400 MHz) : 10.89 (s, 1H), 10.32 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=12.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 3.76 (m, 4H), 3.16 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.3, 368; found, 368.

Example A22: 3-fluoro-2-hydroxy-5-(1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A22)

[0428] ##STR00476##

Step 1: 4-bromo-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazole

[0429] The title compound was prepared from 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(3-bromophenyl)pyrrolidine (2.26 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (876 mg, 30% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3, 292; found, 292.

[0430] Step 2.

[0431] The title compound was prepared from 4-bromo-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazole (292 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as light yellow solid (81 mg, 23% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.91 (s, 1H), 10.33 (s, 1H), 9.02 (s, 1H), 8.20 (s, 1H), 7.96 (d, J=12.0 Hz, 1H), 7.83 (s, 1H), 7.26 (m, 1H), 7.07 (m, 1H), 7.00 (s, 1H), 6.48 (d, J=7.6 Hz, 1H), 3.31 (m, 4H), 1.99 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2, 352; found, 352.

Example A23: 3-fluoro-2-hydroxy-5-(1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A23)

[0432] ##STR00477##

Step 1: 1-(3-(4-bromo-1H-pyrazol-1-yl)phenyl)piperidine

[0433] The title compound was prepared from 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(3-bromophenyl)piperidine (2.40 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (1.28 g, 42% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.16BrN.sub.3, 306; found, 306.

[0434] Step 2.

[0435] The title compound was prepared from 1-(3-(4-bromo-1H-pyrazol-1-yl)phenyl)piperidine (306 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (110 mg, 30% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.91 (s, 1H), 10.33 (s, 1H), 9.05 (s, 1H), 8.21 (s, 1H), 7.95 (d, J=12.0 Hz, 1H), 7.83 (s, 1H), 7.38 (s, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 6.87 (d, J=8.0 Hz, 1H), 3.25 (m, 4H), 1.65 (m, 4H), 1.58 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.20FN.sub.3O.sub.2, 366; found, 366.

Example A24: 3-fluoro-2-hydroxy-5-(1-(3-morpholinophenyl)-1H-pyrazol-4-yl)benzaldehyde (Compound No. A24)

[0436] ##STR00478##

Step 1. 4-(3-(4-bromo-1H-pyrazol-1-yl)phenyl)morpholine

[0437] The title compound was prepared from 4-bromo-1H-pyrazole (1.75 g, 12 mmol), 4-(3-bromophenyl)morpholine (2.42 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (524 mg, 17% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3O, 308; found, 308.

Step 2

[0438] The title compound was prepared from 4-(3-(4-bromo-1H-pyrazol-1-yl)phenyl)morpholine (308 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (144 mg, 39% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.92 (s, 1H), 10.33 (s, 1H), 9.06 (s, 1H), 8.22 (s, 1H), 7.95 (d, J=12.0 Hz, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 3.78 (m, 4H), 3.22 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.3, 368; found, 368.

Example A25: 2-hydroxy-3-methoxy-5-(1-phenyl-1H-pyrazol-3-yl)benzaldehyde (Compound No. A25)

[0439] ##STR00479##

[0440] The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (163 mg, 55% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.13 (s, 1H), 10.01 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.80-7.73 (m, 3H), 7.68 (d, J=1.9 Hz, 1H), 7.49 (dd, J=8.6, 7.4 Hz, 2H), 7.32 (td, J=7.4, 1.1 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 4.03 (s, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.14N.sub.2O.sub.3, 295; found, 295.

Example A26: 3-fluoro-2-hydroxy-5-(1-phenyl-1H-pyrazol-3-yl)benzaldehyde (Compound No. A26)

[0441] ##STR00480##

[0442] The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg, 1.2 mmol) as described in Example A1 to give the title compound as a yellow solid (168 mg, 59% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.98 (s, 1H), 10.02 (d, J=1.9 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.92 (d, J=10.9 Hz, 2H), 7.79-7.74 (m, 2H), 7.53-7.45 (m, 2H), 7.38-7.29 (m, 1H), 6.73 (d, J=2.5 Hz, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.11FN.sub.2O.sub.2, 283; found, 283.

Example A27: 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A27)

[0443] ##STR00481##

Step 1: 3-bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazole

[0444] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(4-bromophenyl)pyrrolidine (2.26 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (379 mg, 13% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3, 292; found, 292.

Step 2

[0445] The title compound was prepared from 3-bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazole (292 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (77 mg, 22% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.05 (br, 1H), 10.34 (s, 1H), 8.34 (s, 1H), 8.02 (m, 2H), 7.66 (m, 2H), 6.98 (s, 1H), 6.63 (m, 2H), 3.27 (m, 4H), 1.98 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2, 352; found, 352.

Example A28: 3-fluoro-2-hydroxy-5-(1-(4-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A28)

[0446] ##STR00482##

Step 1: 1-(4-(3-bromo-1H-pyrazol-1-yl)phenyl)piperidine

[0447] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(4-bromophenyl)piperidine (2.40 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (1.01 g, 33% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.16BrN.sub.3, 306; found, 306.

Step 2

[0448] The title compound was prepared from 1-(4-(3-bromo-1H-pyrazol-1-yl)phenyl)piperidine (306 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (92 mg, 25% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.06 (br, 1H), 10.34 (s, 1H), 8.40 (s, 1H), 8.02 (m, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.03 (m, 3H), 3.18 (m, 4H), 1.64 (m, 4H), 1.55 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.20FN.sub.3O.sub.2, 366; found, 366.

Example A29: 3-fluoro-2-hydroxy-5-(1-(4-morpholinophenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A29)

[0449] ##STR00483##

Step 1. 4-(4-(3-bromo-1H-pyrazol-1-yl)phenyl)morpholine

[0450] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 4-(4-bromophenyl)morpholine (2.42 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (585 mg, 19% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3O, 308; found, 308.

Step 2

[0451] The title compound was prepared from 4-(4-(3-bromo-1H-pyrazol-1-yl)phenyl)morpholine (308 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a yellow solid (118 mg, 32% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.07 (br, 1H), 10.33 (s, 1H), 8.43 (s, 1H), 8.02 (m, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.01 (s, 1H), 3.76 (m, 4H), 3.16 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.3, 368; found, 368.

Example A30: 3-fluoro-2-hydroxy-5-(1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A30)

[0452] ##STR00484##

Step 1: 3-bromo-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazole

[0453] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(3-bromophenyl)pyrrolidine (2.26 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (584 mg, 20% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3, 292; found, 292.

[0454] Step 2. The title compound was prepared from 3-bromo-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazole (292 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a light yellow solid (67 mg, 19% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 10.99 (s, 1H), 10.02 (s, 1H), 7.94 (m, 3H), 7.31 (m, 1H), 6.97 (m, 2H), 6.70 (s, 1H), 6.55 (m, 1H), 3.39 (m, 4H), 2.07 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2, 352; found, 352.

Example A31: 3-fluoro-2-hydroxy-5-(1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A31)

[0455] ##STR00485##

Step 1: 1-(3-(3-bromo-1H-pyrazol-1-yl)phenyl)piperidine

[0456] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 1-(3-bromophenyl)piperidine (2.40 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (370 mg, 12% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.16BrN.sub.3, 306; found, 306.

Step 2

[0457] The title compound was prepared from 1-(3-(3-bromo-1H-pyrazol-1-yl)phenyl)piperidine (306 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a light yellow solid (83 mg, 27% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.10 (br, 1H), 10.34 (s, 1H), 8.57 (s, 1H), 8.04 (m, 2H), 7.39 (s, 1H), 7.28 (m, 2H), 7.05 (s, 1H), 6.89 (m, 1H), 3.24 (m, 4H), 1.65 (m, 4H), 1.57 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.20FN.sub.3O.sub.2, 366; found, 366.

Example A32: 3-fluoro-2-hydroxy-5-(1-(3-morpholinophenyl)-1H-pyrazol-3-yl)benzaldehyde (Compound No. A32)

[0458] ##STR00486##

Step 1: 4-(3-(3-bromo-1H-pyrazol-1-yl)phenyl)morpholine

[0459] The title compound was prepared from 3-bromo-1H-pyrazole (1.75 g, 12 mmol), 4-(3-bromophenyl)morpholine (2.42 g, 10 mmol) as described in Step 1 of Example A19 to give the title compound (524 mg, 17% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3O, 308; found, 308.

Step 2

[0460] The title compound was prepared from 4-(3-(3-bromo-1H-pyrazol-1-yl)phenyl)morpholine (308 mg, 1.0 mmol) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (532 mg, 2.0 mmol) as described in Step 2 of Example A19 to give the title compound as a white solid (114 mg, 31% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.01 (br, 1H), 10.03 (s, 1H), 7.98 (s, 1H), 7.93 (m, 2H), 7.55 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.02 (m, 1H), 6.73 (s, 1H), 3.99 (m, 4H), 3.33 (m, 4H); LC-MS m/z [MH].sup. calc'd for C.sub.20H.sub.18FN.sub.3O.sub.3, 366; found, 366.

Example A33: (E)-2-fluoro-6-(((4-methylpiperazin-1-yl)imino)methyl)-4-(1-phenyl-1H-pyrazol-3-yl)phenol (Compound No. A33)

[0461] ##STR00487##

[0462] In a 20 mL sealed cap glass vial 3-fluoro-2-hydroxy-5-(1-phenyl-1H-pyrazol-3-yl)benzaldehyde (85 mg, 0.3 mmol) and 4-methylpiperazin-1-amine (65 mg, 0.3 mmol) were suspended in ethanol (5 mL) and added trifluoroacetic acid (3 drops) and warmed the mixture to get a clear solution. Then stirred at room temp for 2 hours, the resulting crashed product collected by vacuum filtration and washed the product with small amount of ethanol to give the title product as white solid (85 mg, 75% yield). .sup.1H NMR (500 MHz, Chloroform-d) 11.86 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.77-7.70 (m, 3H), 7.53 (d, J=2.7 Hz, 1H), 7.50-7.42 (m, 3H), 7.29 (td, J=7.3, 1.3 Hz, 2H), 6.67 (d, J=2.5 Hz, 1H), 3.23 (t, J=5.1 Hz, 4H), 2.77-2.50 (m, 4H), 2.37 (s, 3H); LC-MS m/z [MH].sup. calc'd for C.sub.21H.sub.22FN.sub.5O, 380; found, 380.

Example A34: 2-(1,3-dioxan-2-yl)-6-fluoro-4-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)phenol (Compound No. A34)

[0463] ##STR00488##

[0464] A solution of 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (35 mg, 0.1 mmol), propane-1,3-diol (30 mg, 0.4 mmol), and TsOH (5 mg, 0.03 mmol) in toluene was refluxed for 2 hours. The solvent was removed mostly and the residue purified by prep-TLC to give desired product as white solid (13 mg, 32% yield). .sup.1H NMR (CDCl.sub.3, 300 MHz) : 7.95 (s, 1H), 7.86 (s, 1H), 7.74 (m, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.22 (m, 1H), 6.71 (m, 2H), 4.36 (m, 2H), 4.08 (m, 2H), 3.37 (m, 4H), 2.23 (m, 1H), 2.08 (m, 5H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.24FN.sub.3O.sub.3, 411; found, 411.

General Procedure for Example A35 to Example A41:

[0465] 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (1 eq.) and amine compound (2 eq.) were dissolved in ethanol or methanol. The reaction was refluxed for 2 hours. The solvent was removed mostly and the residue was filtered. The cake was washed with ethanol and dried in vacuo to give desired product.

Example A35: (E)-2-fluoro-6-(((4-methylpiperazin-1-yl)imino)methyl)-4-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)phenol (Compound No. A35)

[0466] ##STR00489##

[0467] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (100 mg, 0.28 mmol) and 4-methylpiperazin-1-amine (64 mg, 0.56 mmol) as described in above general procedure to give the title compound as white solid (80 mg, 63% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.60 (br, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.21 (d, J=11.6 Hz, 1H), 7.12 (s, 1H), 6.61 (d, J=8.4 Hz, 2H), 3.33 (m, 8H), 2.80 (m, 4H), 2.49 (s, 3H), 2.04 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.29FN.sub.6O, 449; found, 449.

Example A36: (E)-2-(((4-cyclopropylpiperazin-1-yl)imino)methyl)-6-fluoro-4-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)phenol (Compound No. A36)

[0468] ##STR00490##

[0469] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (20 mg, 0.06 mmol) and 4-cyclopropylpiperazin-1-amine dihydrochloride (12 mg, 0.06 mmol) as described in above general procedure except that sodium acetate (5 mg, 0.06 mmol) base added to the reaction mixture and finally washed the residue with water and ethanol to give the title compound as off-white solid (11 mg, 41% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.52 (br, 1H), 8.69 (s, 1H), 8.01 (s, 1H), 7.90 (m, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.51 (m, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.27 (m, 4H), 3.13 (m, 4H), 2.75 (m, 4H), 1.98 (m, 4H), 1.73 (m, 1H), 0.45 (m, 2H), 0.36 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.27H.sub.31FN.sub.6O, 475; found, 475.

Example A37: (E)-2-fluoro-6-((morpholinoimino)methyl)-4-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)phenol (Compound No. A37)

[0470] ##STR00491##

[0471] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (100 mg, 0.28 mmol) and morpholin-4-amine (57 mg, 0.56 mmol) as described in above general procedure to give the title compound as white solid (85 mg, 69% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.42 (br, 1H), 8.70 (s, 1H), 8.00 (m, 2H), 7.62 (m, 2H), 7.53 (m, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.80 (m, 4H), 3.27 (m, 4H), 3.16 (m, 4H), 1.97 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.24H.sub.26FN.sub.5O.sub.2, 436; found, 436.

Example A38: N-(3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzylidene)acetohydrazide (Compound No. A38)

[0472] ##STR00492##

[0473] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (100 mg, 0.28 mmol) and acetohydrazide (41 mg, 0.56 mmol) as described in above general procedure to give the title compound as white solid (55 mg, 47% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.87 (br, 0.6H), 11.56 (br, 0.6H), 11.45 (br, 0.4H), 10.34 (br, 0.4H), 8.75 (s, 1H), 8.36 (s, 0.6H), 8.29 (s, 0.4H), 8.08 (s, 1H), 7.64 (m, 4H), 6.64 (d, J=8.4 Hz, 2H), 3.27 (m, 4H), 2.25 (s, 1H), 1.97-2.02 (m, 6H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.22H.sub.22FN.sub.5O.sub.2, 408; found, 408.

Example A39: (E)-2-fluoro-6-((phenylimino)methyl)-4-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)phenol (Compound No. A39)

[0474] ##STR00493##

[0475] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (100 mg, 0.28 mmol) and aniline (52 mg, 0.56 mmol) as described in above general procedure to give the title compound as white solid (57 mg, 47% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 13.62 (br, 1H), 8.71 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.32-7.49 (m, 9H), 3.44 (m, 4H), 2.14 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.26H.sub.23FN.sub.4O, 427; found, 427.

Example A40: (E)-3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde O-phenyl Oxime (Compound No. A40)

[0476] ##STR00494##

[0477] The title compound was prepared from 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)benzaldehyde (50 mg, 0.14 mmol) and O-phenylhydroxylamine hydrochloride (31 mg, 0.21 mmol) as described in above general procedure except that TEA (29 mg, 0.28 mmol) base added to the reaction mixture and stirred overnight at room temperature to give the title compound as green solid (27 mg, 44% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.40 (br, 1H), 8.83 (d, J=5.2 Hz, 2H), 8.13 (s, 1H), 7.87 (s, 1H), 7.73 (d, J=12.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.39 (m, 2H), 7.32 (m, 2H), 7.08 (m, 1H), 6.64 (d, J=8.8 Hz, 2H), 3.27 (m, 4H), 1.98 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.26H.sub.23FN.sub.4O.sub.2, 443; found, 443.

Example A41: 3-fluoro-2-hydroxy-5-(4-(4-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (Compound No. A42)

[0478] ##STR00495##

Step 1: 1-(3-(1,3-Dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-4-(4-(pyrrolidin-1-yl)phenyl)-1H-1 ,2,3-triazole

[0479] ##STR00496##

[0480] A mixture of 2-(5-azido-3-fluoro-2-(4-methoxybenzyloxy)phenyl)-1,3-dithiane (0.3 g, 0.77 mmol) (prepared as in Example A43), CuSO.sub.4 (21 mg, 0.13 mmol), and L-ascorbic acid sodium salt (65 mg, 0.39 mmol) in MeOH/water (20 mL/2 mL) was purged with nitrogen for three times, then added 1-(4-Ethynylphenyl)pyrrolidine (112 mg, 0.77 mmol) to the reaction mixture. The reaction was heated at 50 C. for 1 hour. The mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (40 mL3). The organic extracts were combined, washed with brine (40 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 2:1) to give the desired titled product (203 mg, 47% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.30H.sub.31FN.sub.4O.sub.2S.sub.2, 563; found, 563.

Step 2

[0481] A solution of above obtained step 1 product (150 mg, 0.27 mmol), MeI (3.8 g, 26.8 mmol), and NaHCO.sub.3 (448 mg, 5.3 mmol) in acetonitrile/water (15 mL/3 mL) was stirred overnight at 40 C. The solution was diluted with water and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in 4N HCl (5 mL) and the reaction was stirred for 1 hour at room temperature. The solution was poured into ice-cold sat. sodium bicarbonate and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC (DCM/MeOH=20:1) to give the desired product as yellow solid (7 mg, 7% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.07 (s, 1H), 10.03 (s, 1H), 8.01 (s, 1H), 7.84 (m, 2H), 7.75 (m, 2H), 6.68 (m, 2H), 3.36 (m, 4H), 2.05 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17FN.sub.4O.sub.2, 353; found, 353.

Example A42: 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (Compound No. A43)

[0482] ##STR00497##

Step 1: 5-Ethynyl-3-fluoro-2-hydroxybenzaldehyde

[0483] ##STR00498##

[0484] Starting materials PdCl.sub.2(PPh).sub.2 (0.3 g, 0.25 mmol), CuI (0.03 g, 0.1 mmol), and ethynyltrimethylsilane (1.47 g, 15.0 mmol) were added to a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (2.19 g, 10.0 mmol), triethylamine (2.02 g, 20.0 mmol), and triphenylphosphine (0.045 g, 0.125 mmol) in THF (20 mL) under nitrogen protection was refluxed for 60 hours. The mixture was cooled to room temperature, diluted with water/ethyl acetate, and filtered. The cake was washed with ethyl acetate. The filtrate and wash was combined, separated, and the water phase was re-extracted with ethyl acetate for two more times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 300:1) to give 3-fluoro-2-hydroxy-5-((trimethylsilyl)ethynyl)benzaldehyde (1.1 g, 47% yield). The 3-fluoro-2-hydroxy-5-((trimethylsilyl)ethynyl)benzaldehyde (1.0 g, 4.2 mmol) was dissolved in THF (15 mL) and TBAF (2.2 g, 8.4 mmol) was added. The reaction was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 300:1) to give the title product (0.31 g, 45% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 10.96 (br, 1H), 9.89 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 3.08 (s, 1H).

Step 2: 1-(4-Azidophenyl)pyrrolidine

[0485] ##STR00499##

[0486] In a 50 mL dry round bottom flask, BuLi (4 mL, 10.0 mmol, 2.5 M in THF) was added to a solution of 1-(4-bromophenyl)pyrrolidine (0.5 g, 2.2 mmol) in THF (5 mL) at 78 C. The reaction was stirred for 30 min. TsN.sub.3 (1.3 g, 6.7 mmol) was added. The reaction was stirred for 5 hours at room temperature. The reaction was quenched with sat. ammonium chloride (20 mL) and extracted with EtOAc (20 mL3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 400:1) to give title product (150 mg, 36% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.12N.sub.4, 189; found, 189.

Step 3

[0487] A mixture of 1-(4-Azidophenyl)pyrrolidine (100 mg, 0.53 mmol), CuSO.sub.4 (8.5 mg, 0.053 mmol), and L-ascorbic acid sodium salt (52.7 mg, 0.27 mmol) in t-BuOH/water (5 mL/5 mL) was purged with nitrogen for three times and 5-Ethynyl-3-fluoro-2-hydroxybenzaldehyde (131 mg, 0.80 mmol) was added to the reaction mixture. The reaction was heated overnight at 40 C. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL3). The organic extracts were combined, washed with brine (20 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 5:1) and prep-HPLC to give the desired final product as light yellow solid (12 mg, 6% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.17 (br, 1H), 10.37 (s, 1H), 9.15 (s, 1H), 8.04 (m, 2H), 7.68 (d, J=8.8 Hz, 2H), 6.70 (d, J=9.2 Hz, 2H), 3.30 (m, 4H), 2.00 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17FN.sub.4O.sub.2, 353; found, 353.

