Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof

1. A method of inhibiting one or more proteins in the Wnt pathway, the method comprising contacting a cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 , R 2 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 3 is selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 ;

alternatively, one of each of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 10 is independently selected from the group consisting of H, —C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 11 is independently selected from the group consisting of —C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 12 is independently selected from the group consisting of −OR 10 and R 10 ;

each R 13 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 14 is selected from the group consisting of —NR 10 C(=A)R 10 , —NR 10 S(═O)R 11 , —NR 10 SO 2 R 10 , —NR 10 C(═O)N(R 16 ) 2 , —NR 10 C(═S)N(R 10 ) 2 , —NR 10 C(═NR 12 )N(R 10 ) 2 , —N(R 16 ) 2 , —C(═O)NR 10 R 17 , —C(═S)N(R 10 ) 2 , —C(═NR 12 )N(R 10 ) 2 , —OC(=A)R 10 , —C(=A)R 10 , —NR 10 C(=A)OR 10 and —OC(=A)NR 10 R 10 ;

R 15 is 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclylR 13 , heterocyclylR 13 , arylR 13 , heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 16 is —C 1-9 alkyl;

each R 17 is independently selected from the group consisting of -heterocyclylR 13 , —(C 1-9 alkyl)heterocyclylR 13 and —(C 1-9 alkyl)carbocyclylR 13 ;

R 18 and R 19 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

alternatively, R 18 and R 19 are taken together to form a ring which is selected from the group consisting of benzene and pyridine;

each A is independently selected from 0, S and NR 12 ;

Y 1 , Y 2 , and Y 4 are C;

Y 3 is nitrogen and R 8 is absent; and

each n is 0 or 1.

2. The method of claim 1 , wherein the cell is a human cell.

3. The method of claim 1 , wherein the compound inhibits one or more proteins in the Wnt pathway.

4. The method of claim 3 , wherein the compound inhibits signaling induced by one or more Wnt proteins.

5. The method of claim 4 , wherein the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

6. A method of claim 1 , wherein the compound inhibits a kinase activity.

7. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein n is 0.

10. The method of claim 1 , wherein n is 1.

11. The method of claim 1 , wherein A is 0.

12. The method of claim 1 , wherein R 1 , R 2 and R 4 are H and R 3 is independently selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 .

13. The method of claim 12 wherein R 3 is —(C 1-9 alkyl)R 14 .

14. The method of claim 12 wherein R 3 is -carbocyclylR 14 R 15 .

15. The method of claim 12 wherein R 3 is -heterocyclylR 14 R 15 .

16. The method of claim 12 wherein R 3 is -arylR 14 R 15 .

17. The method of claim 12 wherein R 3 is -heteroarylR 14 R 15 .

18. The method of claim 17 wherein R 14 is —NR 10 C(=A)R 10 and A is O.

19. The method of claim 17 wherein R 14 is —C(═O)NR 10 R 17 .

20. The method as in any of claims 17 - 19 , in which the heteroaryl is a pyridine.

21. The method of claim 17 or 18 , in which R 14 is —NHC(═O)R 10 and R 10 is selected from the group consisting of —C 1-9 alkyl, carbocyclyl, aryl and —(C 1-9 alkyl)aryl.

22. The method of claim 17 or 19 , in which R 14 is —C(═O)NHR 17 , R 17 is —(C 1-9 alkyl)carbocyclylR 13 and R 13 is H.

23. The method as in any one of claims 9 - 19 , wherein R 6 is —(C 1-9 alkyl) n heteroarylR 13 , n is 0 and R 13 is H.

24. The method of claim 1 , wherein R 1 , R 2 , R 4 , R 7 , and R 9 are H; R 3 is heteroarylR 14 R 15 ; and R 6 is —(C 1-9 alkyl) n arylR 13 .

25. The method of claim 24 , wherein R 13 is halide.

26. The method of claim 25 , wherein the halide is fluoro.

27. A method of claim 1 , wherein the contacting is in vitro.

28. The method of claim 6 , wherein the protein kinase is from the CDK, VEGF, CLK, HIPK, Abl, JAK or CHK families of kinases.

