Indazole-3-carboxamides and their use as WNT/B-catenin signaling pathway inhibitors
Indazole-3-carboxamide compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole-3-carboxamide compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis 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 of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is selected from the group consisting of 3-pyridylR 6 , 5-pyrimidinylR 6 , and 4-pyridazinylR 6 ;
R 5 is selected from the group consisting of -heteroarylR 7 ;
R 6 is a substituent selected from the group consisting of -(C 1-2 alkyl)heterocyclylR 8 and -heterocyclylR 8 ;
R 7 is 1-2 substituents each independently selected from the group consisting of H, C 1-3 alkyl, halide, —NH 2 , —OCF 3 , —CF 3 , —CN, —OR 10 , -(C 1-2 alkyl)heterocyclylR 9 , -heterocyclylR 9 , and —SO 2 R 11 ;
R 8 is 1-2 substituents each independently selected from the group consisting of H, C 1-3 alkyl, halide, and —OR 12 ;
each R 9 is 1-2 substituents each independently selected from the group consisting of H, C 1-3 alkyl, halide, amino, —OCF 3 , —CF 3 , —CN, and —OR 12 ;
R 10 is selected from the group consisting of H and C 1-3 alkyl;
R 11 is C 1-3 alkyl; and
each R 12 is independently selected from the group consisting of H and C 1-3 alkyl.
2. The method of claim 1 , wherein R 3 is 3-pyridylR 6 .
3. The method of claim 2 , wherein R 6 is -(C 1-2 alkyl)heterocyclylR 8 .
4. The method of claim 2 , wherein R 6 is -heterocyclylR 8 .
5. The method of claim 1 , wherein the R 6 heterocyclyl is independently selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 , wherein the R 7 heterocyclyl is independently selected from the group consisting of azetidinylR 9 , pyrrolidinylR 9 , piperidinylR 9 , piperazinylR 9 , and morpholinylR 9 .
6. The method of claim 3 , wherein R 6 is selected from the group consisting of -(C 1-2 alkyl)piperidinylR 8 , -(C 1-2 alkyl)pyrrolidinylR 8 , and -(C 1-2 alkyl)morpholinylR 8 .
7. The method of claim 3 , wherein R 6 is selected from the group consisting of —CH 2 piperidinylR 8 , —CH2pyrrolidinylR 8 , and —CH 2 morpholinylR 8 .
8. The method of claim 7 , wherein R 6 is —CH 2 piperidinylR 8 .
9. The method of claim 7 , wherein R 6 is —CH 2 pyrrolidinylR 8 .
10. The method of claim 7 , wherein R 6 is —CH 2 morpholinylR 8 .
11. The method of claim 7 , wherein R 8 is 1-2 substituents each independently selected from the group consisting of H and F.
12. The method of claim 11 , wherein R 5 is selected from the group consisting of -pyridylR 7 , -pyrimidinylR 7 , -pyridazinylR 7 , and -pyrazinylR 7 .
13. The method of claim 12 , wherein R 5 is -3-pyridylR 7 .
14. The method of claim 13 , wherein R 7 is selected from the group consisting of H, C 1-3 alkyl, halide, —NH 2 , —CF 3 , —CN, —OR 10 , -heterocyclylR 9 , and —SO 2 R 11 .
15. The method of claim 14 , wherein R 7 is selected from the group
consisting of H, methyl, F, —NH 2 , —CF 3 , —CN, —OMe, —OEt, —OiPr, —SO 2 Me.
16. The method of claim 15 , wherein R 7 is selected from the group
consisting of H, —NH 2 , —CF 3 , —CN, —OMe, —OEt, —OiPr.
17. The method of claim 1 , wherein the compound of Formula (Ia) has a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound of Formula (Ia) has a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound of Formula (Ia) is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the cancer is colon cancer.
21. The method of claim 1 , wherein the cancer is colorectal cancer.
22. The method of claim 1 , wherein the cancer is leukemia.
23. The method of claim 1 , wherein the cancer is breast cancer.
24. The method of claim 1 , wherein the cancer is skin cancer.
25. The method of claim 1 , wherein the cancer is prostate cancer.
26. The method of claim 1 , wherein the cancer is lung cancer.
27. The method of claim 1 , wherein the cancer is liver cancer.
28. The method of claim 1 , wherein the subject is a human.