Example A43: 3-fluoro-2-hydroxy-5-(4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (Compound No. A44)

[0488] ##STR00500##

Step 1: 2-(5-Bromo-3-fluoro-2-(4-methoxybenzyloxy)phenyl)-1,3-dithiane

[0489] ##STR00501##

[0490] In a 100 mL dry round bottom flask, BF.sub.3.OEt.sub.2 (3.41 g, 24.0 mmol) was added to a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (4.36 g, 20.0 mmol) and propane-1,3-dithiol (2.6 g, 24.0 mmol) in DCM (20 mL) under nitrogen protection. The reaction was stirred for 3 hours at room temperature. The solution was poured into ice-water and extracted with ethyl acetate (50 mL3). The organic extracts were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude was dissolved in DMF (20 mL) then PMBCl (6.24 g, 40.0 mmol) and potassium carbonate (8.28 g, 60 mmol) were added. The reaction was stirred for was 2 h at 90 C. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (50 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 400:1) to give titled product (6.37 g, 74% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.51 (s, 1H), 7.42 (m, 2H), 7.24 (m, 1H), 6.94 (m, 2H), 5.48 (s, 1H), 5.07 (s, 2H), 3.84 (s, 3H), 2.98 (m, 2H), 2.88 (m, 2H), 2.15 (m, 1H), 1.90 (m, 1H).

Step 2: 2-(5-Azido-3-fluoro-2-(4-methoxybenzyloxy)phenyl)-1,3-dithiane

[0491] ##STR00502##

[0492] In a 100 mL dry round bottom flask, BuLi (6.6 mL, 10.5 mmol, 1.6 M in THF) was added to a solution of 2-(5-Bromo-3-fluoro-2-(4-methoxybenzyloxy)phenyl)-1,3-dithiane (1.0 g, 2.3 mmol) and TsN.sub.3 (1.38 g, 7.0 mmol) in THF (10 mL) at 78 C. The reaction was stirred for 2.5 hours at room temperature. The reaction was quenched with sat. ammonium chloride (30 mL) and extracted with EtOAc (30 mL3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 50:1) to give the titled product (0.71 g, 78% yield, containing 55% debrominated side product inside). LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.18FN.sub.3O.sub.2S.sub.2, 392; found, 392.

Step 3: 5-Azido-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde

[0493] ##STR00503##

[0494] DMP (2.4 g, 5.6 mmol) was added to a solution of 2-(5-Azido-3-fluoro-2-(4-methoxybenzyloxy)phenyl)-1,3-dithiane (1.1 g, 2.8 mmol) in acetonitrile/DCM/water (16 mL/2 mL/2 mL). The reaction was stirred overnight at 45 C. . The mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with sat. sodium bicarbonate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 50:1) to give the titled product (0.79 g, 93% yield containing 55% debromo-byproduct inside). LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.12FN.sub.3O.sub.3, 302; found, 302.

Step 4: 3-(Pyrrolidin-1-yl)benzaldehyde

[0495] ##STR00504##

[0496] BuLi (20.6 mL, 33.2 mmol, 1.6 M in THF) was added to a solution of 1-(3-bromophenyl)pyrrolidine (5 g, 22.1 mmol) in THF (25 mL) at 78 C. The reaction was stirred for 1 hour at this temperature. A solution of DMF (2.4 g, 33.2 mmol) in THF (5 mL) was added. The reaction was stirred for 2 hours at room temperature. The reaction was quenched with sat. ammonium chloride (50 mL) and extracted with EtOAc (50 mL3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 300:1) to give the desired product (2.85 g, 74% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 9.97 (s, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.04 (s, 1H), 6.83 (dd, J=8.4 Hz, 2.0 Hz, 1H), 3.36 (m, 4H), 2.06 (m, 4H).

Step 5: 1-(3-Ethynylphenyl)pyrrolidine

[0497] ##STR00505##

[0498] BuLi (4.3 mL, 6.9 mmol, 1.6 M in THF) was added to a solution of 3-(Pyrrolidin-1-yl)benzaldehyde (1.0 g, 5.7 mmol) in THF (10 mL) at 78 C. The reaction was stirred for 30 min. TMSN.sub.2 (3.4 mL, 6.9 mmol, 2 M in THF) was added. The reaction was stirred for 1 h at 78 C. The reaction was quenched with sat. ammonium chloride (30 mL) and extracted with EtOAc (30 mL3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=500:1 to 400:1) to give the desired 1-(3-Ethynylphenyl)pyrrolidine (0.63 g, 64% yield).

Step 6. 3-Fluoro-2-(4-methoxybenzyloxy)-5-(4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde

[0499] ##STR00506##

[0500] A mixture of 5-Azido-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde (0.4 g, 1.3 mmol), CuSO.sub.4 (20 mg, 0.13 mmol), and L-ascorbic acid sodium salt (150 mg, 0.75 mmol) in t-BuOH/water (5 mL/5 mL) was purged with nitrogen for three times then added 1-(3-Ethynylphenyl)pyrrolidine (0.2 g, 1.2 mmol) to the reaction mixture. The reaction was heated at 40 C. overnight. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL3). The organic extracts were combined, washed with brine (20 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 2:1) to give PMB-protected desired product (120 mg, 22% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.27H.sub.25FN.sub.4O.sub.3, 473; found, 473.

Step 7

[0501] A solution of 3-Fluoro-2-(4-methoxybenzyloxy)-5-(4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (120 mg, 0.25 mmol) and TFA (86 mg, 0.76 mmol) in DCM (5 mL) was stirred overnight at rt. The solution was diluted with DCM (10 mL) and washed with sat. sodium bicarbonate (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/DCM=20:1:1 to 5:1:1) to give the final desired product as light yellow solid (30 mg, 34% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.51 (s, 1H), 10.40 (s, 1H), 9.31 (s, 1H), 8.21 (dd, J=11.2 Hz, 2.8 Hz, 1H), 8.03 (m, 1H), 7.26 (m, 1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.56 (m, 1H), 3.31 (m, 4H), 2.00 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17FN.sub.4O.sub.2, 353; found, 353.

Example A44: 3-fluoro-2-hydroxy-5-(1-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (Compound No. A45)

[0502] ##STR00507##

Step 1: 1-(3-Azidophenyl)pyrrolidine

[0503] ##STR00508##

[0504] A solution of 3-(pyrrolidin-1-yl)aniline (0.5 g, 3.1 mmol) in acetonitrile (10 mL) was cooled to 0 C. Tert-Butyl nitrite (0.96 g, 9.3 mmol) and TMSN.sub.3 (0.86 g, 7.4 mmol) were added. The reaction was stirred overnight at rt. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=300:1 to 100:1) to give the desired product (190 mg, 33% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.12N.sub.4, 189; found, 189.

Step 2

[0505] A mixture of 1-(3-Azidophenyl)pyrrolidine (100 mg, 0.53 mmol), CuSO.sub.4 (8.5 mg, 0.053 mmol), and L-ascorbic acid sodium salt (52.7 mg, 0.27 mmol) in t-BuOH/water (5 mL/5 mL) was purged with nitrogen for three times then added 5-Ethynyl-3-fluoro-2-hydroxybenzaldehyde (131 mg, 0.80 mmol) (from example A43) to the reaction mixture. The reaction was heated overnight at 40 C. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL3). The organic extracts were combined, washed with brine (20 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 5:1) and prep-TLC to give the final product as white solid (15 mg, 7% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.05 (br, 1H), 10.03 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=11.2 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 6.92 (d, J=7.2 Hz, 1H), 3.48 (m, 4H), 2.16 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17FN.sub.4O.sub.2, 353; found, 353.

Example A45: 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)benzaldehyde (Compound A47)

[0506] ##STR00509##

Step 1: 4-(4-bromo-1H-imidazol-1-yl)aniline

[0507] A mixture of 1-fluoro-4-nitrobenzene (1.16 g, 8.2 mmol, 1.2 eq.), 5-bromo-1H-imidazole (1 g, 6.8 mmol, 1.0 eq.), and potassium carbonate (2.84 g, 20.4 mmol, 3.0 eq.) in DMF (15 mL) was heated at 80 C. for 2 hours under N.sub.2 protection. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 4-bromo-1-(4-nitrophenyl)-1H-imidazole (1.77 g, 6.63 mmol, 98% yield). LC-MS: 268.0, 270.0 (M+H)+, C.sub.9H.sub.6BrN.sub.3O.sub.2. In a 100 mL glass vial, iron powder (2.71 g, 48.32 mmol, 10.0 eq.) was added to a solution of 4-bromo-1-(4-nitrophenyl)-1H-imidazole (1.3 g, 4.83 mmol, 1.0 eq.) in AcOH (20 mL). The reaction was heated for 2 hours at 60 C. The reaction mixture was cooled to room temperature, poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-(4-bromo-1H-imidazol-1-yl)aniline (790 mg, 3.31 mmol, 68% yield).

Step 2: 4-bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-imidazole

[0508] A solution of 4-(4-bromo-1H-imidazol-1-yl)aniline (500 mg, 2.1 mmol, 1.0 eq.) and dihydrofuran-2,5-dione (422 mg, 4.2 mmol, 2.0 eq.) in toluene (15 mL) was stirred overnight at room temperature. The solution was poured into water and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude intermediate (710 mg). This intermediate was then refluxed in thionyl chloride (10 mL) for 1 hour and concentrated in vacuo to get the penultimate intermediate (690 mg). This intermediate (600 mg, 1.88 mmol, 1.0 eq.) was dissolved in THF (10 ml) and the solution was cooled to 0 C. Borane-dimethylsulfide (1.68 mL, 10 M, 9.0 eq.) was added. The reaction was stirred for 2 hours at 50 C. The system was cooled to room temperature, poured into ice water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=20:1 to 10:1) to give 4-bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-imidazole (240 mg, 0.82 mmol, 44% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3, 292; found, 292.

Step 3

[0509] A mixture of 4-bromo-1-(4-(pyrrolidin-1-yl)phenyl)-1H-imidazole (200 mg, 0.69 mmol, 1.0 eq.), 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (459 mg, 1.73 mmol, 2.5 eq.), potassium carbonate (286 mg, 2.07 mmol, 3.0 eq.), PdCl.sub.2(dppf) (85 mg, 0.07 mmol, 0.1 eq.) in dioxane/water (10 mL/3 mL) was heated at 100 C. for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=50:1 to 20:1) to give 3-fluoro-2-hydroxy-5-(1-(4-(pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)benzaldehyde (42 mg, 0.12 mmol, 17% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.87 (br, 1H), 10.33 (s, 1H), 8.14 (d, J=10.4 Hz, 2H), 7.97-7.92 (m, 2H), 7.45 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.27 (m, 4H), 1.98 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2, 352; found, 352.

Example A46: 3-fluoro-2-hydroxy-5-(5-(4-(pyrrolidin-1-yl)phenyl)thiophen-2-yl)benzaldehyde (Compound A50)

[0510] ##STR00510##

Step 1: 1-(4-(thiophen-2-yl)phenyl)pyrrolidine

[0511] A mixture of thiophen-2-ylboronic acid (1.7 g, 13.3 mmol, 1.5 eq.), 1-(4-bromophenyl)pyrrolidine (2 g, 8.89 mmol, 1.0 eq.), potassium carbonate (3.7 g, 26.8 mmol, 3.0 eq.), and PdCl.sub.2(dppf) (0.7 g, 0.89 mmol, 0.1 eq.) in dioxane/water (9 mL/3 mL) was heated at 95 C. for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The cake was washed with ethyl acetate. The filtrate and wash were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100 to 300:1) to give 1-(4-(thiophen-2-yl)phenyl)pyrrolidine (1.2 g, 5.24 mmol, 59% yield).

Step 2: 1-(4-(5-bromothiophen-2-yl)phenyl)pyrrolidine

[0512] A solution of 1-(4-(thiophen-2-yl)phenyl)pyrrolidine (950 mg, 4.15 mmol, 1 eq.) and NBS (1.11 g, 6.23 mmol, 1.5 eq.) in CHCl.sub.3 (20 mL) was stirred for 2 h. The solution was poured into sat. sodium bicarbonate and extracted with CH.sub.2Cl.sub.2 for three times. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (pure petroleum ether) to give 1-(4-(5-bromothiophen-2-yl)phenyl)pyrrolidine (350 mg, 1.13 mmol, 27% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 7.39 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.14 (d, J=4.0 Hz, 1H), 7.08 (d, J=4.0 Hz, 1H), 6.54 (d, J=8.8 Hz, 2H), 3.25 (m, 4H), 1.96 (m, 4H).

Step 3

[0513] A mixture of 1-(4-(5-bromothiophen-2-yl)phenyl)pyrrolidine (340 mg, 1.10 mmol, 1.0 eq.), 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (322 mg, 1.21 mmol, 1.1 eq.), potassium carbonate (456 mg, 3.30 mmol, 3.0 eq.), and PdCl.sub.2(dppf) (90 mg, 0.11 mmol, 0.1 eq.) in dioxane/water (9 mL/3 mL) was heated at 95 C. for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100:1 to 20:1) to give 3-fluoro-2-hydroxy-5-(5-(4-(pyrrolidin-1-yl)phenyl)thiophen-2-yl)benzaldehyde (110 mg, 0.30 mmol, 27% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.10 (br, 1H), 10.31 (s, 1H), 7.90 (dd, J=12.0 Hz, 1.6 Hz, 1H), 7.65 (s, 1H), 7.47 (m, 3H), 7.26 (d, J=3.6 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 3.36 (m, 4H), 1.96 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.18FNO.sub.2S, 368; found, 368.

Example A47: 3-fluoro-2-hydroxy-5-(4-(4-(pyrrolidin-1-yl)phenyl)thiophen-2-yl)benzaldehyde (Compound A51)

[0514] ##STR00511##

Step 1: 5-(4-bromothiophen-2-yl)-3-fluoro-2-hydroxybenzaldehyde

[0515] A mixture of 2,4-dibromothiophene (1 g, 4.1 mmol, 1.0 eq.), 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.2 g, 4.51 mmol, 1.08 eq.), potassium phosphate (4.4 g, 20.8 mmol, 5.0 eq.), Pd(PPh.sub.3).sub.4 (0.48 g, 0.41 mmol, 0.1 eq.) in dioxane/water (20 mL/6 mL) was heated at 100 C. for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100:1 to 20:1) to give 5-(4-bromothiophen-2-yl)-3-fluoro-2-hydroxybenzaldehyde (390 mg, 1.29 mmol, 31% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.11H.sub.6BrFO.sub.2S, 301; found, 301.

Step 2

[0516] A mixture of 5-(4-bromothiophen-2-yl)-3-fluoro-2-hydroxybenzaldehyde (302 mg, 1 mmol, 1.0 eq.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (295 mg, 1.08 mmol, 1.08 eq.), potassium phosphate (1.06 g, 5.0 mmol, 5.0 eq.), Pd(PPh.sub.3).sub.4 (116 mg, 0.1 mmol, 0.1 eq.) in dioxane/water (10 mL/3 mL) was heated at 100 C. for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100:1 to 20:1) to give 3-fluoro-2-hydroxy-5-(4-(4-(pyrrolidin-1-yl)phenyl)thiophen-2-yl)benzaldehyde (60 mg, 0.16 mmol, 16% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.13 (br, 1H), 10.32 (s, 1H), 8.00 (dd, J=12.4 Hz, 2.4 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.72 (s, 1H), 7.61-7.55 (m, 3H), 6.57 (d, J=8.8 Hz, 2H), 3.26 (m, 4H), 1.97 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.18FNO.sub.2S, 368; found, 368.

Example A48: 3-fluoro-2-hydroxy-5-(5-(4-(pyrrolidin-1-yl)phenyl)thiophen-3-yl)benzaldehyde (Compound A52)

[0517] ##STR00512##

Step 1: 1-(4-(4-bromothiophen-2-yl)phenyl)pyrrolidine

[0518] A mixture of 2,4-dibromothiophene (1 g, 4.1 mmol, 1.0 eq.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (1.22 g, 4.51 mmol, 1.08 eq.), potassium phosphate (4.4 g, 20.8 mmol, 5.0 eq.), Pd(PPh.sub.3).sub.4 (0.48 g, 0.41 mmol, 0.1 eq.) in dioxane/water (20 mL/6 mL) was heated at 100 C. for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100 to 500:1) to give 1-(4-(4-bromothiophen-2-yl)phenyl)pyrrolidine (260 mg, 0.84 mmol, 21% yield), used in next step.

[0519] Step 2: The title compound was prepared from 1-(4-(4-bromothiophen-2-yl)phenyl)pyrrolidine (230 mg, 0.74 mmol, 1.0 eq.) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (214 mg, 0.80 mmol, 1.08 eq.) using a method similar to that as described in Example A47 to give the final title compound (110 mg, 0.30 mmol, 41% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.98 (br, 1H), 10.32 (s, 1H), 8.00 (dd, J=12.4 Hz, 2.0 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 6.58 (d, J=8.8 Hz, 2H), 3.27 (m, 4H), 1.97 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.18FNO.sub.2S, 368; found, 368.

Example A49: 3-fluoro-2-hydroxy-5-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-4-yl)benzaldehyde (Compound A57)

[0520] ##STR00513##

Step 1: 4-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole

[0521] A mixture of 2,4-dibromothiazole (500 mg, 2.06 mmol, 1.0 eq.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (620 mg, 2.26 mmol, 1.1 eq.), potassium carbonate (850 mg, 6.18 mmol, 3.0 eq.), and PdCl.sub.2(dppf) (170 mg, 0.21 mmol, 0.1 eq.) in dioxane/water (10 mL/5 mL) was heated at 100 C. for 1 hour under nitrogen protection. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=100 to 500:1) to give 4-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole (397 mg, 1.29 mmol, 63% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.13BrN.sub.2S, 311; found, 311.

Step 2

[0522] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (415 mg, 1.56 mmol, 1.2 eq.) and 4-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole (400 mg, 1.30 mmol, 1.0 eq.) using a method similar to that as described in Example A47 to give the final title compound (110 mg, 0.30 mmol, 41% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.12 (br, 1H), 10.35 (s, 1H), 8.14 (dd, J=10.0 Hz, 2.4 Hz, 2H), 7.97 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.31 (m, 4H), 1.98 (m, 4H). LC-MS m/z [MH].sup. calc'd for C.sub.20H.sub.17FN.sub.2O.sub.2S, 367; found, 367.

Example A50: 3-fluoro-2-hydroxy-5-(5-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazol-3-yl)benzaldehyde (Compound A61)

[0523] ##STR00514##

Step 1: 3-bromo-5-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazole

[0524] A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.5 g, 2.5 mmol, 1.0 eq.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (0.75 g, 2.75 mmol, 1.1 eq.), potassium phosphate (1.59 g, 7.5 mmol, 3.0 eq.), PdCl.sub.2(dppf) (204 mg, 0.25 mmol, 0.1 eq.) in DMF/water (6 mL/2 mL) was heated at 80 C. for 2.5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and poured into water. Then pH of the system was adjusted to 4-5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether/EtOAc=20:1 to 50:1) to give 3-bromo-5-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazole (203 mg, 0.66 mmol, 26% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.12BrN.sub.3S, 312; found, 312.

Step 2

[0525] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (133 mg, 0.50 mmol, 1.1 eq.) and 3-bromo-5-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazole (140 mg, 0.45 mmol, 1.0 eq.) using a method similar to that as described in Example A47 to give the final title compound (30 mg, 0.08 mmol, 18% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.54 (br, 1H), 10.37 (s, 1H), 8.38 (d, J=1.2 Hz, 1H), 8.24 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.8 Hz, 2H), 3.35 (m, 4H), 1.99 (t, J=6.6 Hz, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FN.sub.3O.sub.2S, 370; found, 370.

Example A51: 3-fluoro-2-hydroxy-5-(3-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazol-5-yl)benzaldehyde (Compound A62)

[0526] ##STR00515##

[0527] The title compound was prepared from 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (258 mg, 0.94 mmol, 1.1 eq.) and 5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde (260 mg, 0.86 mmol, 1 eq.) (prepared as in Example A47) using a method similar to that as described in Example A47 to give the final title compound (87 mg, 0.24 mmol, 27% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.88 (br, 1H), 10.36 (s, 1H), 8.22 (dd, J=11.2 Hz, 2.4 Hz, 1H), 8.15 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 6.65 (d, J=9.2 Hz, 2H), 3.32 (t, J=6.8 Hz, 4H), 1.98 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FN.sub.3O.sub.2S, 370; found, 370.

Example A52: 3-fluoro-2-hydroxy-5-(2-phenyloxazol-5-yl)benzaldehyde (Compound A88)

[0528] ##STR00516##

[0529] The title compound was prepared from 5-bromo-2-phenyloxazole (223 mg, 1 mmol, 1 eq.) and 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (244 mg, 1.08 mmol, 1.08 eq.) using a method similar to that as described in Example A47 to give the final title compound (120 mg, 0.42 mmol, 42% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.35 (br, 1H), 10.35 (s, 1H), 8.12-8.06 (m, 3H), 7.92 (s, 1H), 7.86 (s, 1H), 7.57 (m, 3H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.10FNO.sub.3, 284; found, 284.

Example A53: 3-fluoro-2-hydroxy-5-(5-phenyloxazol-2-yl)benzaldehyde (Compound A89)

[0530] ##STR00517##

[0531] 3-fluoro-2-hydroxy-5-(5-phenyloxazol-2-yl)benzaldehyde was synthesized in a manner similar to that described by Ji et al. (RSC Adv., 2018, 8, 13643-13648.)

Step 1a

[0532] 5-bromo-3-fluoro-2-hydroxybenzaldehyde (131 mg, 0.6 mmol), bis(pinacolato)diboron, (253 mg, 0.66 mmol), potassium phosphate tribasic (254.7 mg), XPhos Pd G.sub.3 (50.8 mg) and XPhos (28.6 mg) were placed in a 5 mL microwave vial with a stir bar. Dioxane (2.4 mL) was added and the vial was degassed with argon and sealed. The reaction was heated to 130 C. in a Biotage microwave for 60 minutes.

