1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof
Provided herein are compounds according to Formula I and pharmaceutically acceptable salts thereof, and compositions comprising the same, for use in various methods, including treating cancers such as colon, ovarian, pancreatic, breast, liver, prostate and hematologic cancers:
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 Ib:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 3 , R 5 , R 6 , and R 8 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C1 -9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
one of each R 1 and R 2 , R 2 and R 3 , or R 5 and R 6 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 9 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;
alternatively, two adjacent R 9 , may be taken together with the atoms to which they are attached to form a carbocyclyl or heterocyclyl;
each R 10 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 11 is independently selected from the group consisting of —OR 9 and R 9 ;
each R 12 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 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
R 14 and R 15 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
alternatively, R 14 and R 15 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 11 ;
Y 1 , Y 2 and Y 4 are carbon;
Y 3 is nitrogen;
R 7 is absent; and
each n is 0 or 1.
2. The method of claim 1 , wherein n is 0.
3. The method of claim 1 , wherein n is 1.
4. The method of claim 1 , wherein A is O.
5. The method of claim 1 , wherein R 1 and R 3 are H and R 2 is selected from the group consisting of -carbocyclylR 12 , -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .
6. The method of claim 5 , wherein R 2 is -heteroarylR 12 .
7. The method of claim 6 , wherein the heteroaryl is pyridine.
8. The method of claim 6 , wherein R 12 is selected from the group consisting of —NHC(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —NHC(═O)R 9 , —NHC(═O)CH(R 9 ) 2 and —NHSO 2 R 9 .
9. The method of claim 8 , R 9 is selected from the group consisting of H, —C 1-4 alkyl, carbocyclyl and -heterocyclyl.
10. The method of claim 1 , wherein R 6 and R 8 are H and R 5 is selected from the group consisting of H, -heterocyclylR 12 , -arylR 12 , -heteroarylR 12 , —N(R 9 )C(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)CH(R 9 ) 2 , —CN, —CO 2 R 9 and —C(═O)R 9 .
11. The method of claim 10 , wherein R 5 is selected from the group consisting of -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .
12. The method of claim 11 , wherein R 12 is selected from the group consisting of H and halide.
13. The method of claim 11 , wherein the heteroaryl is pyridine.
14. The method of claim 10 , wherein R 5 is selected from the group consisting of H, —C(═O)N(R 9 ) 2 and —CN.
15. The method of claim 14 , wherein R 9 is selected from the group consisting of H and —C 1-4 alkyl, alternatively, R 9 is taken together to form a fused ring with the nitrogen.
16. The method of claim 1 , wherein the compound of Formula (Ib) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein R 1 , R 3 , R 6 , and R 8 are H; R 2 is heteroarylR 12 , R 5 is arylR 12 .
18. The method of claim 17 , wherein R 5 is selected from the group consisting of:
19. The method of claim 18 , wherein R 2 is pyridineR 12 and R 12 is selected from the group consisting of —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , and —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , R 9 is selected from a group consisting of H and C 1-9 alkyl; and A is O.
20. The method of claim 19 , wherein R 5 is selected from the group consisting of:
21. The method of claim 1 , wherein the compound of Formula (Ib) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. A method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula Ib:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 3 , R 5 , R 6 , and R 8 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C1 -9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
one of each R 1 and R 2 , R 2 and R 3 , or R 5 and R 6 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 9 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;
alternatively, two adjacent R 9 , may be taken together with the atoms to which they are attached to form a carbocyclyl or heterocyclyl;
each R 10 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 11 is independently selected from the group consisting of —OR 9 and R 9 ;
each R 12 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 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
R 14 and R 15 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;
alternatively, R 14 and R 15 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 11 ;
Y 1 , Y 2 and Y 4 are carbon;
Y 3 is nitrogen;
R 7 is absent; and
each n is 0 or 1.
