Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
1. A method for treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is -heteroarylR 3 R 4 ;
R 2 is selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6 and -arylR 7 ;
R 3 is selected from the group consisting of H, -heterocyclylR 8 , —NHC(═O)R 9 , —NHSO 2 R 10 , —NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;
wherein R 2 and R 3 are not both H;
R 4 is 1-3 substituents each selected from the group consisting of H, halide, —CF 3 , —CN, OR 13 and amino;
each R 5 is independently 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , —C(═O)R 11 , amino and —(C 1-6 alkyl)NR 11 R 12 ;
each R 6 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
each R 7 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , amino, —(C 1-6 alkyl)NHSO 2 R 11 , —NR 12 (C 1-6 alkyl)NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;
R 8 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
R 9 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 and —CH 2 carbocyclyl;
R 10 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 , and -carbocyclylR 14 ;
each R 11 is independently selected from C 1-6 alkyl;
each R 12 is independently selected from the group consisting of H and C 1-6 alkyl;
each R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring;
each R 13 is independently selected from the group consisting of H and C 1-6 alkyl; and
R 14 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
with the proviso that the compound of Formula I is not a compound selected from the group consisting of:
2. The method of claim 1 , wherein the cancer is colon cancer.
3. The method of claim 1 , wherein the cancer is colorectal cancer.
4. The method of claim 1 , wherein the cancer is leukemia.
5. The method of claim 1 , wherein the cancer is breast cancer.
6. The method of claim 1 , wherein the cancer is skin cancer.
7. The method of claim 1 , wherein the cancer is prostate cancer.
8. The method of claim 1 , wherein the cancer is lung cancer.
9. The method of claim 1 , wherein the cancer is liver cancer.
10. The method of claim 1 , wherein the mammal is a human.
11. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein R 1 is pyridineR 3 R 4 .
15. The method of claim 14 , wherein R 1 is pyridin-3-ylR 3 R 4 .
16. The method of claim 15 , wherein R 3 is —(C 1-6 alkyl)NR 11 R 12 .
17. The method of claim 16 , wherein R 3 is —(C 1-2 alkyl)NR 11 R 12 , R 11 is —(C 1-2 alkyl), R 12 is —(C 1-2 alkyl) and R 4 is H.
18. The method of claim 16 , wherein R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring and R 4 is H.
19. The method of claim 18 , wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.
20. The method of claim 15 , wherein R 3 is —NHC(═O)R 9 .
21. The method of claim 20 , wherein R 4 is H and R 9 is selected from the group consisting of —(C 2-5 alkyl), phenyl, -carbocyclyl and —CH 2 carbocyclyl.
22. The method of claim 15 , wherein R 3 is —NHSO 2 R 10 .
23. The method of claim 22 , wherein R 4 is H and R 10 is selected from the group consisting of —(C 1-4 alkyl) and phenyl.
24. The method of claim 15 , wherein R 3 is -heterocyclylR 8 .
25. The method of claim 24 , wherein R 4 is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
26. The method of claim 15 , wherein R 3 is H and R 4 is amino.
27. The method of claim 15 , wherein R 2 is -heteroarylR 5 .
28. The method of claim 27 , wherein R 2 is -pyridin-3-ylR 5 .
29. The method of claim 24 , wherein R 2 is -pyridin-3-ylR 5 and R 5 is 1-2 fluorine atoms.
30. The method of claim 15 , wherein R 2 is thiopheneR 5 .
31. The method of claim 15 , wherein R 2 is -heterocyclylR 6 .
32. The method of claim 31 , wherein R 2 is -heterocyclylR 6 , in which R 6 is selected from the group consisting of H, F and —(C 1-4 alkyl), and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
33. The method of claim 15 , wherein R 2 is -arylR 7 .
34. The method of claim 33 , in which R 2 is -phenylR 7 and R 7 is 1-2 fluorine atoms.
35. The method of claim 33 , in which R 2 is -phenylR 7 and R 7 is 2 substituents consisting of 1 fluorine atom and either —NR 12 (C 1-6 alkyl)NR 11 R 12 or —(C 1-6 alkyl)NHSO 2 R 11 .