Step 1b

[0533] An aliquot (0.8 mL) of the reaction mixture from step 1a was added to a microwave vial containing 2-bromo-5-phenyloxazole (44.8 mg, 0.2 mmol), XPhos Pd G.sub.3 (8.5 mg) and XPhos (4.8 mg). The reaction was degassed with argon and heated to to 130 C. in a microwave for 30 minutes. The reaction mixture was diluted with DCM, acidified to pH=3 with citric acid and extracted 3 times with DCM. The combined organic phases were washed with brine and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash column chromatography 0-10% MeOH/DCM. Yield (6.6 mg, 12%). .sup.1H NMR (500 MHz, CDCl.sub.3) 11.22 (s, 1H), 10.04 (d, J=1.7 Hz, 1H), 8.19 (dd, J=2.0, 1.2 Hz, 1H), 8.10 (dd, J=11.0, 2.0 Hz, 1H), 7.98 (s, 1H), 7.85-7.77 (m, 2H), 7.48-7.41 (m, 2H), 7.40-7.33 (m, 1H). MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.10FNO.sub.3, 284; found 284.

Example A54: 3-fluoro-2-hydroxy-5-(4-phenyloxazol-2-yl)benzaldehyde (Compound A90)

[0534] ##STR00518##

[0535] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 2-bromo-4-phenyloxazole. Yield: 14%. .sup.1H NMR (500 MHz, CDCl.sub.3) 11.22 (s, 1H), 10.04 (d, J=1.7 Hz, 1H), 8.19 (dd, J=2.0, 1.2 Hz, 1H), 8.10 (dd, J=11.0, 2.0 Hz, 1H), 7.98 (s, 1H), 7.84-7.78 (m, 2H), 7.49-7.41 (m, 2H), 7.40-7.32 (m, 1H). MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.10FNO.sub.3 284; found 284.

Example A55: 3-fluoro-2-hydroxy-5-(2-phenylthiazol-5-yl)benzaldehyde (Compound A91)

[0536] ##STR00519##

[0537] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 5-bromo-2-phenylthiazole. Yield 9%. .sup.1H NMR (500 MHz, CDCl.sub.3) 11.15 (s, 1H), 10.03 (d, J=1.8 Hz, 1H), 8.03 (dd, J=2.1, 1.2 Hz, 1H), 8.01 (s, 1H), 7.97 (dd, J=11.1, 2.1 Hz, 1H), 7.62-7.59 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.35 (m, 1H). MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.10FNO.sub.2S, 300; found 300.

Example A56: 5-(2-(4-chlorophenyl)thiazol-4-yl)-3-fluoro-2-hydroxybenzaldehyde (Compound A92)

[0538] ##STR00520##

[0539] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 4-bromo-2-(4-chlorophenyl)thiazole. Yield: 14%. 1H NMR (500 MHz, Chloroform-d) 11.03 (s, 1H), 10.04 (d, J=1.8 Hz, 1H), 8.06 (dd, J=2.1, 1.2 Hz, 1H), 8.00-7.95 (m, 3H), 7.47-7.43 (m, 3H). MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.9C.sub.1FNO.sub.2S, 334; found 334.

Example A57: 3-fluoro-2-hydroxy-5-(4-phenylthiazol-2-yl)benzaldehyde (Compound A93)

[0540] ##STR00521##

[0541] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 2-bromo-4-phenylthiazole. Yield: 30%. 1H NMR (500 MHz, CDCl.sub.3) 11.16 (s, 1H), 10.04 (d, J=1.8 Hz, 1H), 8.08-8.04 (m, 1H), 8.07 (s 1H), 7.99-7.97 (m, 2H), 7.50 (s, 1H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H). MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.10FNO.sub.2S 300; found 300.

Example A58: 3-fluoro-2-hydroxy-5-(5-phenyl-1,3,4-thiadiazol-2-yl)benzaldehyde (Compound A94)

[0542] ##STR00522##

[0543] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 2-bromo-5-phenyl-1,3,4-thiadiazole. Yield: 20%. .sup.1H NMR (500 MHz, Chloroform-d) 11.26 (s, 1H), 10.04 (d, J=1.7 Hz, 1H), 8.08 (dd, J=2.0, 1.2 Hz, 1H), 8.02 (tt, J=7.4, 2.1 Hz, 3H), 7.55-7.49 (m, 3H). MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.9FN.sub.2O.sub.2S 301; found 301.

Example A59: 3-fluoro-2-hydroxy-5-(3-phenyl-1,2,4-thiadiazol-5-yl)benzaldehyde (New Compound A95)

[0544] ##STR00523##

[0545] The title compound was prepared using a method similar to that as described in Example A53. However, the intermediate 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde, was synthesized and isolated according to the procedure by DiMauro et al. (J. Org. Chem, 2006, 71(10), 359-3962.)

Step 1

[0546] To a 5 mL microwave vial was added 5-bromo-3fluoro-salicaldehyde (329 mg, 1.5 mmol), bis(pinacolato)diboron (419 mg, 1.65 mmol), potassium acetate (295 mg, 3 mmol) and Pd(dppf)Cl.sub.2 (109 mg, 0.15 mmol) followed by 5 mL of dioxane. The mixture was purged with argon and heated in the microwave for 45 minutes at 140 C. The mixture was cooled, transferred to a round bottom flask, concentrated to dryness and resuspended in DCM. After filtering through celite and concentrating again, the product was purified by flash column chromatography using 0-100% DCM in Hexanes as an eluent to provide 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde as a colorless oil that solidified upon standing (237 mg, 59% yield). .sup.1H NMR (500 MHz, DMSO-d6) 11.35 (s, 1H), 10.27 (s, 1H), 7.82 (dd, J=1.6, 0.7 Hz, 1H), 7.59 (dd, J=11.1, 1.5 Hz, 1H), 1.29 (s, 12H).

Step 2

[0547] To a 2 mL microwave vial was added 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (40 mg, 0.15 mmol) from step 1a, 5-bromo-3-phenyl-1,2,4-thiadiazole (36 mg, 0.15 mmol), XPhos Pd G.sub.3 (6.4 mg, 0.05 eq.) and XPhos (3.6 mg, 0.05 eq.) dioxane (0.6 mL) and degassed 0.5M K.sub.3PO.sub.4 (0.6 mL). The microwave vessel was purged with argon and heated to 130 C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM, acidified to pH=3 with citric acid and extracted 3 times with DCM. The combined organic phases were washed with brine and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash column chromatography 0-10% MeOH/DCM. Yield (8 mg, 17%). .sup.1H NMR (500 MHz, DMSO-d6) 12.02 (bs, 1H), 10.36 (s, 1H), 8.36-8.24 (m, 3H), 8.24-8.15 (m, 1H), 7.64-7.47 (m, 3H). MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.9FN.sub.2O.sub.2S, 301; found 301.

Example A60: 3-fluoro-2-hydroxy-5-(3-phenyl-1H-1,2,4-triazol-5-yl)benzaldehyde (New Compound A96)

[0548] ##STR00524##

[0549] The title compound was prepared using a method similar to that as described in Example A53, using commercially available 5-bromo-3-phenyl-1H-1,2,4-triazole. Yield: 8%. .sup.1H NMR (500 MHz, DMSO-d6) 14.59 (s, 1H), 11.3 (bs, 1H), 10.37 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.07 (d, J=8.9 Hz, 3H), 7.66-7.37 (m, 3H). MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.10FN.sub.3O.sub.2, 284; found 284.

Example A61: 3-fluoro-5-(2-(4-((3aR,6aS)-hexahydrocvclopenta[c]pyrrol-2(1H)-yl)phenyl)thiazol-4-yl)-2-hydroxybenzaldehyde (Compound A97)

[0550] ##STR00525##

[0551] 3-fluoro-5-(2-(4-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)phenyl)thiazol-5-yl)-2-hydroxybenzaldehyde was synthesized from Compound A92 by a similar method described by Maiti et al. (Chem. Sci., 2011, 2, 57-68.) 5-(2-(4-chlorophenyl)thiazol-4-yl)-3-fluoro-2-hydroxybenzaldehyde (24 mg, 0.09 mmol), was added to a 2 mL microwave vial with (3aR,6aS)-octahydrocyclopenta[c]pyrrole hydrochloride (16 mg, 0.11 mmol), RuPhos Pd G.sub.3 (3.67 mg, 0.05 eq.) and RuPhos (2.05 mg, 0.05 eq.). The vial was sealed and evaluated and backfilled with argon three times. THF (0.3 mL) and and 1M LiHMDS in THF (0.3 mL) was added via syringe. The reaction mixture was heated to 65 C. with stirring overnight. The reaction mixture was then diluted with dichloromethane, washed with water, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash column chromatography using 0-30% ethyl acetate in hexanes. Yield: 8 mg, 22%. .sup.1H NMR (499 MHz, Chloroform-d) 10.99 (s, 1H), 10.03 (d, J=1.9 Hz, 1H), 8.06 (dd, J=2.1, 1.1 Hz, 1H), 7.95 (dd, J=11.7, 2.1 Hz, 1H), 7.90-7.85 (m, 2H), 6.60 (dd, J=8.8, 6.7 Hz, 3H), 3.55 (dd, J=9.7, 7.9 Hz, 2H), 3.12 (dd, J=9.7, 3.9 Hz, 2H), 2.82 (m, 2H), 1.89 (m, 2H), 1.83-1.73 (m, 1H), 1.69-1.59 (m, 1H) 1.55 (m, 2H). MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.21FN.sub.2O.sub.2S, 409; found 409.

Example A62: 3-fluoro-2-hydroxy-5-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde (Compound A55)

[0552] ##STR00526##

[0553] The synthesis of Intermediate B, 5-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole, was accomplished by adding 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (476 mg, 1.7 mmol), 2,5-dibromothiazole (508 mg, 2.1 mmol), XantPhos Pd G3 (83 mg, 0.09 mmol) and Xantphos (50.4 mg, 0.09 mmol) to a 40 mL screw top pressure relief vial. Dioxane (8.7 mL) and degassed 0.5M K.sub.3PO.sub.4 (8.7 mL) were added and the vial was degassed with argon. The sealed reaction vessel was heated to 140 C. for 4 hours, cooled, diluted with DCM and extracted with a water and saturated aqueous NaHCO.sub.3. The combined aqueous layers were extracted 2 times more with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. Purified using 0-70% DCM/Hexanes to provide 5-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole (274 mg, 51% yield). 1H NMR (500 MHz, DMSO-d6) 7.79 (s, 1H), 7.74-7.61 (m, 2H), 6.67-6.52 (m, 2H), 3.29-3.22 (m, 4H), 2.08-1.87 (m, 4H).

[0554] Compound A55, 3-Fluoro-2-hydroxy-5-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde, was synthesized by coupling Int. A, 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (94 mg, 0.35 mmol), with Intermediate B, 5-bromo-2-(4-(pyrrolidin-1-yl)phenyl)thiazole (109 mg, 0.35 mmol), in a method similar to that as described in Example A59. Yield: 32 mg, 25%. 1H NMR (500 MHz, DMSO-d6) 11.20 (bs, 1H), 10.31 (s, 1H), 8.14 (s, 1H), 7.96 (dd, J=11.9, 2.3 Hz, 1H), 7.82-7.72 (m, 2H), 7.64 (dd, J=2.3, 1.0 Hz, 1H), 6.66-6.57 (m, 2H), 3.31-3.28 (m, 4H), 2.02-1.94 (m, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.17FN.sub.2O.sub.2S, 369; found 369.

Example A63: 3-fluoro-2-hydroxy-5-(4-methyl-2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde (Compound A98)

[0555] ##STR00527##

[0556] The title compound was prepared using a method similar to that as described in Example A62 using 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (50 mg, 0.19 mmol) and 5-bromo-4-methyl-2-(4-(pyrrolidin-1-yl)phenyl)thiazole (58 mg, 0.19 mmol), made a method similar to that as described for Int. B in Example A62, was used to make 3-fluoro-2-hydroxy-5-(4-methyl-2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde (28 mg, 40% yield). .sup.1H NMR (500 MHz, Chloroform-d) 10.98 (s, 1H), 9.97 (d, J=1.8 Hz, 1H), 7.88-7.73 (m, 2H), 7.50-7.43 (m, 2H), 6.57 (dd, J=9.1, 2.6 Hz, 2H), 3.41-3.32 (m, 4H), 2.51 (s, 3H), 2.04 (ddd, J=6.7, 4.2, 2.9 Hz, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.19FN.sub.2O.sub.2S, 383; found 383.

Example A64: 5-hydroxy-2-(2-phenylthiazol-5-yl)isonicotinaldehyde (Compound A99)

[0557] ##STR00528##

[0558] 5-Hydroxy-2-(2-phenylthiazol-5-yl)isonicotinaldehyde was synthesized by coupling 2-bromo-5-hydroxyisonicotinaldehyde (50 mg, 0.25 mmol) with commercially available 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (71 mg, 0.25 mmol) using a method similar to that as described in Example A59. Yield: 8 mg, 11%. .sup.1H NMR (499 MHz, Chloroform-d) 10.35 (s, 1H), 10.11 (d, J=0.6 Hz, 1H), 8.55 (d, J=0.7 Hz, 1H), 8.22 (s, 1H), 8.04-7.96 (m, 2H), 7.83 (d, J=0.7 Hz, 1H), 7.52-7.42 (m, 3H). MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.10N.sub.202S, 283; found 283.

Example A65: 5-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde (Compound A100)

[0559] ##STR00529##

[0560] The title compound was prepared from 3,3-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (176 mg, 0.58 mmol, 1.1 eq) and 5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde (162 mg, 0.53 mmol, 1.0 eq.) (prepared as in Example A47) using a method similar to that as described in Example A46 to give the final title compound (22 mg, 0.06 mmol, 10% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.87 (br, 1H), 10.36 (s, 1H), 8.23 (m, 1H), 8.16 (s, 1H), 8.10 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 3.41 (t, J=6.8 Hz, 2H), 3.11 (s, 2H), 1.80 (t, J=6.8 Hz, 2H), 1.13 (s, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.20FN.sub.3O.sub.2S, 398; found, 398.

Example A66: 3-fluoro-2-hydroxy-5-(2-(3-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde (Compound A101)

[0561] ##STR00530##

[0562] 3-Fluoro-2-hydroxy-5-(2-(3-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde was synthesized using a method similar to that as described in Example A62 with 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (11 mg, 0.04 mmol) and 5-bromo-2-(3-(pyrrolidin-1-yl)phenyl)thiazole (14 mg, 0.17 mmol), made by a method similar to that as described for Int. B in Example A62, as the starting materials. Yield: 8 mg, 51%. .sup.1H NMR (500 MHz, DMSO-d6) 11.28 (s, 1H), 10.32 (s, 1H), 8.28 (s, 1H), 8.02 (dd, J=11.8, 2.3 Hz, 1H), 7.78-7.67 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.15 (dt, J=7.6, 1.1 Hz, 1H), 7.07 (t, J=2.1 Hz, 1H), 6.67 (dd, J=8.2, 2.5 Hz, 1H), 3.30-3.27 (m, 4H), 2.03-1.95 (m, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.17FN.sub.2O.sub.2S, 369; found 369.

Example A67: 3-fluoro-2-hydroxy-5-(2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazol-5-yl)benzaldehyde (New Compound A102)

[0563] ##STR00531##

[0564] The title compound was made using a method similar to that as described in Example A62 Starting from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (25 mg, 0.09 mmol) and 5-bromo-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole (29 mg, 0.09 mmol), made by a method similar to that as described for Int. B in Example A62. Yield: 31 mg, 89%. .sup.1H NMR (500 MHz, DMSO-d6) 11.24 (s, 1H), 10.31 (s, 1H), 8.65 (dd, J=2.5, 0.7 Hz, 1H), 8.19 (s, 1H), 8.01-7.94 (m, 2H), 7.65 (dd, J=2.4, 1.0 Hz, 1H), 6.56 (dd, J=9.0, 0.8 Hz, 1H), 3.45 (d, J=6.4 Hz, 4H), 2.01-1.93 (m, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FN.sub.3O.sub.2S, 370; found 370.

Example A68: 3-fluoro-2-hydroxy-5-(4-methyl-2-(3-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)benzaldehyde (Compound A103)

[0565] ##STR00532##

[0566] The title compound was made using a method similar to that as described in Example A62 using 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (46 mg, 0.17 mmol) and 5-bromo-4-methyl-2-(3-(pyrrolidin-1-yl)phenyl)thiazole (55 mg, 0.17 mmol), made in a similar manner to Int. B in Example A62. Yield: 31 mg, 47%. .sup.1H NMR (500 MHz, DMSO-d6) 11.26 (s, 1H), 10.32 (s, 1H), 7.74 (dd, J=11.7, 2.3 Hz, 1H), 7.59 (dd, J=2.3, 1.0 Hz, 1H), 7.31-7.22 (m, 1H), 7.14-7.07 (m, 1H), 7.03 (t, J=2.1 Hz, 1H), 6.65 (ddd, J=8.3, 2.5, 0.9 Hz, 1H), 3.31-3.25 (m, 4H), 2.48 (s, 3H), 2.02-1.93 (m, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.19FN.sub.2O.sub.2S, 383; found 383.

Example A69: 3-fluoro-2-hydroxy-5-(4-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazol-5-yl)benzaldehyde (Compound A104)

[0567] ##STR00533##

[0568] The title compound was made using a method similar to that as described in Example A62 starting from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (49 mg, 0.18 mmol) and 5-bromo-4-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole (59 mg, 0.18 mmol), made in a similar manner to Int. B in Example A62. Yield: 62 mg, 89%. .sup.1H NMR (499 MHz, DMSO-d6) 11.23 (s, 1H), 10.32 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 7.96 (dd, J=8.9, 2.5 Hz, 1H), 7.71 (dd, J=11.7, 2.3 Hz, 1H), 7.56 (dd, J=2.3, 1.0 Hz, 1H), 6.54 (dd, J=11.2, 8.9 Hz, 1H), 3.45 (d, J=6.5 Hz, 4H), 2.44 (s, 3H), 1.96 (h, J=3.3 Hz, 4H). MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2S, 384; found 384.

Example A70: 5-(4-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)thiazol-2-yl)-3-fluoro-2-hydroxybenzaldehyde (Compound A105)

[0569] ##STR00534##

[0570] The title compound was prepared from 3,3-Dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (153 mg, 0.51 mmol, 1.1 eq.) and 5-(4-bromothiazol-2-yl)-3-fluoro-2-hydroxybenzaldehyde (140 mg, 0.46 mmol, 1.0 eq.) (prepared as in Example A47) using a method similar to that as described in Example A46 to give the final title compound (48 mg, 0.12 mmol, 26% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.51 (br, 1H), 10.35 (s, 1H), 8.11 (dd, J=11.2 Hz, 2.0 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.79 (s, 1H), 6.56 (d, J=8.8 Hz, 2H), 3.38 (m, 2H), 3.07 (s, 2H), 1.78 (d, J=6.8 Hz, 2H), 1.12 (s, 6H). LC-MS m/z [MH].sup. calc'd for C.sub.22H.sub.21FN.sub.2O.sub.2S, 395; found, 395.

Example A71: 3-fluoro-2-hydroxy-5-(2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazol-4-yl)benzaldehyde (Compound A123)

[0571] ##STR00535##

Step 1: 4-bromo-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole

[0572] A mixture of 2,4-dibromothiazole (486 mg, 2.0 mmol, 1.0 eq.), 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (603 mg, 2.2 mmol, 1.1 eq.), potassium carbonate (828 mg, 6.0 mmol, 3.0 eq.), and PdCl.sub.2(dppf) (146 mg, 0.2 mmol, 0.1 eq.) in dioxane/water (10 mL/5 mL) was heated at 100 C. for 1 hour under nitrogen protection. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column using hexane-EtOAc (0-100%)) to give 4-bromo-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole (520 mg, 84% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.12BrN.sub.3S, 311; found, 311.

Step 2

[0573] In a 30 mL sealed cap glass vial, 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (266 mg, 1.0 mmol, 1.0 eq.), 4-bromo-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole (310 mg, 1.30 mmol, 1.0 eq.), sodium carbonate (318 mg, 3.0 mmol, 3.0 eq.) combined in 1:1 dioxane-water (10 mL) then passed nitrogen for 2 min through the mixture and added Pd(PPh.sub.3).sub.4 (112 mg, 0.1 mmol, 0.1 eq) and sealed the cap and continued at 105 C. for 8 hours. Then cooled room temperature and added water and extracted with EtOAc (225 mL) and washed with brine and dried over sodium sulfate and evaporated. The resulting crude product purified by column chromatography using hexane-EtOAc (0-100%) eluent to give the final title compound (108 mg, 29% yield) as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 11.00 (s, 1H), 10.02 (d, J=1.8 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.11-8.02 (m, 2H), 7.94 (dd, J=11.7, 2.0 Hz, 1H), 7.29 (s, 1H), 6.43 (d, J=8.9 Hz, 1H), 3.54 (m, 4H), 2.10-2.01 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FN.sub.3O.sub.2S, 370; found, 370.