23. The method of claim 1 , wherein the compound inhibits signaling induced by one or more Wnt proteins.
24. The method of claim 23 , 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.
25. The method of claim 1 , wherein the compound inhibits a kinase activity.
26. The method of claim 22 , wherein the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer leukemia, lymphoma, sarcoma, and ovarian cancer.
27. The method of claim 22 , wherein the cancer is hepatocellular carcinoma.
28. The method of claim 22 , wherein the cancer is colon cancer.
29. The method of claim 22 , wherein the cancer is colorectal cancer.
30. The method of claim 22 , wherein the cancer is breast cancer.
31. The method of claim 22 , wherein the cancer is pancreatic cancer.
32. The method of claim 22 , wherein the cancer is leukemia.
33. The method of claim 22 , wherein the cancer is lymphoma.
34. The method of claim 22 , wherein the cancer is sarcoma.
35. The method of claim 22 , wherein the cancer is ovarian cancer.
36. The method of claim 22 , wherein the cancer is lung cancers.
37. The method of claim 22 , wherein the cancer is melanoma.
38. The method of claim 22 , wherein the cancer is squamous cell carcinoma.
39. The method of claim 22 , wherein the cancer is adenocarcinoma.
40. The method of claim 22 , wherein the patient is a human.
41. The method of claim 1 , wherein the cell is a human cell.
42. The method of claim 41 , wherein the human cell is a cancerous cell.
43. The method of claim 42 , wherein the cancerous cell is a colon cancer cell.
44. The method of claim 1 , wherein the contacting is in vitro.
45. The method of claim 25 , wherein the protein kinase is from the CDK, VEGF, CLK, HIPK, Abl, JAK, or CHK families of kinases.
46. The method of claim 22 , wherein n is 0.
47. The method of claim 22 , wherein n is 1.
48. The method of claim 22 , wherein A is O.
49. The method of claim 22 , wherein R 1 and R 3 are H and R 2 is selected from the group consisting of -carbocyclylR 12 , -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .
50. The method of claim 49 , wherein R 2 is -heteroarylR 12 .
51. The method of claim 50 , wherein the heteroaryl is pyridine.
52. The method of claim 50 , wherein R 12 is selected from the group consisting of —NHC(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —NHC(═O)R 9 , —NHC(═O)CH(R 9 ) 2 and —NHSO 2 R 9 .
53. The method of claim 52 , R 9 is selected from the group consisting of H, —C 1-4 alkyl, carbocyclyl and -heterocyclyl.
54. The method of claim 22 , wherein R 6 and R 8 are H and R 5 is selected from the group consisting of H, -heterocyclylR 12 , -arylR 12 , -heteroarylR 12 , —N(R 9 )C(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)CH(R 9 ) 2 , —CN, —CO 2 R 9 and —C(═O)R 9 .
55. The method of claim 54 , wherein R 5 is selected from the group consisting of -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .
56. The method of claim 55 , wherein R 12 is selected from the group consisting of H and halide.
57. The method of claim 55 , wherein the heteroaryl is pyridine.
58. The method of claim 54 , wherein R 5 is selected from the group consisting of H, —C(═O)N(R 9 ) 2 and —CN.
59. The method of claim 58 , wherein R 9 is selected from the group consisting of H and —C 1-4 alkyl, alternatively, R 9 is taken together to form a fused ring with the nitrogen.
60. The method of claim 22 , wherein the compound of Formula (Ib) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
61. The method of claim 22 , wherein R 1 , R 3 , R 6 , and R 8 are H; R 2 is heteroarylR 12 ; and R 5 is arylR 12 .
62. The method of claim 61 , wherein R 5 is selected from the group consisting of:
63. The method of claim 62 , wherein R 2 is pyridineR 12 and R 12 is selected from the group consisting of —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , and —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , R 9 is selected from a group consisting of H and C 1-9 alkyl; and A is O.
64. The method of claim 63 , wherein R 5 is selected from the group consisting of:
65. The method of claim 22 , wherein the compound of Formula (Ib) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.