36. The method of claim 1 , wherein the cancer is pancreatic cancer.
37. The method of claim 1 , wherein the cancer is lymphoma.
38. The method of claim 1 , wherein the cancer is sarcoma.
39. The method of claim 1 , wherein the cancer is ovarian cancer.
40. The method of claim 1 , wherein the cancer is melanoma.
41. The method of claim 1 , wherein the cancer is squamous cell carcinoma.
42. The method of claim 1 , wherein the cancer is adenocarcinoma.
43. The method of claim 1 , wherein the cancer is gastrointestinal cancer.
44. 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 is -heteroarylR 3 R 4 ;
R 2 is selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6 and -arylR 7 ;
R 3 is selected from the group consisting of H, -heterocyclylR 8 , —NHC(═O)R 9 , —NHSO 2 R 10 , —NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;
wherein R 2 and R 3 are not both H;
R 4 is 1-3 substituents each selected from the group consisting of H, halide, —CF 3 , —CN, OR 13 and amino;
each R 5 is independently 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , —C(═O)R 11 , amino and —(C 1-6 alkyl)NR 11 R 12 ;
each R 6 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
each R 7 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , amino, —(C 1-6 alkyl)NHSO 2 R 11 , —NR 12 (C 1-6 alkyl)NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;
R 8 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
R 9 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 and —CH 2 carbocyclyl;
R 10 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 , and -carbocyclylR 14 ;
each R 11 is independently selected from C 1-6 alkyl;
each R 12 is independently selected from the group consisting of H and C 1-6 alkyl;
each R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring;
each R 13 is independently selected from the group consisting of H and C 1-6 alkyl; and
R 14 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
with the proviso that the compound of Formula I is not a compound selected from the group consisting of:
45. The method of claim 44 , wherein R 1 is pyridineR 3 R 4 .
46. The method of claim 45 , wherein R 1 is pyridin-3-ylR 3 R 4 .
47. The method of claim 46 , wherein R 3 is —(C 1-6 alkyl)NR 11 R 12 .
48. The method of claim 47 , wherein R 3 is —(C 1-2 alkyl)NR 11 R 12 , R 11 is —(C 1-2 alkyl), R 12 is —(C 1-2 alkyl) and R 4 is H.
49. The method of claim 47 , wherein R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring and R 4 is H.
50. The method of claim 49 , wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.
51. The method of claim 46 , wherein R 3 is —NHC(═O)R 9 .
52. The method of claim 51 , wherein R 4 is H and R 9 is selected from the group consisting of —(C 2-5 alkyl), phenyl, -carbocyclyl and —CH 2 carbocyclyl.
53. The method of claim 46 , wherein R 3 is —NHSO 2 R 10 .
54. The method of claim 53 , wherein R 4 is H and R 10 is selected from the group consisting of —(C 1-4 alkyl) and phenyl.
55. The method of claim 46 , wherein R 3 is -heterocyclylR 8 .
56. The method of claim 55 , wherein R 4 is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
57. The method of claim 46 , wherein R 3 is H and R 4 is amino.
58. The method of claim 46 , wherein R 2 is -heteroarylR 5 .
59. The method of claim 58 , wherein R 2 is -pyridin-3-ylR 5 .
60. The method of claim 59 , wherein R 2 is -pyridin-3-ylR 5 and R 5 is 1-2 fluorine atoms.
61. The method of claim 46 , wherein R 2 is thiopheneR 5 .
62. The method of claim 46 , wherein R 2 is -heterocyclylR 6 .
63. The method of claim 62 , wherein R 2 is -heterocyclylR 6 , in which R 6 is selected from the group consisting of H, F and —(C 1-4 alkyl), and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
64. The method of claim 46 , wherein R 2 is -arylR 7 .
65. The method of claim 64 , wherein R 2 is -phenylR 7 and R 7 is 1-2 fluorine atoms.
66. The method of claim 64 , wherein R 2 is -phenylR 7 and R 7 is 2 substituents consisting of 1 fluorine atom and either —NR 12 (C 1-6 alkyl)NR 11 R 12 or —(C 1-6 alkyl)NHSO 2 R 11 .
67. The method of claim 1 , wherein the mammal is a human.
68. The method of claim 44 , wherein the cell is a human cell.
69. The method of claim 68 , wherein the human cell is a cancerous cell.
70. The method of claim 69 , wherein the cancerous cell is a colon cancer cell.
71. The method of claim 44 , wherein the contacting is in vitro.
72. The method of claim 44 , wherein the compound inhibits a kinase activity.
73. The method of claim 44 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
74. The method of claim 44 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
75. The method of claim 44 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
76. The method of claim 50 , wherein the compound inhibits one or more proteins in the Wnt pathway.
77. The method of claim 76 , wherein the compound inhibits signaling induced by one or more Wnt proteins.
78. The method of claim 77 , 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.
79. The method of claim 72 , wherein the protein kinase is from the CDK, VEGF, CLK, HIPK, Abl, JAK, or CHK families of kinases.