Example A72: 3-fluoro-2-hydroxy-5-(2-(3-(pyrrolidin-1-yl)phenyl)thiazol-4-yl)benzaldehyde (Compound A124)

[0574] ##STR00536##

Step 1: 4-bromo-2-(3-(pyrrolidin-1-yl)phenyl)thiazole

[0575] The title compound was prepared from 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (601 mg, 2.2 mmol, 1.1 eq.) and 2,4-dibromothiazole (486 mg, 2.0 mmol, 1.0 eq.) using a method similar to that as described in Example A71 to give the desired product (540 mg, 87% yield) as off-white solid. LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.13BrN.sub.2S, 310; found, 310.

Step 2

[0576] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (133 mg, 0.5 mmol, 1.0 eq.) and 4-bromo-2-(3-(pyrrolidin-1-yl)phenyl)thiazole (155 mg, 0.5 mmol, 1.0 eq.) using a method similar to that as described in Example A46 to give the final title compound (110 mg, 41% yield) as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 11.01 (s, 1H), 10.04 (d, J=1.9 Hz, 1H), 8.06 (t, J=1.6 Hz, 1H), 7.97 (dd, J=11.6, 2.1 Hz, 1H), 7.40 (s, 1H), 7.33-7.27 (m, 2H), 7.20 (t, J=2.0 Hz, 1H), 6.66 (dt, J=8.2, 1.6 Hz, 1H), 3.39 m, 4H), 2.15-1.96 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.17FN.sub.2O.sub.2S, 369; found, 369.

Example A73: 3-fluoro-2-hydroxy-5-(2-(6-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)benzaldehyde (Compound A114)

[0577] ##STR00537##

[0578] 3-Fluoro-2-hydroxy-5-(2-(6-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)benzaldehyde was synthesized using a method similar to that as described in Example A62 using 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (69 mg, 0.35 mmol) with 5-bromo-2-(6-(pyrrolidin-1l-yl)-5-(trifluoromethyl)pyridin-3-yl)thiazole (97 mg, 0.35 mmol), synthesized using a similar method as that described for Int. B in Example A62. Yield: 50 mg, 45%. 1H NMR (499 MHz, DMSO-d6) 11.28 (s, 1H), 10.31 (s, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 8.27 (s, 1H), 8.00 (dd, J=11.9, 2.3 Hz, 1H), 7.67 (dd, J=2.3, 1.0 Hz, 1H), 3.60 (d, J=6.3 Hz, 4H), 1.98-1.88 (m, 4H). LC-MS m/z [MH].sup.+ calc'd for C.sub.20H.sub.15F.sub.4N.sub.302S, 438, found 438.

Example A74: 3-fluoro-2-hydroxy-5-(5-(3-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazol-3-yl)benzaldehyde (Compound A125)

[0579] ##STR00538##

Step 1: 3-bromo-5-(3-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazole

[0580] The title compound was prepared from 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (601 mg, 2.2 mmol, 1.1 eq.) and 3-bromo-5-chloro-1,2,4-thiadiazole (310 mg, 2.0 mmol, 1.0 eq.) using a method similar to that as described in Example A71 to give the desired product (351 mg, 57% yield) as yellow solid. LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.12BrN.sub.3S, 311; found, 311.

Step 2

[0581] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200 mg, 0.75 mmol, 1.5 eq.) and 3-bromo-5-(3-(pyrrolidin-1-yl)phenyl)-1,2,4-thiadiazole (155 mg, 0.5 mmol, 1.0 eq.) using a method similar to that as described in Example A46 to give the final title compound (42 mg, 49% yield) as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 11.21 (s, 1H), 10.06 (d, J=1.8 Hz, 1H), 8.46 (t, J=1.6 Hz, 1H), 8.39 (dd, J=11.4, 2.0 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.28-7.23 (m, 1H), 7.17 (t, J=2.1 Hz, 1H), 6.74 (dd, J=8.3, 2.5 Hz, 1H), 3.45-3.28 (m, 4H), 2.07 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FN.sub.3O.sub.2S, 370; found, 370.

Example A75: 3-fluoro-2-hydroxy-5-(2-(6-(piperidin-1-yl)pyridin-3-yl)thiazol-4-yl)benzaldehyde (Compound A126)

[0582] ##STR00539##

Step 1: 4-bromo-2-(6-(piperidin-1-yl)pyridin-3-yl)thiazole

[0583] The title compound was prepared from 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (634 mg, 2.2 mmol, 1.1 eq.) and 2,4-dibromothiazole (486 mg, 2.0 mmol, 1.0 eq.) using a method similar to that as described in Example A71 to give the desired product (352 mg, 54% yield) as yellow solid. LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3S, 325; found, 325.

Step 2

[0584] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200 mg, 0.75 mmol, 1.5 eq.) and 4-bromo-2-(6-(piperidin-1-yl)pyridin-3-yl)thiazole (162 mg, 0.5 mmol, 1.0 eq.) using a method similar to that as described in Example A46 to give the final title compound (21 mg, 11% yield) as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 11.00 (s, 1H), 10.03 (d, J=1.9 Hz, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.07 (dd, J=9.0, 2.5 Hz, 1H), 8.04 (t, J=1.6 Hz, 1H), 7.94 (dd, J=11.7, 2.1 Hz, 1H), 7.30 (s, 1H), 6.69 (d, J=9.0 Hz, 1H), 3.74-3.40 (m, 4H), 1.74-1.63 (m, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2S, 384; found, 384.

Example A76: 3-fluoro-2-hydroxy-5-(2-(6-(piperidin-1-yl)pyridin-3-yl)thiazol-5-yl)benzaldehyde (Compound A127)

[0585] ##STR00540##

Step 1: 5-bromo-2-(6-(piperidin-1-yl)pyridin-3-yl)thiazole

[0586] The title compound was prepared from 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (634 mg, 2.2 mmol, 1.1 eq.) and 2,5-dibromothiazole (486 mg, 2.0 mmol, 1.0 eq.) using a method similar to that as described in Example A71 to give the desired product (225 mg, 35% yield) as yellow solid. LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.14BrN.sub.3S, 325; found, 325.

Step 2

[0587] The title compound was prepared from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (80 mg, 0.3 mmol, 1.2 eq.) and 5-bromo-2-(6-(piperidin-1-yl)pyridin-3-yl)thiazole (81 mg, 0.25 mmol, 1.0 eq.) using a method similar to that as described in Example A46 to give the final title compound (78 mg, 81% yield) as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 10.98 (s, 1H), 9.99 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H), 8.00 (dd, J=9.0, 2.5 Hz, 1H), 7.87 (s, 1H), 7.62-7.53 (m, 2H), 6.69 (d, J=9.0 Hz, 1H), 3.77-3.48 (m, 4H), 1.75-1.63 (m, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FN.sub.3O.sub.2S, 384; found, 384.

Example A77: 5-(2-(4-(2-azaspiro[3.3]heptan-2-yl)phenyl)thiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde (Compound A116)

[0588] ##STR00541##

Step 1

[0589] Starting from 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (175 mg, 0.66 mmol) and commercially available 5-bromo-2-(4-chlorophenyl)thiazole (181 mg, 0.66 mmol) the procedure from Example A95 was used to make 5-(2-(4-chlorophenyl)thiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde, Compound A130 (68 mg, 31% yield). LC-MS m/z [MH].sup.+ calc'd for C.sub.16H.sub.9ClFNO.sub.2S, 334; found, 334.

Step 2

[0590] A method similar to that as described in Example A61 was used to make 5-(2-(4-(2-azaspiro[3.3]heptan-2-yl)phenyl)thiazol-5-yl)-3-fluoro-2-hydroxybenzaldehyde in 11% yield. 1H NMR (500 MHz, DMSO-d6) 11.22 (s, 1H), 10.31 (d, J=3.0 Hz, 1H), 8.15 (s, 1H), 7.97-7.92 (m, 1H), 7.74 (d, J=6.7 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J=2.3, 1.0 Hz, 1H), 6.50-6.44 (m, 2H), 3.87 (s, 4H), 2.19 (t, J=7.6 Hz, 4H), 1.87-1.75 (m, 2H). LC-MS m/z [MH].sup.+ calc'd for C.sub.22H.sub.19FN.sub.2O.sub.2S, 395; found, 395.

Example A78: 5-hydroxy-2-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)isonicotinaldehyde (Compound A112)

[0591] ##STR00542##

Step 1

[0592] The starting material, Int. B, was synthesized using a similar method as described in Example A62. Int. C, 2-(4-(pyrrolidin-1-yl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole, was made using a similar method used to make 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde in Example A59. However, the Int. C was not purified before using in the next reaction. After completion of the reaction, the crude mixture was taken up in DCM filtered through celite and concentrated to dryness.

Step 2

[0593] Using a similar method as described in Example A59, crude 2-(4-(pyrrolidin-1-yl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (123 mg), Int. C, and 2-bromo-5-hydroxyisonicotinaldehyde (70 mg, 0.35 mmol) were used to make 5-hydroxy-2-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-5-yl)isonicotinaldehyde (12 mg, Yield: 10%). .sup.1H NMR (500 MHz, DMSO-d6) 11.29 (bs, 1H), 10.39 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.83-7.73 (m, 2H), 6.67-6.55 (m, 2H), 3.32-3.29 (m, 4H), 2.36-1.61 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17N.sub.302S, 352; found 352.

Example B1: 3-fluoro-2-hydroxy-5-((4-(pyrrolidin-1-yl)phenyl)ethynyl)benzaldehyde (Compound No. B1)

[0594] ##STR00543##

Step 1: 1-(4-ethynylphenyl)pyrrolidine

[0595] ##STR00544##

[0596] To a solution of TMS-diazomethane (17.14 mL, 34.29 mmol) in THF (50 mL) was added BuLi (13.72 mL, 34.29 mmol, 2 M in THF) at 78 C. The reaction was stirred for 30 min at 78 C. Then 4-(pyrrolidin-1-yl)benzaldehyde (5 g, 28.57 mmol) was added. The reaction was stirred for another 1 h at 78 C. The mixture was quenched with sat. NH.sub.4Cl (150 mL) and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200:1 to 100:1) to give the desired product as a white solid (2.1 g, 43% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.35 (d, J=8.4 Hz, 2H), 6.46 (d, J=8.4 Hz, 2H), 3.29 (t, J=6.2 Hz, 4H), 2.98 (s, 1H), 2.01 (t, J=6.2 Hz, 4H).

Step 2

[0597] A mixture of 5-bromo-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde (988 mg, 2.92 mmol), 1-(4-ethynylphenyl)pyrrolidine (600 mg, 3.51 mmol), TBAF.3H.sub.2O (5.5 g, 17.54 mmol), and Pd(PPh.sub.3).sub.2Cl.sub.2 (62 mg, 0.09 mmol) in THF (20 mL) was heated at 80 C. for 2 h. The mixture was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 10:1) to give the PMB-protected penultimate product (417 mg, 33% yield). The PMB-protected intermediate (100 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL) and TFA (3 mL) was added. The reaction was stirred for 30 min at room temp. The solvent was removed in vacuo and the residue was purified by prep-TLC (petroleum ether/ethyl acetate=5:1) to afford the title compound as yellow solid (23 mg, 32% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.00 (s, 1H), 9.90 (s, 1H), 7.52 (s, 1H), 7.46 (d, J=11.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 3.31 (m, 4H), 2.02 (m, 4H); LC-MS m/z [MH].sup. calc'd for C.sub.19H.sub.16FNO.sub.2, 308; found, 308.

Example B2: 3-fluoro-2-hydroxy-5-((4-(piperidin-1-yl)phenyl)ethynyl)benzaldehyde (Compound No. B2)

[0598] ##STR00545##

Step 1: 1-(4-ethynylphenyl)piperidine

[0599] ##STR00546##

[0600] To a solution of TMS-diazomethane (6.3 mL, 12.6 mmol) in THF (20 mL) was added BuLi (6.3 mL, 12.6 mmol, 2 M in THF) at 78 C. The reaction was stirred for 30 min at 78 C. Then 4-(piperidin-1-yl)benzaldehyde (1.89 g, 10 mmol) was added in THF. The reaction was stirred for another 1 h at 78 C. The mixture was quenched with sat. NH.sub.4Cl (100 mL) and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography to give the desired product (1.42 g, 77% yield).

Step 2

[0601] The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-ethynylphenyl)piperidine (185 mg, 1.0 mmol) using a method similar to that as described in Example B1 to give the title compound as yellow solid (91 mg, 28% yield). .sup.1H NMR (DMSO-d6, 400 MHz) (11.33 (br, 1H), 10.26 (s, 1H), 7.67 (d, J=11.2 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 3.24 (m, 4H), 1.57 (m, 6H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FNO.sub.2, 324; found, 324.

Example B3: 3-fluoro-2-hydroxy-5-((4-morpholinophenyl)ethynyl)benzaldehyde (Compound No. B3)

[0602] ##STR00547##

Step 1: 4-(4-ethynylphenyl)morpholine

[0603] ##STR00548##

[0604] To a solution of TMS-diazomethane (6.3 mL, 12.6 mmol) in THF (20 mL) was added BuLi (6.3 mL, 12.6 mmol, 2 M in THF) at 78 C. The reaction was stirred for 30 min at 78 C. Then 4-morpholinobenzaldehyde (2 g, 10.5 mmol) was added. The reaction was stirred for another 1 h at 78 C. The mixture was quenched with sat. NH.sub.4Cl (100 mL) and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200:1 to 100:1) to give the desired product as a white solid (1.1 g, 56% yield).

Step 2

[0605] A mixture of 5-bromo-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde (561 mg, 3.0 mmol), 4-(4-ethynylphenyl)morpholine (1.01 g, 3.0 mmol), TBAF.3H.sub.2O (5.68 g, 18.0 mmol), and Pd(PPh.sub.3).sub.2Cl.sub.2 (63 mg, 0.09 mmol) in THF (20 mL) was heated at 80 C. for 3 h. The mixture was cooled to rt, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1 to 1:1) to give PMB-protected penultimate product as yellow solid (410 mg, 31% yield). PMB-protected intermediate (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and TFA (3 mL) was added. The reaction was stirred for 30 min at rt. The solvent was removed in vacuo and the residue was purified by prep-TLC (petroleum ether/ethyl acetate=1:1) to afford the title product as a yellow solid (27 mg, 37% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.20 (s, 1H), 7.43-7.46 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 3.73 (m, 4H), 3.17 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FNO.sub.3, 326; found, 326.

Example B4: 2-fluoro-6-hydroxy-4-((4-(pyrrolidin-1-yl)phenyl)ethynyl)benzaldehyde (Compound No. B4)

[0606] ##STR00549##

[0607] A mixture of 4-bromo-2-fluoro-6-hydroxybenzaldehyde (900 mg, 4.1 mmol), 1-(4-ethynylphenyl)pyrrolidine (847 mg, 5.0 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (290 mg, 0.4 mmol), and TBAF.3H.sub.2O (7.8 g, 24.8 mmol) in THF (30 mL) was refluxed for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (50 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 20:1) to give the title product as a yellow solid (900 mg, 71% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.53 (s, 1H), 10.18 (s, 1H), 7.40 (d, J=8.8 Hz, 2H), 6.83 (s, 1H), 6.71 (m, 1H), 6.51 (d, J=8.4 Hz, 2H), 3.32 (m, 4H), 2.03 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FNO.sub.2, 310; found, 310.

Example B5: 2-fluoro-6-hydroxy-4-((4-(piperidin-1-yl)phenyl)ethynyl)benzaldehyde (Compound No. B5)

[0608] ##STR00550##

[0609] The title compound was prepared from 4-bromo-2-fluoro-6-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-ethynylphenyl)piperidine (185 mg, 1.0 mmol) using a method similar to that as described in Example B1 to give the title compound as a yellow solid (181 mg, 56% yield). .sup.1H NMR (DMSO-d6, 400 MHz) 11.37 (br, 1H), 10.22 (s, 1H), 7.39 (d, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.88 (m, 2H), 3.28 (m, 4H), 1.58 (m, 6H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.18FNO.sub.2, 324; found, 324.

Example B6: 2-fluoro-6-hydroxy-4-((4-morpholinophenyl)ethynyl)benzaldehyde (Compound No. B6)

[0610] ##STR00551##

[0611] The title compound was prepared from 4-bromo-2-fluoro-6-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 4-(4-ethynylphenyl)morpholine (187 mg, 1.0 mmol) using a method similar to that as described in Example B1 to give the title compound as a yellow solid (134 mg, 41% yield). .sup.1H NMR (DMSO-d6, 400 MHz) 11.38 (br, 1H), 10.22 (s, 1H), 7.45 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.91 (m, 2H), 3.73 (m, 4H), 3.22 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16FNO.sub.3, 326; found, 326.

Example B7: 2-hydroxy-6-methoxy-4-((4-(pyrrolidin-1-yl)phenyl)ethynyl)benzaldehyde (Compound No. B7)

[0612] ##STR00552##

[0613] A mixture of 4-bromo-2-hydroxy-6-methoxybenzaldehyde (462 mg, 2.0 mmol), 1-(4-ethynylphenyl)pyrrolidine (340 mg, 2.0 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (140 mg, 0.2 mmol), and TBAF.3H.sub.2O (3.78 g, 12.0 mmol) in THF (30 mL) was refluxed for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (50 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=300:1:1 to 200:1:20) to give the title product as a yellow solid (320 mg, 50% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) 12.03 (s, 1H), 10.26 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 6.64 (s, 1H), 6.47-6.53 (m, 3H), 3.60 (s, 3H), 3.31 (m, 4H), 2.03 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19NO.sub.3, 322; found, 322.

Example B8: 2-hydroxy-3-methoxy-5-((4-morpholinophenyl)ethynyl)benzaldehyde (Compound No. B8)

[0614] ##STR00553##

[0615] A mixture of 5-bromo-3-methoxy-2-(4-methoxybenzyloxy)benzaldehyde (1.3 g, 3.74 mmol), 4-(4-ethynylphenyl)morpholine (700 mg, 3.74 mmol), TBAF.3H.sub.2O (7 g, 22.44 mmol), and Pd(PPh.sub.3).sub.2Cl.sub.2 (79 mg, 0.11 mmol) in THF (20 mL) was heated at 80 C. for 2 h. The mixture was cooled to rt, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL3). The organic extracts were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1 to 1:1) to give a PMB-protected penultimate product (880 mg, 51% yield). The PMB-protected intermediate (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and TFA (3 mL) was added. The reaction was stirred for 30 min at room temperature. The solvent was removed in vacuo, and the residue was purified by prep-TLC (petroleum ether/ethyl acetate=1:1) to afford the title product as a yellow solid (31 mg, 42% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.23 (s, 1H), 9.90 (s, 1H), 7.44 (m, 2H), 7.38 (s, 1H), 7.22 (s, 1H), 6.89 (m, 2H), 3.93 (s, 3H), 3.88 (m, 4H), 3.23 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19NO.sub.4, 338; found, 338.

Example B9: N-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide (Compound No. B9)

[0616] ##STR00554##

Step 1: 3-fluoro-2-hydroxy-5-nitrobenzaldehyde

[0617] In a 125 mL round bottom flask, HNO.sub.3 (2.23 mL, 50.0 mmol) in TFA (20 mL) was added to a solution of 3-fluoro-2-hydroxybenzaldehyde (2 g, 14.3 mmol) in acetic acid (10 mL) at 0 C. The reaction was stirred for 1 hour at 0 C. The solution was poured into ice-water, and the resulting precipitate was filtered and washed with petroleum ether to give 3-fluoro-2-hydroxy-5-nitrobenzaldehyde (1.8 g, 68% yield), which was used for next reaction without further purification. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.67 (s, 1H), 10.05 (s, 1H), 8.45 (s, 1H), 8.27 (dd, J=10.0 Hz, 2.8 Hz, 1H).

Step 2: 2-(3-fluoro-2-(4-methoxybenzyloxy)-5-nitrophenyl)-1,3-dithiane

[0618] BF.sub.3.Et.sub.2O (4.9 mL, 18.2 mmol) was added to a mixture of 3-fluoro-2-hydroxy-5-nitrobenzaldehyde (2.8 g, 15.1 mmol) and propane-1,3-dithiol (1.82 mL, 18.2 mmol) in dichloromethane (30 mL). The reaction was stirred overnight at room temperature. The mixture was poured into ice water and the resulting precipitate was filtered and washed with petroleum ether/dichloromethane (10:1). The cake was dried to give intermediate (3.9 g, 94% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 12.01 (br, 1H), 8.09 (m, 2H), 5.73 (s, 1H), 3.17 (m, 2H), 2.91 (m, 2H), 2.13 (m, 1H), 1.77 (m, 1H). The intermediate (2.75 g, 10.0 mmol) was dissolved in DMF (20 mL) then added PMBCl (3.12 g, 20.0 mmol) and potassium carbonate (4.1 g, 30.0 mmol, 3 eq.) to the reaction mixture. The reaction was heated at 90 C. for 3 hours. The mixture was poured into water and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 2-(3-fluoro-2-(4-methoxybenzyloxy)-5-nitrophenyl)-1,3-dithiane (3.3 g, 84% yield), which was used for the next reaction without further purification.

