Indazole-3-carboxamides and their use as Wnt/β-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 a disorder selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver; liver fibrosis; adhesions, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis; fibrotic scarring in neuro-degenerative disorders; fibrotic scarring in proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis, in a subject, the method comprising administering to the subject in need thereof 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, —OW 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 , and 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 , —CH 2 pyrrolidinylR 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. A method of treating a fibrotic disorder in a subject, the method comprising administering to the subject in need thereof a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is 3-pyridylR 6 ;
R 5 is selected from the group consisting of pyridylR 7 , -pyrimidinylR 7 , and -pyridazinylR 7 ;
R 6 is —CH 2 heterocyclylR 8 ;
R 7 is 1-2 substituents each independently selected from the group consisting of H, F, methyl, —NH 2 , —CF 3 , —CN, —OMe, —SO 2 Me,
R 8 is 1-2 substituents each independently selected from the group consisting of H and halide.
21. The method of claim 20 , wherein the R 6 heterocyclyl is selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 .
22. The method of claim 20 , wherein R 6 is —CH 2 piperidinylR 8 .
23. The method of claim 22 , wherein R 7 is selected from the group consisting of H, —CF 3 , —OMe, —CN,
24. A method of treating scleroderma in a subject, the method comprising administering to the subject in need thereof 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, —(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.
25. A method of treating scleroderma in a subject, the method comprising administering to the subject in need thereof a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is 3-pyridylR 6 ;
R 5 is selected from the group consisting of pyridylR 7 , -pyrimidinylR 7 , and -pyridazinylR 7 ;
R 6 is —CH 2 heterocyclylR 8 ;
R 7 is 1-2 substituents each independently selected from the group consisting of H, F, methyl, —NH 2 , —CF 3 , —CN, —OMe, -OEt, -OiPr, —SO 2 Me,
and
R 8 is 1-2 substituents each independently selected from the group consisting of H and halide.
26. The method of claim 25 , wherein the R 6 heterocyclyl is independently selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 .
27. The method of claim 25 , wherein R 6 is —CH 2 piperidinylR 8 .
28. The method of claim 27 , wherein R 7 is selected from the group consisting of H, —OMe, -OEt, -OiPr, —CF 3 , —CN,
29. The method of claim 25 , wherein the compound of Formula (Ia) has a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
30. The method of claim 25 , wherein the compound of Formula (Ia) is:
or a pharmaceutically acceptable salt thereof.
31. The method of claim 20 , wherein the fibrotic disorder is a skin fibrosis.
32. The method of claim 20 , wherein the fibrotic disorder is scleroderma.
33. The method of claim 20 , wherein the fibrotic disorder is pulmonary fibrosis.
34. The method of claim 20 , wherein the fibrotic disorder is renal fibrosis.
35. The method of claim 20 , wherein the fibrotic disorder is cirrhosis of the liver.
36. The method of claim 20 , wherein the fibrotic disorder is liver fibrosis.
37. The method of claim 20 , wherein the subject is a human.