29. The method of claim 2 , wherein the human cell is a cancerous cell.

30. The method of claim 29 , wherein the cancerous cell is a colon cancer cell.

31. A method of treating cancer, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 , R 2 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 3 is selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 ;

alternatively, one of each of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 10 is independently selected from the group consisting of H, —C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 11 is independently selected from the group consisting of —C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 12 is independently selected from the group consisting of −OR 10 and R 10 ;

each R 13 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 14 is selected from the group consisting of —NR 10 C(=A)R 10 , —NR 10 S(═O)R 11 , —NR 10 SO 2 R 10 , —NR 10 C(═O)N(R 16 ) 2 , —NR 10 C(═S)N(R 10 ) 2 , —NR 10 C(═NR 12 )N(R 10 ) 2 , —N(R 16 ) 2 , —C(═O)NR 10 R 17 , —C(═S)N(R 10 ) 2 , —C(═NR 12 )N(R 10 ) 2 , —OC(=A)R 10 , —C(=A)R 10 , —NR 10 C(=A)OR 10 and —OC(=A)NR 10 R 10 ;

R 15 is 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclylR 13 , heterocyclylR 13 , arylR 13 , heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

R 16 is —C 1-9 alkyl;

each R 17 is independently selected from the group consisting of -heterocyclylR 13 , —(C 1-9 alkyl)heterocyclylR 13 and —(C 1-9 alkyl)carbocyclylR 13 ;

R 18 and R 19 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , (C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 ), —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 and —(C 1-9 alkyl) n C(=A)R 10 ;

alternatively, R 18 and R 19 are taken together to form a ring which is selected from the group consisting of benzene and pyridine;

each A is independently selected from O, S and NR 12 ;

Y 1 , Y 2 , and Y 4 are C;

Y 3 is nitrogen and R 8 is absent; and

each n is 0 or 1.

32. The method of claim 31 , wherein the cancer is hepatocellular carcinoma.

33. The method of claim 31 , wherein the cancer is colon cancer.

34. The method of claim 31 , wherein the cancer is colorectal cancer.

35. The method of claim 31 , wherein the cancer is breast cancer.

36. The method of claim 31 , wherein the cancer is pancreatic cancer.

37. The method of claim 31 , wherein the cancer is leukemia.

38. The method of claim 31 , wherein the cancer is lymphoma.

39. The method of claim 31 , wherein the cancer is sarcoma.

40. The method of claim 31 , wherein the cancer is ovarian cancer.

41. The method of claim 31 , wherein the cancer is lung cancers.

42. The method of claim 31 , wherein the cancer is melanoma.

43. The method of claim 31 , wherein the cancer is squamous cell carcinoma.

44. The method of claim 31 , wherein the cancer is adenocarcinoma.

45. The method of claim 31 , wherein the patient is a human.

46. The method of claim 31 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

47. The method of claim 31 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

48. The method of claim 31 , wherein n is 0.

49. The method of claim 31 , wherein n is 1.

50. The method of claim 31 , wherein A is 0.

51. The method of claim 31 , wherein R 1 , R 2 and R 4 are H and R 3 is independently selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 .

52. The method of claim 51 wherein R 3 is —(C 1-9 alkyl)R 14 .

53. The method of claim 51 wherein R 3 is -carbocyclylR 14 R 15 .

54. The method of claim 51 wherein R 3 is -heterocyclylR 14 R 15 .

55. The method of claim 51 wherein R 3 is -arylR 14 R 15 .

56. The method of claim 51 wherein R 3 is -heteroarylR 14 R 15 .

57. The method of claim 56 wherein R 14 is NR 10 C(A)R 10 and A is 0.

58. The method of claim 56 wherein R 14 is —C(═O)NR 10 R 17 .

59. The method as in any one of claims 56 - 58 , in which the heteroaryl is a pyridine.

60. The method of claim 56 or 57 , in which R 14 is —NHC(═O)R 10 and R 10 is selected from the group consisting of —C 1-9 alkyl, carbocyclyl, aryl and —(C 1-9 alkyl)aryl.

61. The method of claim 56 or 58 , in which R 14 is —C(═O)NHR 17 , R 17 is —(C 1-9 alkyl)carbocyclylR 13 and R 13 is H.

62. The method as in any one of claims 48 - 58 , wherein R 6 is —(C 1-9 alkyl) n heteroarylR 13 , n is 0 and R 13 is H.

63. The method of claim 31 , wherein R 1 , R 2 , R 4 , R 7 , and R 9 are H; R 3 is heteroarylR 14 R 15 ; and R 6 is —(C 1-9 alkyl) n arylR 13 .

64. The method of claim 63 , wherein R 13 is halide.

65. The method of claim 64 , wherein the halide is fluoro.