Step 3: 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)aniline

[0619] A mixture of 2-(3-fluoro-2-(4-methoxybenzyloxy)-5-nitrophenyl)-1,3-dithiane (2.1 g, 5.3 mmol) and iron (3 g, 53.2 mmol) in acetic acid (20 mL) was heated at 60 C. for 3 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was neutralized with sodium bicarbonate to pH 8-9, and the organic layer was separated. The water phase was re-extracted with ethyl acetate for two more times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)aniline (1.2 g, 62% yield), which was used for the next reaction without further purification. .sup.1H NMR (DMSO-d6, 400 MHz) : 7.38 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H), 6.50 (s, 1H), 6.34 (d, J=13.2 Hz, 1H), 5.42 (s, 1H), 5.31 (br, 2H), 4.81 (s, 2H), 3.77 (s, 3H), 3.02 (m, 2H), 2.89 (m, 2H), 2.12 (m, 1H), 1.69 (m, 1H).

Step 4: N-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)benzamide

[0620] A solution of 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)aniline (500 mg, 1.37 mmol), benzoyl chloride (289 mg, 2.05 mmol), and triethylamine (415 mg, 4.11 mmol) in dichloromethane (20 mL) was stirred overnight at room temperature. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 5:1) to give N-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)benzamide (620 mg, 96% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.24FNO.sub.3S.sub.2, 470; found, 470.

Step 5: N-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide

[0621] A mixture of N-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl) benzamide (620 mg, 1.32 mmol) and DMP (1.12 g, 2.64 mmol) in acetonitrile/dichloromethane/water (16 mL/2 mL/2 mL) was stirred overnight at 45 C. The mixture was filtered and the cake was washed with dichloromethane. The filtrate and wash were washed with 5% sodium bicarbonate solution. The water phase was re-extracted with dichloromethane for two more times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=50:1:1 to 20:1:1) to give PMB-protected N-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide (250 mg, 50% yield). The PMB-protected N-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide (250 mg, 0.66 mmol) was dissolved in dichloromethane (5 mL) and added TFA (230 mg, 1.98 mmol) to the mixture. The reaction was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=20:1:1 to 10:1:1) to give N-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide (60 mg, 0.23 mmol, 35% yield) as a white solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.74 (s, 1H), 10.39 (s, 1H), 10.32 (s, 1H), 7.90-8.04 (m, 4H), 7.52-7.61 (m, 3H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.10FNO.sub.3, 260; found, 260.

Example B10: 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-phenylurea (Compound No. B10)

[0622] ##STR00555##

Step 1: 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-phenylurea

[0623] DPPA (1.1 g, 4 mmol) and triethylamine (0.42 g, 4 mmol) were added to a solution of benzoic acid (0.35 g, 2.9 mmol) in dioxane (10 mL). The reaction was stirred for 30 min at room temperature. Then, 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)aniline (0.5 g, 1.4 mmol, 1 eq.) was added to the reaction mixture and the reaction was heated at 90 C. for 3 hours. The solvent was removed and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=30:1:1 to 10:1:1) to give 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-phenylurea (610 mg, 92% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.25FN.sub.2O.sub.3S.sub.2, 485; found, 485.

Step 2: 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-phenylurea

[0624] A solution of 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-phenylurea (300 mg, 0.62 mmol), MeI (1.76 g, 12.4 mmol), and NaHCO.sub.3 (1 g, 12.4 mmol) in acetonitrile/water (15 mL/3 mL) was stirred overnight at 50 C. The solution was diluted with water and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=10:1:1 to 5:1:1) to give PMB-protected 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-phenylurea (170 mg, 70% yield). The PMB-protected 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-phenylurea (80 mg, 0.20 mmol) was dissolved in 6 N HCl/dioxane (5 mL) and the reaction was stirred for 30 min at room temperature. The solution was poured into ice-cold sat. sodium bicarbonate and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC (CH.sub.2Cl.sub.2/MeOH=20:1) to give 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-phenylurea (30 mg, 0.23 mmol, 54% yield) as an off-white solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.50 (s, 1H), 10.28 (s, 1H), 8.78 (s, 1H), 8.70 (s, 1H), 7.74 (m, 1H), 7.46 (m, 3H), 7.27 (m, 2H), 6.97 (m, 1H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.11FN.sub.2O.sub.3, 275; found, 275.

Example B11: 3-fluoro-5-formyl-4-hydroxy-N-phenylbenzamide (Compound No. B11)

[0625] ##STR00556##

Step 1: 3-fluoro-5-formyl-4-hydroxybenzoic acid

[0626] A solution of HMPA (28 g, 0.2 mol, 2 eq.) in TFA (20 mL) was added to a solution of 3-fluoro-4-hydroxybenzoic acid (15.6 g, 0.1 mol) in TFA (30 mL). The reaction was stirred overnight at 100 C. The solution was cooled to room temperature and poured into 3 M HCl (200 mL). The mixture was stirred for 30 min and the resulting precipitate was filtered and dried to give 3-fluoro-5-formyl-4-hydroxybenzoic acid, which was used for the next reaction without further purification. LC-MS m/z [MH].sup. calc'd for C.sub.8H.sub.5FO.sub.4, 183; found, 183.

Step 2: 3-fluoro-5-formyl-4-hydroxy-N-phenylbenzamide

[0627] HATU (0.63 g, 1.7 mmol) and N-Methylmorpholine (0.67 g, 6.6 mmol) were added to a mixture of 3-fluoro-5-formyl-4-hydroxybenzoic acid (0.2 g, 1.1 mmol) and aniline hydrochloride (0.43 g, 3.3 mmol) in dichloromethane (30 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the residue dissolved in a mixture of ether (6 mL) and 4 M HCl (6 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL3). The organic extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=10:1:1 to 2:1:1) to give the desired 3-fluoro-5-formyl-4-hydroxy-N-phenylbenzamide product as light yellow solid (4% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.67 (br, 1H), 10.36 (s, 1H), 10.30 (s, 1H), 8.20 (s, 1H), 8.11 (dd, J=12.0 Hz, 2.4 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.11 (m, 1H); LC-MS m/z [MH].sup. calc'd for C.sub.14H.sub.10FNO.sub.3, 258; found, 258.

Example B12: 3-fluoro-5-formyl-4-hydroxy-N-(4-(pyrrolidin-1-yl)phenyl)benzamide (Compound No. B12)

[0628] ##STR00557##

[0629] The title compound was synthesized in a similar manner as described for 3-fluoro-5-formyl-4-hydroxy-N-phenylbenzamide in Example B11 to obtain the desired product as a green solid (67% yield). .sup.1H NMR (DMSO-d6,400 MHz) : 11.57 (br, 1H), 10.35 (s, 1H), 10.03 (br, 1H), 8.18 (s, 1H), 8.09 (dd, J=12.0 Hz, 2.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.0 Hz, 2H), 3.22 (m, 4H), 1.95 (m, 4H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.17FN.sub.2O.sub.3, 329; found, 329.

Example B13: 3-fluoro-5-formyl-4-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (Compound No. B13)

[0630] ##STR00558##

Step 1: 3-fluoro-5-formyl-4-methoxybenzoic acid

[0631] A mixture of 3-fluoro-5-formyl-4-hydroxybenzoic acid (0.5 g, 2.7 mmol), MeI (1.16 g, 8.2 mmol), and potassium carbonate (1.13 g, 8.2 mmol) in DMF (5 mL) was heated at 50 C. for 3 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL3). The organic extracts were combined, washed with brine (10 mL2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 20:1) to give methyl ether intermediate (0.58 g, quantitative yield). The methyl ether intermediate (0.58 g, 2.7 mmol) was dissolved in THF/water (2 mL/2 mL), and LiOH.H.sub.2O (0.57 g, 13.5 mmol) was added. The reaction was stirred for 1 hour at room temperature. The pH of the reaction system was adjusted to 4-5 and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 3-fluoro-5-formyl-4-methoxybenzoic acid (0.5 g, 94% yield), which was used for the next reaction without further purification.

Step 2: 3-fluoro-5-formyl-4-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide

[0632] A drop of DMF was added to a solution of 3-fluoro-5-formyl-4-methoxybenzoic acid (0.2 g, 1.0 mmol) and oxalyl chloride (0.39 g, 3.0 mmol) in DCM (5 mL). The reaction was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was co-evaporated two times with dichloromethane. The residue was then dissolved in dichloromethane (5 mL). 4-Trifluoromethylanaline (0.5 g, 3.0 mmol), DMAP (0.02 g, 0.1 mmol), and triethylamine (0.5 g, 5.0 mmol) were added. The reaction was stirred for 1 hour. LC-MS showed formation of the desired product. The solvent was removed and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=20:1:1 to 5:1:1) to give 3-fluoro-5-formyl-4-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (130 mg, 38% yield), containing 4-trifluoromethylanaline inside at the same spot. LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.11F.sub.4NO.sub.3, 342; found, 342.

Step 3: 3-fluoro-5-formyl-4-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide

[0633] BBr.sub.3 (191 mg, 0.76 mmol) was added to a solution of 3-fluoro-5-formyl-4-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (130 mg, 0.38 mmol) in dichloromethane (5 mL) at 78 C. The reaction was stirred for 30 min at room temperature. The solution was diluted with dichloromethane and washed with sat. sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was removed in vacuo and the residue was co-evaporated two times with dichloromethane. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=20:1:1 to 5:1:1) to give 3-fluoro-5-formyl-4-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (50 mg, 40% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.77 (br, 1H), 10.62 (s, 1H), 10.36 (s, 1H), 8.22 (s, 1H), 8.13 (dd, J=12.0 Hz, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.9F.sub.4NO.sub.3, 328; found, 328.

Example B14: N-(3-Chloro-4-(trifluoromethyl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound No. B14)

[0634] ##STR00559##

[0635] The title product was synthesized in a similar manner as described for 3-fluoro-5-formyl-4-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide in Example B13. Yield for step 3: 22%, brown solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.84 (br, 1H), 10.74 (s, 1H), 10.37 (s, 1H), 8.20 (m, 2H), 8.11 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.92 (m, 2H); LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.8ClF.sub.4NO.sub.3, 362; found, 362.

Example B15: 3-fluoro-5-formyl-4-hydroxy-N-(4-(pyrrolidin-1-yl)phenyl)benzenesulfonamide (Compound B17)

[0636] ##STR00560##

Step 1: 3-fluoro-5-formyl-4-hydroxybenzene-1-sulfonyl Chloride

[0637] Chlorosulfonic acid (1.66 g, 14.3 mmol, 10 eq.) was added dropwise to a solution of 3-fluoro-2-hydroxybenzaldehyde (200 mg, 1.4 mmol, 1.0 eq.) in dichloromethane (10 mL) at 0 C. The reaction was stirred overnight at room temperature. The reaction mixture was poured into ice-water (30 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude 3-fluoro-5-formyl-4-hydroxybenzene-1-sulfonyl chloride (390 mg, quantitative yield), which was used in next reaction without further purification. LC-MS m/z [MHCl].sup. calc'd for C.sub.7H.sub.4C.sub.1FO.sub.4S, 219; found, 219.

Step 2

[0638] A solution of 3-fluoro-5-formyl-4-hydroxybenzene-1-sulfonyl chloride (390 mg, 1.64 mmol, 1.0 eq.), 4-(pyrrolidin-1-yl)aniline (664 mg, 4.10 mmol, 2.5 eq.), and N-methyl morpholine (497 mg, 4.92 mmol, 3.0 eq.) in dichloromethane (10 mL) was stirred for 5 hours. The reaction mixture was poured into 4 N HCl. The reaction was stirred for 3 hours and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and prep-TLC to give 3-fluoro-5-formyl-4-hydroxy-N-(4-(pyrrolidin-1-yl)phenyl)benzenesulfonamide (23 mg, 0.06 mmol, 4% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 12.03 (br, 1H), 10.26 (br, 1H), 9.57 (s, 1H), 7.75 (s, 1H), 7.62 (dd, J=10.4 Hz, 2.4 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.38 (d, J=8.0 Hz, 2H), 3.13 (m, 4H), 1.90 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.17FN.sub.2O.sub.4S, 365; found, 365.

Example B16: 3-fluoro-5-formyl-4-hydroxy-N-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzamide (Compound B59)

[0639] ##STR00561##

Step 1: 5-nitro-2-(pyrrolidin-1-yl)pyrimidine

[0640] A mixture of 2-chloro-5-nitropyrimidine (2 g, 12.6 mmol, 1.0 eq.), pyrrolidine (1.3 g, 18.9 mmol, 1.5 eq.), and potassium carbonate (3.5 g, 25.2 mmol, 2.0 eq.) in DMF (10 mL) was stirred for 5 hours at room temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 5-nitro-2-(pyrrolidin-1-yl)pyrimidine (2.3 g, 94% yield), which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.8H.sub.10N.sub.4O.sub.2, 195; found, 195.

Step 2: 2-(pyrrolidin-1-yl)pyrimidin-5-amine

[0641] A mixture of 5-nitro-2-(pyrrolidin-1-yl)pyrimidine (2.3 g, 11.9 mmol, 1.0 eq.) and Pd/C (0.2 g) in methanol (10 mL) was hydrogenated for 2 hours. Pd/C was filtered off and washed with methanol. The filtrate and wash were combined and concentrated to give 2-(pyrrolidin-1-yl)pyrimidin-5-amine (1.63 g, 84% yield), which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.8H.sub.12N.sub.4, 165; found, 165.

Step 3

[0642] HATU (0.71 g, 1.87 mmol, 1.5 eq.) and N-methyl morpholine (0.4 g, 3.74 mmol, 3.0 eq.) were added to a mixture of 3-fluoro-5-formyl-4-hydroxybenzoic acid (0.23 g, 1.25 mmol, 1.0 eq.) and 2-(pyrrolidin-1-yl)pyrimidin-5-amine (0.5 g, 3.05 mmol, 2.5 eq.) in dichloromethane (30 mL). The mixture was stirred overnight at 30 C. The solvent was removed and the residue dissolved in a mixture of dioxane (6 mL) and 4 N HCl (6 mL). The mixture was stirred for 2 hours at 55 C. The mixture was diluted with water (20 mL) and washed with ethyl acetate (30 mL). The wash was discarded. The water phase was neutralized with sodium bicarbonate and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/acetone=20:1 to 5:1) to give 3-fluoro-5-formyl-4-hydroxy-N-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzamide (15 mg, 0.05 mmol, 4% yield) as a pale yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.70 (br, 1H), 10.35 (s, 1H), 10.22 (br, 1H), 8.59 (s, 2H), 8.20 (s, 1H), 8.07 (dd, J=11.6 Hz, 2.0 Hz, 1H), 3.48 (m, 4H), 1.94 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.16H.sub.15FN.sub.4O.sub.3, 331; found, 331.

Example B17: 3-fluoro-5-formyl-4-hydroxy-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)benzamide (Compound B61)

[0643] ##STR00562##

Step 1: 5-nitro-2-(pyrrolidin-1-yl)pyridine

[0644] A mixture of 2-chloro-5-nitropyridine (2 g, 12.6 mmol, 1.0 eq.), pyrrolidine (1.3 g, 18.9 mmol, 1.5 eq.), and potassium carbonate (3.5 g, 25.2 mmol, 2.0 eq.) in DMF (10 mL) was stirred for 5 hours at room temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 5-nitro-2-(pyrrolidin-1-yl)pyridine (2.4 g, 99% yield), which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.9H.sub.11N.sub.3O.sub.2, 194; found, 194.

Step 2: 6-(pyrrolidin-1-yl)pyridin-3-amine

[0645] A mixture of 5-nitro-2-(pyrrolidin-1-yl)pyridine (2 g, 10.4 mmol, 1.0 eq.) and Pd/C (0.2 g) in methanol (10 mL) was hydrogenated for 2 h. Pd/C was filtered off and washed with methanol. The filtrate and wash were combined and concentrated to give 6-(pyrrolidin-1-yl)pyridin-3-amine (1.38 g, 82% yield), which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.9H.sub.13N.sub.3, 164; found, 164.

Step 3

[0646] HATU (1.24 g, 3.26 mmol, 1.5 eq.) and N-methyl morpholine (0.66 g, 6.51 mmol, 3.0 eq.) were added to a mixture of 3-fluoro-5-formyl-4-hydroxybenzoic acid (0.4 g, 2.17 mmol, 1.0 eq.) and 6-(pyrrolidin-1-yl)pyridin-3-amine (0.89 g, 5.43 mmol, 2.5 eq.) in DCM (30 mL). The mixture was stirred overnight at 30 C. The solvent was removed and the residue dissolved in a mixture of dioxane (6 mL) and 4 N HCl (6 mL). The mixture was stirred for 3 h at 55 C. The mixture was neutralized with lithium hydroxide to pH 9-10 and washed with dichloromethane and ethyl acetate each for two times. The water phase was then treated with HCl to pH-3 then to pH-7-8 with sodium bicarbonate. The mixture was then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/acetone=20:1 to 5:1) to give 3-fluoro-5-formyl-4-hydroxy-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)benzamide (75 mg, 0.23 mmol, 11% yield) as a pale yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.69 (br, 1H), 10.35 (br, 1H), 10.11 (br, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.07 (d, J=10.8 Hz, 1H), 7.82 (m, 1H), 6.47 (d, J=9.2 Hz, 1H), 3.45 (m, 4H), 1.94 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.17H.sub.16FN.sub.3O.sub.3, 330; found, 330.

Example B18: 3-fluoro-5-formyl-4-hydroxy-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)benzamide (Compound B63)

[0647] ##STR00563##

Step 1: 1-methyl-4-(4-nitrophenyl)-1H-pyrazole

[0648] A mixture of 4-iodo-1-methyl-1H-pyrazole (0.7 g, 3.4 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (1.1 g, 5.0 mmol, 1.5 eq.), potassium carbonate (1.4 g, 10.1 mmol, 3.0 eq.) and Pd(dppf)Cl.sub.2 (0.2 g, 0.34 mmol, 0.1 eq.) in dioxane/water (30 mL/10 mL) was heated for 3 hours at 90 C. The mixture was concentrated, diluted with water (30 mL), and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc/DCM=50:1:1 to 5:1:1) to give 1-methyl-4-(4-nitrophenyl)-1H-pyrazole (0.6 g, 88% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.9N.sub.3O.sub.2, 204; found, 204.

Step 2: 4-(1-methyl-1H-pyrazol-4-yl)aniline

[0649] A mixture of 1-methyl-4-(4-nitrophenyl)-1H-pyrazole (0.6 g, 3.0 mmol, 1.0 eq.) and Pd/C (0.1 g) in methanol (10 mL) was hydrogenated for 2 hours. Pd/C was filtered off and washed with methanol. The filtrate and wash were combined and concentrated to give 4-(1-methyl-1H-pyrazol-4-yl)aniline (0.48 g, 94% yield) as a grey solid, which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.11N.sub.3, 174; found, 174.

Step 3

[0650] HATU (0.66 g, 1.74 mmol, 1.5 eq.) and N-methyl morpholine (0.35 g, 3.48 mmol, 3.0 eq.) were added to a mixture of 3-fluoro-5-formyl-4-hydroxybenzoic acid (0.21 g, 1.16 mmol, 1.0 eq.) and 4-(1-methyl-1H-pyrazol-4-yl)aniline (0.4 g, 2.31 mmol, 2.0 eq.) in dichloromethane (30 mL). The reaction was stirred overnight at rt. The resulting precipitate was filtered and dissolved in a mixture of dioxane (6 mL) and 3 N HCl (6 mL). The mixture was stirred for 2 hours at room temperature and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The solid was stirred in dichloromethane (10 mL) for 10 min and filtered. The filtrate was concentrated, dissolved in dichloromethane (5 mL), and petroleum ether was added slowly. The resulting precipitate was collected and dried to give 3-fluoro-5-formyl-4-hydroxy-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)benzamide (45 mg, 0.13 mmol, 11% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.65 (br, 1H), 10.35 (s, 1H), 10.27 (s, 1H), 8.19 (s, 1H), 8.09 (m, 2H), 7.83 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.86 (s, 3H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.14FN.sub.3O.sub.3, 340; found, 340.

Example B19: 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-(4-fluorophenyl)urea (Compound B64)

[0651] ##STR00564##

Step 1: 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)benzoic Acid

[0652] A mixture of 3-(1,3-dithian-2-yl)-5-fluoro-4-hydroxybenzoic acid (1 g, 3.6 mmol, 1.0 eq.), PMBCl (1.2 g, 7.6 mmol, 2.1 eq.), and potassium carbonate (1 g, 7.2 mmol, 2.0 eq.) in DMF (5 mL) was heated for 3 hours at 90 C. The mixture was poured into water (30 mL) and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude intermediate (1.9 g, quantitative yield), which was used for next reaction without further purification. The crude intermediate (1.9 g, 3.6 mmol, 1.0 eq.) was dissolved in water/THF (5 mL/5 mL) and LiOH.H.sub.2O (0.76 g, 18.0 mmol, 5.0 eq.) was added. The reaction was stirred for 5 hours at 80 C. pH of the system was adjusted to 3-4 with 5% KHSO.sub.4. The resulting mixture was extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)benzoic acid (1.4 g, quantitative yield), which was used for next reaction without further purification. LC-MS m/z [MH].sup. calc'd for C.sub.19H.sub.19FO.sub.4S.sub.2, 393; found, 393.

Step 2: 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-(4-fluorophenyl)urea

[0653] A solution of 3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)benzoic acid (0.3 g, 0.76 mmol, 1.0 eq.), DPPA (251 mg, 0.91 mmol, 1.2 eq.), and TEA (231 mg, 2.28 mmol, 3.0 eq.) in dioxane (10 mL) was stirred for 30 min at room temperature and 4-fluoroaniline (169 mg, 1.52 mmol, 2.0 eq.) was added. The reaction was then heated overnight at 90 C. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=20:1 to 3:1) to give 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-(4-fluorophenyl)urea (240 mg, 63% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.24F.sub.2N.sub.2O.sub.3S.sub.2, 503; found, 503.

Step 3

[0654] MeI (6.5 g, 45.8 mmol, 100 eq.) was added to a mixture of 1-(3-(1,3-dithian-2-yl)-5-fluoro-4-(4-methoxybenzyloxy)phenyl)-3-(4-fluorophenyl)urea (230 mg, 0.46 mmol, 1.0 eq.) and NaHCO.sub.3 (770 mg, 9.17 mmol, 20.0 eq.) in acetonitrile/water (30 mL/6 mL). The reaction was heated for 6 hours at 40 C. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was stirred in dichloromethane (3 mL) and the solid was collected to give the intermediate (100 mg). The intermediate (100 mg) was dissolved in dioxane (2 mL) and 6 N HCl/dioxane (3 mL) was added. The reaction was stirred for 1 hour at room temperature. The solution was poured into ice-cold sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The solid was stirred in dichloromethane (3 mL) for 10 min and filtered. The cake was collected and dried to give 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-(4-fluorophenyl)urea (45 mg, 0.15 mmol, 34% yield) as an off-white solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.51 (br, 1H), 10.27 (s, 1H), 8.77 (d, J=14.4 Hz, 2H), 8.69 (dd, J=12.8 Hz, 2.4 Hz, 1H), 7.45 (m, 3H), 7.12 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.10F.sub.2N.sub.2O.sub.3, 293; found, 293.

Example B20: 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-(4-(pyrrolidin-1-yl)phenyl)urea (Compound B65)

[0655] ##STR00565##

[0656] 4-(Pyrrolidin-1-yl)aniline (176 mg, 1.09 mmol, 1.0 eq.) was added to a solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (200 mg, 1.09 mmol, 1.0 eq.) in dioxane (5 mL). The reaction was stirred for 10 min at room temperature. The resulting mixture was concentrated and the residue was stirred in dichloromethane (20 mL) for 10 min, and then filtered. The cake was dried and re-suspended in dioxane (30 mL). DPPA (448 mg, 1.63 mmol, 1.5 eq.) and TEA (329 mg, 3.26 mmol, 3.0 eq.) were added. The reaction was stirred for 30 min at room temperature. Then 4-(pyrrolidin-1-yl)aniline (176 mg, 1.09 mmol, 1.0 eq.) was added and the reaction was heated for 3 hours at 90 C. The mixture was cooled to room temperature and poured into 4 N HCl/water (50 mL). After stirring for 1 hour at room temperature, the mixture was extracted with ethyl acetate for three times and dichloromethane for 4 times. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=20:1 to 3:1) and prep-TLC to give 1-(3-fluoro-5-formyl-4-hydroxyphenyl)-3-(4-(pyrrolidin-1-yl)phenyl)urea (25 mg, 0.07 mmol, 7% yield) as a green solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.45 (br, 1H), 10.27 (s, 1H), 8.63 (br, 1H), 8.57 (br, 1H), 7.71 (dd, J=13.2 Hz, 2.4 Hz, 1H), 7.46 (s, 1H), 7.31 (m, 2H), 6.74 (m, 2H), 3.93 (m, 4H), 1.99 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.18FN.sub.3O.sub.3, 344; found, 344.

Example B21: 3-fluoro-5-formyl-4-hydroxy-N-(4-(piperidin-1-yl)phenyl)benzamide (New Compound B66)

[0657] ##STR00566##

[0658] In a 50 mL glass vial, a solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (200 mg, 1.09 mmol, 1.0 eq.), 4-(piperidin-1-yl)aniline (478 mg, 2.73 mmol, 2.5 eq.), HATU (619 mg, 1.63 mmol, 1.5 eq.), and N-methyl morpholine (329 mg, 3.26 mmol, 3.0 eq.) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into 4 N HCl. The reaction was stirred for 30 min and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and prep-TLC to give 3-fluoro-5-formyl-4-hydroxy-N-(4-(piperidin-1-yl)phenyl)benzamide (23 mg, 0.04 mmol, 4% yield) as a yellow solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.30 (br, 1H), 10.02 (s, 1H), 8.03 (s, 1H), 7.89 (d, J=10.0 Hz, 1H), 7.74 (br, 1H), 7.51 (m, 2H), 7.02 (m, 2H), 3.16 (m, 4H), 1.76 (m, 6H). ). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.19FN.sub.2O.sub.3, 343; found, 343.

Example B22: N-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B67)

[0659] ##STR00567##

Step 1: 3,3-difluoropyrrolidine Hydrochloride

[0660] DAST (4.03 g, 67.6 mmol, 2.5 eq.) was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5 g, 27.0 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction was stirred for 5 hours at room temperature. The reaction mixture was poured into ice cold sat. NaHCO.sub.3 solution (100 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude Boc-3,3-difluoropyrrolidine (5.9 g, quantitative yield), which was then treated with 6 N HCl in dioxane to give 3,3-difluoropyrrolidine hydrochloride (4.1 g, quantitative yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.4H.sub.8ClF.sub.2N, 110; found, 110.

Step 2: 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine

[0661] A mixture of 3,3-difluoropyrrolidine hydrochloride (1.43 g, 1.0 mmol, 1.0 eq.) 1-bromo-4-nitrobenzene (2.01 g, 1.0 mmol, 1 eq.), BINAP (0.94 g, 0.15 mmol, 0.15 eq.), Cs.sub.2CO.sub.3 (8.15 g, 2.5 mmol, 2.5 eq.), and Pd(OAc).sub.2 (0.23 g, 0.1 mmol, 0.1 eq.) in toluene (20 mL) was heated overnight at 95 C. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine (1.5 g, 66% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.10F.sub.2N.sub.2O.sub.2, 229; found, 229.

Step 3: 4-(3,3-difluoropyrrolidin-1-yl)aniline

[0662] Iron powder (3.7 g, 66.1 mmol, 10.0 eq.) was added to a solution of 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine (1.5 g, 6.6 mmol, 1.0 eq.) in AcOH (30 mL). The reaction was heated for 2 hours at 60 C. The reaction mixture was cooled to room temperature, poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 4-(3,3-difluoropyrrolidin-1-yl)aniline (1.1 g, 84% yield), which was used for next reaction without further purification. LC-MS m/z [M+H].sup.+ calc'd for C.sub.10H.sub.12F.sub.2N.sub.2, 199; found, 199.

Step 4

[0663] A solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (200 mg, 1.09 mmol, 1.0 eq.), 4-(3,3-difluoropyrrolidin-1-yl)aniline (430 mg, 2.17 mmol, 2.0 eq.), HATU (619 mg, 1.63 mmol, 1.5 eq.), and N-methyl morpholine (329 mg, 3.26 mmol, 3.0 eq.) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into 4 N HCl. The reaction was stirred for 30 min and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and prep-TLC to give N-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (50 mg, 0.13 mmol, 12% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.61 (br, 1H), 10.35 (s, 1H), 10.10 (br, 1H), 8.18 (s, 1H), 8.09 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 6.63 (d, J=9.2 Hz, 2H), 3.68 (t, J=9.6 Hz, 2H), 3.43 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.15F.sub.3N.sub.2O.sub.3, 365; found, 365.

Example B23: N-(4-(4,4-difluoropiperidin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (New Compound B68)

[0664] ##STR00568##

[0665] A solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (200 mg, 1.09 mmol, 1.0 eq.), 4-(4,4-difluoropiperidin-1-yl)aniline (460 mg, 2.17 mmol, 2.0 eq.) (prepared as in Example B22), HATU (619 mg, 1.63 mmol, 1.5 eq.), and N-methyl morpholine (329 mg, 3.26 mmol, 3.0 eq.) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into 4 N HCl. The reaction was stirred for 30 min and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and prep-TLC to give N-(4-(4,4-difluoropiperidin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (13 mg, 0.03 mmol, 3% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.63 (br, 1H), 10.35 (s, 1H), 10.15 (br, 1H), 8.18 (s, 1H), 8.09 (d, J=11.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.29 (m, 4H), 2.05 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17F.sub.3N.sub.2O.sub.3, 379; found, 379.

Example B24: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B69)

[0666] ##STR00569##

[0667] A solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (200 mg, 1.09 mmol, 1.0 eq.), 4-(4-cyclopropylpiperazin-1-yl)aniline (590 mg, 2.73 mmol, 2.5 eq.) (prepared as in Example B22), HATU (619 mg, 1.63 mmol, 1.5 eq.), and N-methyl morpholine (329 mg, 3.26 mmol, 3.0 eq.) in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into 4 N HCl. The reaction was stirred for 30 min and then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and prep-TLC to give N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (25 mg, 0.03 mmol, 6% yield) as a pale yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.65 (br, 1H), 10.36 (s, 1H), 10.21 (s, 1H), 8.19 (s, 1H), 8.10 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.65 (d, J=9.2 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.77 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 3.06 (m, 2H), 2.93 (m, 1H), 1.10 (m, 2H), 0.82 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.22FN.sub.3O.sub.3, 384; found, 384.

Example B25: N-(4-(4-cyclopropyl-1,4-diazepan-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (New Compound B70)

[0668] ##STR00570##

Step 1: 1-cyclopropyl-4-(4-nitrophenyl)-1,4-diazepane

[0669] In a 100 mL glass vial, a mixture of 1-fluoro-4-nitrobenzene (1.1 g, 7.80 mmol, 1.1 eq.), 1-cyclopropyl-1,4-diazepane (1 g, 7.14 mmol, 1.0 eq.), and K.sub.2CO.sub.3 (4.9 g, 35.5 mmol, 5.0 eq.) in DMF (20 mL) was heated for 7 hours at 50 C. The mixture was poured into water and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (pure DCM) to give 1-cyclopropyl-4-(4-nitrophenyl)-1,4-diazepane (1.57 g, 6.01 mmol, 84% yield) as a yellow oil. LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.19N.sub.3O.sub.2, 262; found, 262.

Step 2: 4-(4-cyclopropyl-1,4-diazepan-1-yl)aniline

[0670] In a 100 mL glass vial, iron powder (794 mg, 14.18 mmol, 10 eq.) was added to a solution of 1-cyclopropyl-4-(4-nitrophenyl)-1,4-diazepane (370 mg, 1.42 mmol, 1.0 eq.) in AcOH (10 mL). The reaction was heated for 2 hours at 60 C. The reaction mixture was cooled to room temperature, poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-(4-cyclopropyl-1,4-diazepan-1-yl)aniline (290 mg, 1.26 mmol, 88% yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.21N.sub.3, 232; found, 232.

Step 3a: 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic Acid

[0671] In a 100 mL glass vial, a solution of 3-fluoro-5-formyl-4-hydroxybenzoic acid (2 g, 10.9 mmol, 1.0 eq.), 2,2-dimethylpropane-1,3-diol (2.26 g, 21.8 mmol, 2.0 eq.), and p-TsOH.H.sub.2O (414 mg, 2.18 mmol, 0.2 eq.) in toluene (30 mL) was heated for 3 hours at 90 C. The solvent was removed in vacuo and the residue was dissolved in water/EtOAc. The mixture was then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (2.97 g, quantitative yield). LC-MS m/z [M+H].sup.+ calc'd for C.sub.13H.sub.15FO.sub.5, 271; found, 271.

Step 3

[0672] In a 100 mL glass vial, a solution of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (193 mg, 0.71 mmol, 1.0 eq.), 4-(4-cyclopropyl-1,4-diazepan-1-yl)aniline (180 mg, 0.79 mmol, 1.1 eq.), HATU (324 mg, 0.85 mmol, 1.2 eq.), and NMM (215 mg, 2.13 mmol, 3.0 eq.) in THF (10 mL) was stirred for 4 hours at room temperature. The solution was poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (CH.sub.2Cl.sub.2/MeOH=300:1 to 150:1) and prep-TLC to give the intermediate (40 mg, 0.08 mmol, 12% yield). The intermediate (30 mg, 0.06 mmol, 1.0 eq.) was dissolved in THF/4 N HCl (2 mL/4 mL) and the reaction was stirred for 30 min at room temperature. pH of the system was adjusted to 7-7.5 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give N-(4-(4-cyclopropyl-1,4-diazepan-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (7 mg, 0.02 mmol, 29% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.32 (s, 1H), 9.96 (s, 1H), 8.14 (s, 1H), 8.00 (d, J=12.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.68 (d, J=9.2 Hz, 2H), 3.49 (m, 4H), 2.92 (m, 2H), 2.75 (m, 2H), 2.01 (m, 1H), 1.89 (m, 2H), 0.47 (m, 2H), 0.38 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.22H.sub.24FN.sub.3O.sub.3, 398; found, 398.

Example B26: 3-fluoro-5-formyl-4-hydroxy-N-(3-(pyrrolidin-1-yl)phenyl)benzamide (Compound B71)

[0673] ##STR00571##

[0674] In a 100 mL glass vial, a solution of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (300 mg, 1.11 mmol, 1.0 eq.), 3-(pyrrolidin-1-yl)aniline (180 mg, 1.11 mmol, 1.0 eq.), HATU (633 mg, 1.67 mmol, 1.5 eq.), and NMM (336 mg, 3.33 mmol, 3.0 eq.) in THF (10 mL) was stirred overnight at rt. The solution was poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc=20:1 to 5:1) to give an intermediate (110 mg, 0.27 mmol, 24% yield). The intermediate (100 mg, 0.24 mmol, 1.0 eq.) was dissolved in THF/4 N HCl (2 mL/4 mL) and the reaction was stirred for 30 min at room temperature. The mixture was extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc=10:1 to 5:1) to give 3-fluoro-5-formyl-4-hydroxy-N-(3-(pyrrolidin-1-yl)phenyl)benzamide (65 mg, 0.20 mmol, 83% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.62 (br, 1H), 10.35 (s, 1H), 10.07 (s, 1H), 8.19 (s, 1H), 8.10 (dd, J=11.6 Hz, 1.6 Hz, 1H), 7.08 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.29 (m, 1H), 3.22 (m, 4H), 1.97 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.18H.sub.17FN.sub.2O.sub.3, 329; found, 329.

Example B27: 3-fluoro-5-formyl-4-hydroxy-N-(3-(piperidin-1-yl)phenyl)benzamide (Compound B72)

[0675] ##STR00572##

[0676] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (250 mg, 0.93 mmol, 1 eq.) and 3-(piperidin-1-yl)aniline (163 mg, 0.93 mmol, 1 eq.) using a method similar to that as described in Example B25 to give the title compound 3-fluoro-5-formyl-4-hydroxy-N-(3-(piperidin-1-yl)phenyl)benzamide (7 mg, 0.02 mmol, 11% yield) as a light yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.66 (br, 1H), 10.35 (s, 1H), 10.11 (s, 1H), 8.19 (s, 1H), 8.10 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.15 (m, 1H), 6.69 (m, 1H), 3.14 (m, 4H), 1.62 (m, 4H), 1.55 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.19FN.sub.2O.sub.3, 343; found, 343.

Example B28: N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B73)

[0677] ##STR00573##

[0678] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (270 mg, 1.0 mmol, 1.0 eq.) and 4-(3,3-dimethylpyrrolidin-1-yl)aniline (190 mg, 1 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (130 mg, 0.37 mmol, 74% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.60 (br, 1H), 10.34 (s, 1H), 9.99 (s, 1H), 8.16 (d, J=1.2 Hz, 1H), 8.06 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.47 (d, J=9.2 Hz, 2H), 3.35-3.28 (m, 2H), 3.00 (s, 2H), 1.75 (t, J=10.8 Hz, 2H), 1.11 (s, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.21FN.sub.2O.sub.3, 357; found, 357.

Example B29: N-(4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B74)

[0679] ##STR00574##

[0680] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (310 mg, 1.15 mmol, 1.0 eq.) and 4-(3-azabicyclo[3.1.0]hexan-3-yl)aniline (200 mg, 1.15 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (60 mg, 0.18 mmol, 39% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.62 (br, 1H), 10.34 (s, 1H), 10.01 (s, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.06 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.53 (d, J=9.2 Hz, 2H), 3.48 (d, J=9.2 Hz, 2H), 3.12 (m, 2H), 1.67 (m, 2H), 0.70 (m, 1H), 0.27 (m, 1H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.17FN.sub.2O.sub.3, 341; found, 341.

Example B30: 3-fluoro-5-formyl-4-hydroxy-N-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)benzamide (Compound B75)

[0681] ##STR00575##

[0682] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (270 mg, 1.0 mmol, 1.0 eq.) and 4-((3aR,6aS)-dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)aniline (204 mg, 1.0 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (60 mg, 0.16 mmol, 36% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.59 (br, 1H), 10.34 (s, 1H), 10.06 (s, 1H), 8.17 (s, 1H), 8.08 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.85 (m, 2H), 3.54 (m, 2H), 3.31 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19FN.sub.2O.sub.4, 371; found, 371.

Example B31: 3-fluoro-5-formyl-N-(4-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)phenyl)-4-hydroxybenzamide (Compound B76)

[0683] ##STR00576##

[0684] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (270 mg, 1.0 mmol, 1.0 eq.) and 4-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)aniline (202 mg, 1.0 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (220 mg, 0.60 mmol, 62% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.60 (br, 1H), 10.34 (s, 1H), 10.04 (s, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.08 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.52 (d, J=9.2 Hz, 2H), 6.60 (d, J=9.2 Hz, 2H), 3.36 (m, 2H), 2.94 (m, 2H), 2.74 (m, 2H), 1.79 (m, 2H), 1.54 (m, 1H), 1.49 (m, 1H), 1.45 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.21FN.sub.2O.sub.3, 369; found, 369.

Example B32: N-(4-(2-azaspiro[3.3]heptan-2-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B77)

[0685] ##STR00577##

[0686] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (270 mg, 1.0 mmol, 1.0 eq.) and 4-(2-azaspiro[3.3]heptan-2-yl)aniline (188 mg, 1 mmol, 1.0 eq.) (Ref: 2-Azaspiro[3.3]heptane, hydrochloride prepared as in Zhang, Hui et al., PCT Int. Appl., 2013013504, 31 Jan. 2013) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (140 mg, 0.40 mmol, 53% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.60 (br, 1H), 10.34 (s, 1H), 10.05 (s, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.07 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 6.39 (d, J=8.8 Hz, 2H), 3.74 (s, 4H), 2.16 (t, J=5.0 Hz, 4H), 1.84-1.80 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19FN.sub.2O.sub.3, 355; found, 355.

Example B33: 3-fluoro-5-formyl-4-hydroxy-N-(4-(6-oxo-5-azaspiro[2.4]heptan-5-yl)phenyl)benzamide (Compound B78)

[0687] ##STR00578##

[0688] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (281 mg, 1.04 mmol, 1.0 eq.) and 5-(4-aminophenyl)-5-azaspiro[2.4]heptan-6-one (210 mg, 1.04 mmol, 1.0 eq.) (prepared as in Example B22) using a method similar to that as described in Example B25 to give the title compound (100 mg, 0.27 mmol, 49% yield) as a white solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.68 (br, 1H), 10.36 (s, 1H), 10.33 (s, 1H), 8.20 (s, 1H), 8.11 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.62 (d, J=9.2 Hz, 2H), 3.75 (s, 2H), 2.56 (s, 2H), 0.70 (s, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.17FN.sub.2O.sub.4, 369; found, 369.

Example B34: N-(4-(5-azaspiro[2.4]heptan-5-yl)phenyl)-3-fluoro-5-form-4-hydroxybenzamide (Compound B79)

[0689] ##STR00579##

Step 1: 4-(5-azaspiro[2,4]heptan-5-yl)aniline

[0690] 5-(4-Nitrophenyl)-5-azaspiro[2.4]heptan-6-one (300 mg, 1.29 mmol, 1.0 eq.) was dissolved in THF (10 ml) and the solution was cooled to 0 C. Borane-dimethylsulfide (0.26 mL, 10 M in DMS, 2.58 mmol, 2.0 eq.) was added. The reaction was stirred for 1 hour at 50 C. The system was cooled to room temperature, poured into ice water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 5-(4-nitrophenyl)-5-azaspiro[2.4]heptane (305 mg, quantitative yield). In a 100 mL glass vial, iron powder (770 mg, 13.75 mmol, 10 eq.) was added to a solution of 5-(4-nitrophenyl)-5-azaspiro[2.4]heptane (305 mg, 1.29 mmol, 1.0 eq.) in AcOH (20 mL). The reaction was heated for 2 hours at 60 C. The reaction mixture was cooled to room temperature, poured into sat. NaHCO.sub.3 and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 4-(5-azaspiro[2.4]heptan-5-yl)aniline (180 mg, 0.96 mmol, 74% yield), which was used for next reaction without further purification.

Step 2

[0691] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (284 mg, 1.05 mmol, 1.0 eq.) and 4-(5-azaspiro[2.4]heptan-5-yl)aniline (180 mg, 0.96 mmol, 1 eq.) using a method similar to that as described in Example B25 to give the title compound (70 mg, 0.20 mmol, 44% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.34 (br, 1H), 10.00 (br, 1H), 8.16 (s, 1H), 8.06 (d, J=11.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 6.49 (d, J=8.8 Hz, 2H), 3.36 (m, 2H), 3.15 (s, 2H), 1.91 (t, J=6.4 Hz, 2H), 0.62 (d, J=8.0 Hz, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19FN.sub.2O.sub.3, 355; found, 355.

Example B35: N-cyclopropyl-4-((3-fluoro-5-formyl-4-hydroxyphenyl)ethynyl)benzamide (Compound B80)

[0692] ##STR00580##

Step 1: methyl 4-(iodoethynyl)benzoate

[0693] In a 100 mL glass vial, PhI(OAc).sub.2 (3.66 g, 11.4 mmol, 1.0 eq.) was added to a solution of methyl 4-ethynylbenzoate (1.82 g, 11.4 mmol, 1.0 eq.) and TBAI (5.04 g, 13.7 mmol, 1.2 eq.) in acetonitrile (20 mL). The reaction was stirred for 5 hours at room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude methyl 4-(iodoethynyl)benzoate (3.64 g, quantitative yield) as a yellow solid, which was used for next reaction without further purification.

Step 2: N-cyclopropyl-4-(iodoethynyl)benzamide

[0694] In a 50 mL glass vial, LiOH.H.sub.2O (1.34 g, 28.4 mmol, 2.5 eq.) was added to a solution of methyl 4-(iodoethynyl)benzoate (crude, 3.64 g, 11.4 mmol, 1.0 eq.) in water/THF (10 mL/10 mL). The reaction was stirred for 2 hours at room temperature. The solution was diluted with water and extracted with petroleum ether for two times. The petroleum ether layers were discarded. Then pH of the water phase was adjusted to 3-4 with 5% KHSO.sub.4 and then the mixture was extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give acid (2.36 g, 76% yield) as a white solid. The resulting acid (2.36 g, 8.7 mmol, 1.0 eq.) was dissolved in CH.sub.2Cl.sub.2 (10 mL) in a 50 mL glass vial. HATU (3.96 g, 10.4 mmol, 1.2 eq.), cyclopropanamine (1.24 g, 21.7 mmol, 2.5 eq.), and N-methyl morpholine (2.63 g, 26.0 mmol, 3.0 eq.) were added. The mixture was stirred for 2 hours at room temperature. The mixture was poured into water and extracted with CH.sub.2Cl.sub.2 for two times. The organic extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=20:1 to 5:1) to give N-cyclopropyl-4-(iodoethynyl)benzamide (1.86 g, 6.0 mmol, 69% yield) as a yellow solid. LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.10NO, 312; found, 312.

Step 3

[0695] In a 100 mL glass vial, a mixture of N-cyclopropyl-4-(iodoethynyl)benzamide (520 mg, 1.67 mmol, 1.0 eq.), 3-fluoro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (488 mg, 1.83 mmol, 1.1 eq.), K.sub.2CO.sub.3 (690 mg, 5.0 mmol, 3.0 eq.), and Pd(dppf)Cl.sub.2 (136 mg, 0.17 mmol, 0.1 eq.) in dioxane/water (9 mL/3 mL) was stirred for 1 hour at room temperature. The mixture was poured into water, acidified to pH 4-5 with 5% KHSO.sub.4, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (CH.sub.2Cl.sub.2/MeOH=100 to 300:1) to give N-cyclopropyl-4-((3-fluoro-5-formyl-4-hydroxyphenyl)ethynyl)benzamide (13 mg, 0.04 mmol, 2% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.52 (br, 1H), 10.28 (s, 1H), 8.55 (d, J=4.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.78 (dd, J=11.2 Hz, 2.0 Hz, 1H), 7.67-7.61 (m, 3H), 2.84 (m, 1H), 0.85 (m, 2H), 0.72 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.14FNO.sub.3, 324; found, 324.

Example B36: 3-fluoro-5-formyl-4-hydroxy-N-(4-(isoindolin-2-yl)phenyl)benzamide (New Compound B81)

[0696] ##STR00581##

[0697] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (296 mg, 1.1 mmol, 1.0 eq.) and 4-(isoindolin-2-yl)aniline (230 mg, 1.10 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (190 mg, 0.51 mmol, 60% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.57 (br, 1H), 10.36 (s, 1H), 10.08 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=11.6 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.41 (m, 2H), 7.31 (m, 2H), 6.68 (d, J=8.8 Hz, 2H), 4.61 (s, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.22H.sub.17FN.sub.2O.sub.3, 377; found, 377.

Example B37: N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3-fluoro-5-form-4-hydroxybenzamide (Compound B82)

[0698] ##STR00582##

[0699] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (416 mg, 1.56 mmol, 1.0 eq.) and 4-(3,4-dihydroisoquinolin-2(1H)-yl)aniline (350 mg, 1.56 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (130 mg, 0.33 mmol, 51% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.66 (br, 1H), 10.35 (s, 1H), 10.10 (s, 1H), 8.17 (s, 1H), 8.07 (dd, J=11.6 Hz, 1.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.23-7.16 (m, 4H), 7.01 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 3.51 (t, J=5.6 Hz, 2H), 2.91 (d, J=5.6 Hz, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.19FN.sub.2O.sub.3, 391; found, 391.

Example B38: 3-fluoro-5-formyl-4-hydroxy-N-(4-(4-phenylpiperazin-1-yl)phenyl)benzamide (Compound B83)

[0700] ##STR00583##

[0701] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (373 mg, 1.38 mmol, 1.0 eq.) and 4-(4-phenylpiperazin-1-yl)aniline (350 mg, 1.38 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (4 mg, 0.01 mmol, 2% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.60 (br, 1H), 10.35 (br, 1H), 10.14 (br, 1H), 8.19 (s, 1H), 8.10 (d, J=10.0 Hz, 1H), 7.63 (m, 2H), 7.24 (m, 2H), 7.02 (m, 2H), 6.81 (m, 1H), 3.27 (m, 8H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.24H.sub.22FN.sub.3O.sub.3, 420; found, 420.

Example B39: 3-fluoro-5-formyl-4-hydroxy-N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)benzamide (Compound B84)

[0702] ##STR00584##

[0703] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (170 mg, 0.63 mmol, 1.0 eq.) and 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)aniline (140 mg, 0.57 mmol, 1.0 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (47 mg, 0.11 mmol, 48% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 10.14 (s, 1H), 9.51 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.55 (d, J=9.2 Hz, 2H), 7.45 (d, J=13.6 Hz, 2.4 Hz, 1H), 6.88 (d, J=9.2 Hz, 2H), 3.60 (d, J=12.4 Hz, 2H), 2.75 (m, 4H), 2.641 (t, J=11.6 Hz, 2H), 2.54 (m, 1H), 1.97 (d, J=12.0 Hz, 2H), 1.75 (m, 4H), 1.55 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.26FN.sub.3O.sub.3, 412; found, 412.

Example B40: 3-fluoro-5-formyl-4-hydroxy-N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)benzamide (Compound B85)

[0704] ##STR00585##

[0705] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (283 mg, 1.05 mmol, 1.1 eq.) and 4-(indolin-1-yl)aniline (200 mg, 0.95 mmol, 1 eq.) (prepared as in Example B25) using a method similar to that as described in Example B25 to give the title compound (7 mg, 0.02 mmol, 7% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.63 (br, 1H), 10.36 (s, 1H), 10.25 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.11 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.23 (dd, J=8.8 Hz, 2.8 Hz, 2H), 7.16 (d, J=7.2 Hz, 1H), 7.04 (m, 2H), 6.71 (m, 1H), 3.92 (d, J=8.4 Hz, 2H), 3.09 (d, J=8.4 Hz, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.22H.sub.17FN.sub.2O.sub.3, 377; found, 377.

Example B41: 3-fluoro-5-formyl-4-hydroxy-N-(6-(isoindolin-2-yl)pyridin-3-yl)benzamide (Compound B86)

[0706] ##STR00586##

[0707] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (637 mg, 2.37 mmol, 1.0 eq.) and 6-(isoindolin-2-yl)pyridin-3-amine (500 mg, 2.37 mmol, 1.0 eq.) (prepared as in Example B16) using a method similar to that as described in Example B25 to give the title compound (47 mg, 0.12 mmol, 15% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.81 (br, 1H), 10.76 (br, 1H), 10.36 (s, 1H), 8.65 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 8.24-8.21 (m, 2H), 7.45 (m, 2H), 7.39 (m, 2H), 7.20 (d, J=7.2 Hz, 1H), 4.95 (s, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.16FN.sub.3O.sub.3, 378; found, 378.

Example B42: N-(6-(3,3-dimethylindolin-1-yl)pyridin-3-yl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B87)

[0708] ##STR00587##

[0709] The title compound was prepared from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (475 mg, 1.76 mmol, 1.0 eq.) and 6-(3,3-dimethylindolin-1-yl)pyridin-3-amine (420 mg, 1.76 mmol, 1.0 eq.) (prepared as in Example B16) using a method similar to that as described in Example B25 to give the title compound (87 mg, 0.21 mmol, 25% yield). .sup.1H NMR (DMSO-d6, 400 MHz) : 11.67 (br, 1H), 10.36 (s, 1H), 10.34 (s, 1H), 8.63 (d, J=2.8 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.18-8.04 (m, 3H), 7.20 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.14 (m, 1H), 6.89 (m, 1H), 6.85 (m, 1H), 3.78 (s, 2H), 1.35 (s, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.20FN.sub.3O.sub.3, 406; found, 406.

Example B43: 3-fluoro-N-(6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-yl)-5-formyl-4-hydroxybenzamide (Compound B99)

[0710] ##STR00588##

Step 1: 5-fluoro-3,3-dimethyl-1-(5-nitropyridin-2-yl)indoline

[0711] A mixture of 5-fluoro-3,3-dimethylindoline (1 g, 6.1 mmol, 1.0 eq.), 2-chloro-5-nitropyridine (1.44 g, 9.1 mmol, 1.5 eq.), cesium carbonate (4.94 g, 15.2 mmol, 2.5 eq.), BINAP (566 mg, 0.91 mmol, 0.15 eq.), and Pd(OAc).sub.2 (136 mg, 0.61 mmol, 0.1 eq.) in toluene (30 m) was heated at 95 C. for 30 Example B25. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=300:1 to 100:1) to give 5-fluoro-3,3-dimethyl-1-(5-nitropyridin-2-yl)indoline (910 mg, 52% yield), used in next step.

Step 2: 6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-amine

[0712] 6-(5-Fluoro-3,3-dimethylindolin-1-yl)pyridin-3-amine (690 mg, 2.7 mmol, 871.0 yield) was prepared from 5-fluoro-3,3-dimethyl-benzo-(5-nitropyridin-2-yl)indoline (900 mg, 3.1 mmol, 1.0 eq.) and Fe (1.76 g, 31.4 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.15H.sub.16FN.sub.3, 258; found, 258.

Step 3: 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-yl)-4-hydroxybenzamide

[0713] 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-yl)-4-hydroxybenzamide (550 mg, 4718% yield) was prepared from 6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-amine (600 mg, 2.3 mmol, 1.0 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (630 mg, 2.3 mmol, 1.0 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.28H.sub.29F.sub.2N.sub.3O.sub.4, 510; found, 510.

Step 4

[0714] 3-Fluoro-N-(6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-yl)-5-formyl-4-hydroxybenzamide (80 mg, 18% yield) was prepared as a yellow solid from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-(5-fluoro-3,3-dimethylindolin-1-yl)pyridin-3-yl)-4-hydroxybenzamide (550 mg, 1.08 mmol, 1.0 eq.) following the similar procedure as in Example B25. Pos. LC-MS: 423.9 (M+H).sup.+, C.sub.23H.sub.19F.sub.2N.sub.3O.sub.3. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.67 (br, 1H), 10.36 (br, 1H), 10.33 (br, 1H), 8.62 (br, 1H), 8.22 (m, 2H), 8.13-8.06 (m, 2H), 7.11 (m, 1H), 6.95-6.89 (m, 2H), 3.80 (s, 2H), 1.35 (s, 6H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.19F.sub.2N.sub.3O.sub.3, 424; found, 424.

Example B44: N-(4-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B90)

[0715] ##STR00589##

Step 1: 4-(4-nitrophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0716] 4-(4-Nitrophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.43 g, 5.6 mmol, 56% yield) was prepared from 3,4-dihydro-2H-benzo[b][1,4]oxazine (1.35 g, 10.0 mmol, 1.0 eq.) and 1-fluoro-4-nitrobenzene (1.7 g, 12.0 mmol, 1.1 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2. 4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)aniline

[0717] 4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)aniline (847 mg, 3.75 mmol, 67% yield) was prepared from 4-(4-nitrophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.43 g, 5.59 mmol, 1.0 eq.) and Fe (3.13 g, 55.9 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.14H.sub.14N.sub.2O, 227; found, 227.

Step 3. N-(4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide

[0718] N-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (403 mg, 0.84 mmol, 45% yield) was prepared from 4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)aniline (420 mg, 1.86 mmol, 1 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (502 mg, 1.86 mmol, 1.0 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.27H.sub.27FN.sub.2O.sub.5, 479; found, 479.

Step 4

[0719] N-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (110 mg, 0.28 mmol, 33% yield) was prepared as a yellow solid from N-(4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (400 mg, 0.84 mmol, 1.0 eq.) following the similar procedure for Example B25. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.67 (br, 1H), 10.36 (s, 1H), 10.31 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.10 (dd, J=11.6 Hz, 2.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 6.81-6.69 (m, 4H), 4.25 (t, J=4.0 Hz, 2H), 3.67 (d, J=4.0 Hz, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.22H.sub.17FN.sub.2O.sub.4, 393; found, 393.

Example B45: 3-fluoro-5-formyl-4-hydroxy-N-(4-(methyl(neopentyl)amino)phenyl)benzamide (Compound B94)

[0720] ##STR00590##

Step 1. N-methyl-N-neopentyl-4-nitroaniline

[0721] N-Methyl-N-neopentyl-4-nitroaniline (670 mg, 3.02 mmol, 91% yield) was prepared from N,2,2-trimethylpropan-1-amine hydrochloride (500 mg, 3.64 mmol, 1.1 eq.) and 1-fluoro-4-nitrobenzene (466 mg, 3.30 mmol, 1.0 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2: N1-methyl-N1-neopentylbenzene-1,4-diamine

[0722] N1-Methyl-N1-neopentylbenzene-1,4-diamine (320 mg, 1.66 mmol, 55% yield) was prepared from N-methyl-N-neopentyl-4-nitroaniline (670 mg, 3.02 mmol, 1.0 eq.) and Fe (1.69 g, 30.2 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.20N.sub.2, 193; found, 193.

Step 3. 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(4-(methyl(neopentyl) amino)phenyl)benzamide

[0723] 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(4-(methyl(neopentyl)amino)phenyl) benzamide (170 mg, 0.38 mmol, 74% yield) was prepared from N1-methyl-N1-neopentylbenzene-1,4-diamine (100 mg, 0.52 mmol, 1 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (155 mg, 0.57 mmol, 1.1 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.33FN.sub.2O.sub.4, 445; found, 445.

Step 4

[0724] 3-Fluoro-5-formyl-4-hydroxy-N-(4-(methyl(neopentyl)amino)phenyl)benzamide (60 mg, 0.17 mmol, 44% yield) was prepared as a yellow solid from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(4-(methyl(neopentyl)amino)phenyl)benzamide (170 mg, 0.38 mmol, 1 eq.) following the similar procedure for Example B25. .sup.1H NMR (CDCl.sub.3, 400 MHz) :11.26 (br, 1H), 10.00 (br, 1H), 7.97 (s, 1H), 7.85 (d, J=10.8 Hz, 1H), 7.56 (br, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.74 (br, 2H), 3.14 (s, 2H), 3.00 (s, 3H), 1.00 (s, 9H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.23FN.sub.2O.sub.3, 359; found, 359.

Example B46: N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B95)

[0725] ##STR00591##

Step 1: (1s,4s)-7-(4-nitrophenyl)-7-azabicyclo[2.2.1]heptane

[0726] (1s,4s)-7-(4-Nitrophenyl)-7-azabicyclo[2.2.1]heptane (710 mg, 3.26 mmol, 96% yield) was prepared from (1s,4s)-7-azabicyclo[2.2.1]heptane hydrochloride (500 mg, 3.73 mmol, 1.1 eq.) and 1-fluoro-4-nitrobenzene (480 mg, 3.40 mmol, 1.1 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2. 4-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)aniline

[0727] 4-((1s,4s)-7-Azabicyclo[2.2.1]heptan-7-yl)aniline (490 mg, 2.61 mmol, 80% yield) was prepared from (1s,4s)-7-(4-nitrophenyl)-7-azabicyclo[2.2.1]heptane (710 mg, 3.26 mmol, 1 eq.) and Fe (1.8 g, 32.6 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.12H.sub.16N.sub.2, 189; found, 189.

Step 3. N-(4-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide

[0728] N-(4-((1s,4s)-7-Azabicyclo[2.2.1]heptan-7-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (360 mg, 0.82 mmol, 37% yield) was prepared from 4-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)aniline (420 mg, 2.23 mmol, 1 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (660 mg, 2.44 mmol, 1.1 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.29FN.sub.2O.sub.4, 441; found, 441.

[0729] Step 4.

[0730] N-(4-((1s,4s)-7-Azabicyclo[2.2.1]heptan-7-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (75 mg, 0.21 mmol, 59% yield) was prepared as a light yellow solid from N-(4-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (160 mg, 0.36 mmol, 1 eq.) following the similar procedure for Example B25. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.28 (br, 1H), 9.98 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J=10.8 Hz, 1H), 7.65 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.16 (t, J=2.0 Hz, 2H), 1.80 (t, J=3.2 Hz, 4H), 1.44 (d, J=6.8 Hz, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.19FN.sub.2O.sub.3, 355; found, 355.

Example B47: N-(4-(8-azabicyclo[3.2.1]octan-8-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (Compound B96)

[0731] ##STR00592##

Step 1: (1R,5S)-8-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane

[0732] (1R,5S)-8-(4-Nitrophenyl)-8-azabicyclo[3.2.1]octane (740 mg, 3.19 mmol, 98% yield) was prepared from (1R,5S)-8-azabicyclo[3.2.1]octane hydrochloride (500 mg, 3.39 mmol, 1.05 eq.) and 1-fluoro-4-nitrobenzene (455 mg, 3.23 mmol, 1.0 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2. 4-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)aniline

[0733] 4-((1R,5S)-8-Azabicyclo[3.2.1]octan-8-yl)aniline (610 mg, 3.02 mmol, 95% yield) was prepared from (1R,5S)-8-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane (740 mg, 3.19 mmol, 1.0 eq.) and Fe (1.8 g, 31.9 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. No LCMS was taken for this compound.

Step 3

[0734] N-(4-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide N-(4-((1R,5S)-8-Azabicyclo[3.2.1]octan-8-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (420 mg, 0.93 mmol, 47% yield) was prepared from 4-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)aniline (400 mg, 1.98 mmol, 1 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (588 mg, 2.18 mmol, 1.1 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.26H.sub.31FN.sub.3O.sub.4, 455; found, 455.

Step 4

[0735] N-(4-((1R,5S)-8-Azabicyclo[3.2.1]octan-8-yl)phenyl)-3-fluoro-5-formyl-4-hydroxybenzamide (190 mg, 0.52 mmol, 56% yield) was prepared as a yellow solid from N-(4-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzamide (420 mg, 0.93 mmol, 1 eq.) following the similar procedure for Example B25. Pos. LC-MS: 369.0 (M+H).sup.+, C.sub.21H.sub.21FN.sub.2O.sub.3. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 11.26 (br, 1H), 10.00 (s, 1H), 7.96 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=10.8 Hz, 1H), 7.63 (br, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.77 (br, 2H), 4.18 (br, 2H), 2.09 (m, 2H), 1.98-1.81 (m, 4H), 1.56 (m, 2H), 1.23 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.21H.sub.21FN.sub.2O.sub.3, 369; found, 369.

Example B48: 3-fluoro-5-formyl-4-hydroxy-N-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl) benzamide (Compound B91)

[0736] ##STR00593##

Step 1: 1-(4-nitro-2-(trifluoromethyl)phenyl)pyrrolidine

[0737] 1-(4-Nitro-2-(trifluoromethyl)phenyl)pyrrolidine (930 mg, 3.6 mmol, 75% yield) was prepared from pyrrolidine (357 mg, 5.0 mmol, 1.05 eq.) and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (1 g, 4.8 mmol, 1.0 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2. 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)aniline

[0738] 4-(Pyrrolidin-1-yl)-3-(trifluoromethyl)aniline (790 mg, 3.4 mmol, 98% yield) was prepared from 1-(4-nitro-2-(trifluoromethyl)phenyl)pyrrolidine (900 mg, 3.5 mmol, 1.0 eq.) and Fe (1.94 g, 34.6 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.11H.sub.13N.sub.3O.sub.2, 231; found, 231.

Step 3. 4-(benzyloxy)-3-(1,3-dithian-2-yl)-5-fluoro-N-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)benzamide

[0739] Benzyl bromide (BnBr) (3.62 g, 21.2 mmol, 2.0 eq.) was added to a solution of 3-(1,3-dithian-2-yl)-5-fluoro-4-hydroxybenzoic acid (2.9 g, 10.6 mmol, 1.0 eq.) and potassium carbonate (2.9 g, 21.0 mmol, 2.0 eq.) in DMF (25 mL). The mixture was stirred for 3 hours at room temperature and poured into water. The mixture was then extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude bis-Bn protected ester (3.1 g, 6.8 mmol, 64% yield) as light yellow solid. The ester (3.1 g, 6.8 mmol, 1.0 eq.) was mixed with LiOH.H.sub.2O (833 mg, 20.5 mmol, 3 eq.) in THF/water (5 mL/5 mL). The reaction was stirred for 2 hours at room temperature. Then pH of the reaction system was acidified to 3-4 and the mixture was extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized in ethyl acetate/petroleum ether to give 4-(benzyloxy)-3-(1,3-dithian-2-yl)-5-fluorobenzoic acid (1.5 g, 4.1 mmol, 60% yield) as white solid. The resulting 4-(benzyloxy)-3-(1,3-dithian-2-yl)-5-fluorobenzoic acid (445 mg, 1.2 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) and oxalyl chloride (311 mg, 2.4 mmol, 2.0 eq.) and DMF (1 drop) was added. The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was co-evaporated with dichloromethane for two times. The residue was then dissolved in dichloromethane and the solution was cooled to 0 C. Then, 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)aniline (309 mg, 1.3 mmol, 1.1 eq.) and TEA (369 mg, 3.6 mmol, 3.0 eq.) were added successively. The reaction was stirred for 3 hours at room temperature. The solution was poured into water and extracted with dichloromethane for two times. The organic extracts were washed with 1% KHSO.sub.4, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 to 5:1) to give 4-(benzyloxy)-3-(1,3-dithian-2-yl)-5-fluoro-N-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)benzamide (370 mg, 0.64 mmol, 53% yield) as a yellow powder. LC-MS m/z [M+H].sup.+ calc'd for C.sub.29H.sub.28F.sub.4N.sub.2O.sub.2S.sub.2, 577; found, 577.

Step 4

[0740] A mixture of 4-(benzyloxy)-3-(1,3-dithian-2-yl)-5-fluoro-N-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)benzamide (350 mg, 0.61 mmol, 1.0 eq.), MeI (12.3 g, 60.8 mmol, 100 eq.), and sodium bicarbonate (1.46 g, 12.2 mmol, 20 eq.) in acetonitrile/water (25 mL/5 mL) was heated at 40 C. for 2 hours. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=100:1 to 20:1) to give the intermediate (290 mg, 0.60 mmol, 98% yield) as a yellow solid. The intermediate (190 mg, 0.39 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) and anhydrous AlCl.sub.3 (208 mg, 1.56 mmol, 4.0 eq.) was added. The reaction was stirred overnight at room temperature. The mixture was poured into ice-water and dichloromethane. The insoluble stuff was filtered off and the filtrate was extracted with DCM for three times. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give 4-(benzyloxy)-3-fluoro-5-formyl-N-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)benzamide (80 mg, 0.20 mmol, 52% yield) as a yellow solid. .sup.1H NMR (DMSO-d6, 400 MHz) : 10.34 (s, 1H), 10.30 (s, 1H), 8.19 (s, 1H), 8.07 (m, 2H), 7.88 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 3.20 (m, 4H), 1.89 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.19H.sub.16F.sub.4N.sub.2O.sub.3, 397; found, 397.

Example B49: 3-fluoro-5-formyl-4-hydroxy-N-(6-(4-phenylpiperazin-1-yl)pyridin-3-yl)benzamide (Compound B102)

[0741] ##STR00594## ##STR00595##

Step 1: 1-(5-nitropyridin-2-yl)-4-phenylpiperazine

[0742] 1-(5-Nitropyridin-2-yl)-4-phenylpiperazine (2.1 g, 7.4 mmol, 74% yield) was prepared from 1-phenylpiperazine hydrochloride (1.78 g, 11.0 mmol, 1.1 eq.), potassium carbonate (4.4 g, 31.89 mmol, 3.0 eq.), and 2-chloro-5-nitropyridine (1.58 g, 10.0 mmol, 1.0 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2. 6-(4-phenylpiperazin-1-yl)pyridin-3-amine

[0743] 6-(4-Phenylpiperazin-1-yl)pyridin-3-amine (750 mg, 2.95 mmol, 84% yield) was prepared from 1-(5-nitropyridin-2-yl)-4-phenylpiperazine (1 g, 3.52 mmol, 1.0 eq.) and Fe (1.97 g, 35.2 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. No LCMS was taken for this compound.

Step 3. 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(6-(4-phenylpiperazin-1-yl)pyridin-3-yl)benzamide

[0744] 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(6-(4-phenylpiperazin-1-yl)pyridin-3-yl)benzamide (270 mg, 0.53 mmol, 53% yield) was prepared from 6-(4-phenylpiperazin-1-yl)pyridin-3-amine (254 mg, 1.0 mmol, 1.0 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (270 mg, 1.0 mmol, 1.0 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.28H.sub.31FN.sub.4O.sub.4, 507; found, 507.

Step 4

[0745] 3-Fluoro-5-formyl-4-hydroxy-N-(6-(4-phenylpiperazin-1-yl)pyridin-3-yl)benzamide (120 mg, 0.29 mmol, 54% yield) was prepared as a yellow solid from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxy-N-(6-(4-phenylpiperazin-1-yl)pyridin-3-yl)benzamide (270 mg, 0.53 mmol, 1 eq.) following the similar procedure for Example B25. .sup.1H NMR (DMSO-d6, 400 MHz) : 11.69 (br, 1H), 10.35 (br, 1H), 10.21 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 8.08 (dd, J=11.6 Hz, 1H), 7.93 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.24 (m, 2H), 6.99 (m, 2H), 6.96 (d, J=8.8 Hz, 1H), 6.81 (m, 1H), 3.61 (m, 4H), 3.25 (m, 4H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.23H.sub.21FN.sub.4O.sub.3, 421; found, 421.

Example B50: 3-fluoro-5-formyl-N-(6-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-yl)-4-hydroxybenzamide (Compound B103)

[0746] ##STR00596##

Step 1

[0747] (3 aR,6aS)-2-(5-nitropyridin-2-yl)octahydrocyclopenta[c]pyrrole (3aR,6aS)-2-(5-Nitropyridin-2-yl)octahydrocyclopenta[c]pyrrole (680 mg, 2.9 mmol, 86% yield) was prepared from (3aR,6aS)-octahydrocyclopenta[c]pyrrole hydrochloride (0.5 g, 3.4 mmol, 1.0 eq.), potassium carbonate (1.4 g, 10.2 mmol, 3.0 eq.), and 2-chloro-5-nitropyridine (0.53 g, 3.7 mmol, 1.1 eq.) following the similar procedure for 3,3-dimethyl-1-(4-nitrophenyl)pyrrolidine in Example B25. No LCMS was taken for this compound.

Step 2

[0748] 6-((3 aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-amine 6-((3aR,6aS)-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-amine (410 mg, 2.0 mmol, 94% yield) was prepared from (3aR,6aS)-2-(5-nitropyridin-2-yl)octahydrocyclopenta[c]pyrrole (0.5 g, 2.1 mmol, 1.0 eq.) and Fe (1.2 g, 21.5 mmol, 10 eq.) following the similar procedure for 4-(3,3-dimethylpyrrolidin-1-yl)aniline in Example B25. No LCMS was taken for this compound.

Step 3. 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-yl)-4-hydroxybenzamide

[0749] 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-yl)-4-hydroxybenzamide (160 mg, 0.35 mmol, 33% yield) was prepared from 6-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-amine (240 mg, 1.18 mmol, 1.1 eq.) and 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-4-hydroxybenzoic acid (290 mg, 1.07 mmol, 1.0 eq.) following the similar procedure for 3-(5,5-dimethyl-1,3-dioxan-2-yl)-N-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5-fluoro-4-hydroxybenzamide in Example B25. LC-MS m/z [M+H].sup.+ calc'd for C.sub.25H.sub.30FN.sub.3O.sub.4, 456; found, 456.

Step 4

[0750] 3-Fluoro-5-formyl-N-(6-((3 aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-yl)-4-hydroxybenzamide (70 mg, 0.19 mmol, 54% yield) was prepared as a yellow solid from 3-(5,5-dimethyl-1,3-dioxan-2-yl)-5-fluoro-N-(6-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-3-yl)-4-hydroxybenzamide (160 mg, 0.35 mmol, 1 eq.) following the similar procedure for Example B25. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 10.01 (br, 1H), 8.78 (br, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 8.17 (m, 1H), 8.03 (d, J=10.8 Hz, 1H), 6.50 (d, J=9.2 Hz, 1H), 3.72 (m, 2H), 3.32 (m, 2H), 2.84 (m, 2H), 1.92 (m, 2H), 1.78 (m, 1H), 1.65 (m, 1H), 1.53 (m, 2H). LC-MS m/z [M+H].sup.+ calc'd for C.sub.20H.sub.20FN.sub.3O.sub.3, 370; found, 370.

Biological Example 1: In Vitro Assay

[0751] i. TLR2 Assays

[0752] Synthetic diacylated lipoprotein (Pam2CSK4, TLR2/6 agonist) and synthetic triacylated lipoprotein (Pam3CSK4, TLR1/2 agonist) were obtained from InvivoGen and were dissolved in endotoxin-free water to a concentration 1 mg/mL, vortexed until complete solubilization, and stored in aliquots at 20 C. Prior to addition to cells, an aliquot of the dissolved ligand was vortexed shortly and then was diluted in medium to 25 ng/mL Pam2CSK4 or 1000 ng/mL Pam3CSK4. The EC.sub.50 of the agonists for each assay run was determined by using 3-fold dilutions of each agonist from the following starting concentrations: 5 ng/mL for Pam2CSK4, and 200 ng/mL for Pam3CSK4.

[0753] Test compounds were solubilized fresh to 10-20 mM stocks in DMSO and sonicated for 5-10 minutes in a water bath sonicator. Serial dilutions were prepared in DMSO, and then diluted in medium. The final concentration of DMSO used in the assay was 1%.

[0754] HEK-Blue hTLR2 reporter cells (InvivoGen) are HEK-293 cells stably expressing both the human TLR2 gene and a secreted embryonic alkaline phosphatase (SEAP) reporter construct downstream of NFB promotor sites. HEK-Blue hTLR2 reporters were cultured according to manufacturer's protocol using Dulbecco's Modified Eagle Medium (DMEM; Gibco) containing 1 GlutaMax (Gibco), 10% heat-inactivated Fetal Bovine Serum (Gibco), Pen-Strep (50 U/mL penicillin, 50 g/mL streptomycin, Gibco), 100 g/mL Normocin (InvivoGen), and the selective antibiotic, 1HEK-Blue Selection (InvivoGen). Quanti-Blue reagent (InvivoGen) for detection and quantification of secreted alkaline phosphatase was dissolved in 100 mL of endotoxin-free water, warmed to 37 C. for 30 minutes and then filtered using a 0.2 m membrane.

ii. TLR9 Assay

[0755] Synthetic ODNs (ODN 2006 (ODN7909), class B CpG oligonucleotide, TLR9 agonist) was obtained from InvivoGen and was dissolved in endotoxin-free water to a concentration 500 M, vortexed until complete solubilization, and stored in aliquots at 20 C. Prior to addition to cells, an aliquot of the dissolved ligand was vortexed shortly and then was diluted in medium to 50 M. The EC.sub.50 of the agonist for each assay run was determined by using 3-fold dilutions from the starting concentration 10 M.

[0756] Test compounds were solubilized fresh to 10-20 mM stocks in DMSO and sonicated for 5-10 minutes in a water bath sonicator. Serial dilutions were prepared in DMSO, and then diluted in medium. The final concentration of DMSO used in the assay was 1%.

[0757] HEK-Blue hTLR9 reporter cells (InvivoGen) are HEK-293 cells stably expressing both the human TLR9 gene and a secreted embryonic alkaline phosphatase (SEAP) reporter construct downstream of NFB promotor sites. HEK-Blue hTLR9 cells were cultured according to manufacturer's protocol using Dulbecco's Modified Eagle Medium (DMEM; Gibco) containing 1 GlutaMax (Gibco), 10% heat-inactivated Fetal Bovine Serum (Gibco), Pen-Strep (50 U/mL penicillin, 50 g/mL streptomycin, Gibco), 100 g/mL Normocin (InvivoGen), and the selective antibiotics, 10 g/mL Blasticidin (InvivoGen), and 100 g/mL Zeocin (InvivoGen). Quanti-Blue reagent (InvivoGen) for detection and quantification of secreted alkaline phosphatase was dissolved in 100 mL of endotoxin-free water, warmed to 37 C. for 30 minutes and then filtered using a 0.2 m membrane.

Biological Example 2: HEK-Blue hTLR2 Antagonism Assay

[0758] i. TLR2 Assays

[0759] On day 1, 50 L of each test compound dilution in duplicates or a vehicle control was added to each well of a 96-well plate followed by addition of 150 L of HEK-Blue hTLR2 cell suspension (110.sup.5 cells/well) and incubated at 37 C./5% CO.sub.2 for 2 h. Next, 50 L of an approximate 3EC.sub.50 concentration of each agonist (Pam2CSK4 or Pam3CSK4) was added to the wells containing test compounds or the vehicle control. The plates were then incubated at 37 C./5% CO.sub.2 for 18 h. For each assay run, non-treated HEK-Blue hTLR2 cells were treated with serial dilutions of agonists to determine EC.sub.50 values for the respective run.

[0760] On day 2, secreted alkaline phosphatase (SEAP) activity was detected in cell culture supernatants. In brief, 20 L was collected from each well and transferred to a 96-well plate. Next, 200 L of Quanti-Blue detection reagent was added to each well. Plates were incubated at room temperature for 15 min. and SEAP activity was assessed by spectrophotometer OD reading at 655 nm. Table A and Table B show the activities of the compounds tested in HEK cells using Pam2CSK4 and Pam3CSK4 as agonists. The activities of the compounds against Pam2CSK4 and Pam3CSK4 are presented as IC.sub.50 values which were defined as concentrations of the compounds where percent inhibition of the signal induced by agonist is equal to 50. IC.sub.50 values were calculated based on 8-point dilutions for each compound.

ii. TLR9 Assay

[0761] On day 1, 50 L of each test compound dilution in duplicates or a vehicle control was added to each well of a 96-well plate followed by addition of 150 L of HEK-Blue hTLR9 cell suspension (110.sup.5 cells/well) and incubated at 37 C./5% CO.sub.2 for 2 h. Next, 50 L of an approximate 3EC.sub.50 concentration of TLR9 agonist, ODN 2006, was added to the wells containing test compounds or the vehicle control. The plates were then incubated at 37 C./5% CO.sub.2 for 18 h. For each assay run, vehicle-treated HEK-Blue hTLR9 cells were treated with serial dilutions of agonist to determine EC.sub.50 values for the respective run.

[0762] On day 2, secreted alkaline phosphatase (SEAP) activity was detected in cell culture supernatants. In brief, 30 L was collected from each well and transferred to a 96-well plate. Next, 200 L of Quanti-Blue detection reagent was added to each well. Plates were incubated at 37 C. for 60 min. and SEAP activity was assessed by spectrophotometer OD reading at 655 nm. Table A and Table B show the activities of the compounds tested in HEK-Blue hTLR9 cells against ODN 2006. The activities of the compounds against ODN 2006 are presented as IC.sub.50 values which were defined as concentrations of the compounds where percent inhibition of the signal induced by agonist is equal to 50. Exact IC.sub.50 values were calculated based on 8-point dilutions for each compound. Approximate IC.sub.50 values ( or <) were calculated based on 4-point dilutions for each compound.

TABLE-US-00003 TABLE A IC.sub.50 (M) IC.sub.50 (M) ~IC50 (M) Example Compound with with with No. No. Pam2CSK4 Pam3CSK4 ODN2006 A1 A1 2.2 0.9 ~2 A2 A2 >100 >100 >33 A3 A3 9.9 8.3 ND A4 A4 8.5 10.5 ND A5 A5 >100 >100 ND A6 A6 14.1 12.0 ND A7 A7 36.8 42.3 >33 A8 A8 85.5 >100 >33 A9 A9 3.8 5.1 ND A10 A10 5.2 5.2 ND A11 A11 2.3 2.0 ND A12 A12 >100 >100 >33 A13 A13 45.7 39.7 >33 A14 A14 42.2 42.6 >33 A15 A15 >100 >100 >33 A16 A16 >100 >100 >33 A17 A17 52.6 43.4 ND A18 A18 >100 >100 ND A19 A19 0.5 0.5 <1.2 A20 A20 0.5 0.2 ND A21 A21 2.6 1.1 ND A22 A22 0.9 0.9 >10 A23 A23 0.8 0.9 ND A24 A24 4.3 5.4 ND A25 A25 1.9 1.2 ~3 A26 A26 2.9 2.7 ~3 A27 A27 0.9 0.8 <1.2 A28 A28 0.9 0.8 ND A29 A29 6.4 7.6 ND A30 A30 2.1 2.2 ND A31 A31 3.4 6.2 ND A32 A32 12.7 17.4 ND A33 A33 4.0 3.6 ~4 A34 A34 6.9 3.9 ND A35 A35 1.6 0.7 ND A36 A36 >100 >100 ND A37 A37 >100 >100 ND A38 A38 0.4 0.4 ND A39 A39 0.5 0.5 ND A40 A40 7.2 2.7 ND A41 A42 0.4 0.3 0.1 A42 A43 1.1 1.1 <1.2 A43 A44 1.0 0.7 ~1.2 A44 A45 1.3 1.3 ND A45 A47 2.3 1.3 <1.2 A46 A50 4.1 0.9 ND A47 A51 1.7 0.7 <1.2 A48 A52 0.7 0.2 <1.2 A49 A57 1.0 0.3 0.3 A50 A61 3.2 1.0 <1.2 A51 A62 0.7 0.4 0.2 A52 A88 2.1 1.3 ~3 A53 A89 >100 >100 ND A54 A90 6.5 4.5 ND A55 A91 3.8 2.1 <1.2 A56 A92 3.5 0.9 ND A57 A93 4.8 2.1 <1.2 A58 A94 14.8 9.2 <1.2 A59 A95 3.0 2.3 ~1.4 A60 A96 12.1 8.8 ~6.3 A61 A97 0.9 0.3 ND A62 A55 0.6 0.4 0.2 A63 A98 1.4 1.0 ND A64 A99 3.3 2.2 ND A65 A100 1.4 0.6 ND A66 A101 3.2 1.0 ND A67 A102 1.9 1 ND A68 A103 3.9 1.3 ND A69 A104 6.8 3.9 ND A70 A105 1.9 0.5 ND A71 A123 1.7 1.5 ND A72 A124 1.7 1.0 ND A73 A114 0.7 0.4 ND A74 A125 3.3 2.0 ND A75 A126 1.1 0.6 ND A76 A127 1.2 0.7 ND A77 A116 1.3 0.6 ND A78 A112 0.3 0.2 ND ND = Not Determined

TABLE-US-00004 TABLE B IC.sub.50 (M) IC.sub.50 (M) ~IC50 (M) Example Compound with with with No. No. Pam2CSK4 Pam3CSK4 ODN2006 B1 B1 1.1 0.7 <1.2 B2 B2 0.5 0.3 ND B3 B3 3.7 2.2 <1.2 B4 B4 6.3 2.7 ~1.5 B5 B5 1.9 1.1 ND B6 B6 3.8 1.8 ND B7 B7 35.7 20.8 >33 B8 B8 2.9 1.6 ND B9 B9 8.1 6.8 ND B10 B10 11.6 7.2 ND B11 B11 12.0 10.6 <1.2 B12 B12 2.7 2.0 0.7 B13 B13 1.9 1.9 ND B14 B14 1.3 1.5 >33 B15 B17 12.7 6.6 ~2.9 B16 B59 32.7 19.8 ND B17 B61 16.4 9.3 ND B18 B63 30.1 11.3 ND B19 B64 10.9 8.0 ND B20 B65 8.7 3.7 <1.2 B21 B66 1.8 1.0 ND B22 B67 3.3 1.2 <1.2 B23 B68 3.5 1.0 <1.2 B24 B69 7.6 2.3 ND B25 B70 11.5 6.5 ND B26 B71 2.6 1.7 ~2.5 B27 B72 4.6 2.4 ND B28 B73 0.6 0.3 0.3 B29 B74 1.6 0.8 <1.2 B30 B75 13.0 6.0 ~4.7 B31 B76 1.2 0.6 <1.2 B32 B77 0.6 0.3 <1.2 B33 B78 34.4 18.5 ND B34 B79 4.1 1.4 ND B35 B80 15.5 35.9 ND B36 B81 1.0 0.5 ND B37 B82 1.2 0.7 ND B38 B83 1.0 0.3 ND B39 B84 33.9 14.3 ND B40 B85 1.3 0.7 ND B41 B86 4.3 1.8 ND B42 B87 0.5 0.4 0.1 B43 B99 0.6 0.5 ND B44 B90 2.9 1.9 ND B45 B94 1.0 0.9 ND B46 B95 3.7 2.8 ND B47 B96 1.4 1.1 ND B48 B91 2.2 1.6 ND B49 B102 2.0 1.0 ND B50 B103 1.7 1.0 ND ND = Not Determined