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 of treating a bone or cartilage disease selected from the group consisting of osteoarthritis and osteochondrodysplasia in a subject, the method comprising administering to the subject 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 -arylR 7 ;
R 3 is a —NHC(=O)R 9 ;
R 4 is H;
each R 7 is independently 1-2 substituents each selected from the group consisting of halide, —CF 3 , —CN, —(C 1-6 alkyl)NHSO 2 R 11 , —(C 1-6 alkyl)NR 11 R 12 , and —NR 12 (C 1-6 alkyl)NR 11 R 12 ;
R 9 is selected from the group consisting of —(C 1-6 alkyl), -aryl, -carbocyclyl, and —CH 2 carbocyclyl;
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); and
each R 11 and R 12 are optionally linked to form a four to six membered heterocyclyl ring.
2. The method of claim 1 , wherein R 1 is pyridinylR 3 R 4 .
3. The method of claim 2 , wherein R 1 is pyridin-3-ylR 3 R 4 .
4. The method of claim 2 , wherein R 9 is —(C 1-6 alkyl).
5. The method of claim 2 , wherein R 9 is —(C 2-5 alkyl).
6. The method of claim 2 , wherein R 9 is carbocyclyl.
7. The method of claim 2 , wherein R 9 is —CH 2 carbocyclyl.
8. The method claim 2 , wherein R 9 is phenyl.
9. The method of claim 5 , wherein R 7 is halide.
10. The method of claim 9 , wherein R 7 is fluorine.
11. The method of claim 5 , wherein R 7 is 2 substituents consisting of a fluorine atom and —(C 1-6 alkyl)NR 11 R 12 .
12. The method of claim 11 , wherein R 11 and R 12 are both —(C 1-2 alkyl).
13. The method of claim 11 , wherein R 11 and R 12 are linked to form an azetidine ring.
14. The method of claim 11 , wherein R 11 and R 12 are linked to form a pyrrolidine ring.
15. The method of claim 11 , wherein R 11 and R 12 are linked to form a piperidine ring.
16. The method of claim 5 , wherein R 7 is 2 substituents consisting of a fluorine atom and —NR 12 (C 1-6 alkyl)NR 11 R 12 .
17. The method of claim 16 , wherein R 7 is 2 substituents consisting of a fluorine atom and —NHCH 2 CH 2 NR 11 R 12 .
18. The method of claim 17 , wherein R 11 and R 12 are both —(C 1-2 alkyl).
19. The method of claim 5 , wherein R 7 is 2 substituents consisting of a fluorine atom and —(C 1-6 alkyl)NHSO 2 R 11 .
20. The method of claim 19 , wherein R 7 is 2 substituents consisting of a fluorine atom and —CH 2 NHSO 2 R 11 .
21. The method of claim 20 , wherein R 11 is —(C 1-2 alkyl).
22. The method of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. A method of treating a bone or cartilage disease selected from the group consisting of osteoarthritis and osteochondrodysplasia in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is -pyridin-3-ylR 3 R 4 ;
R 2 is -phenylR 7 ;
R 3 is a —NHC(=O)R 9 ;
R 4 is H;
each R 7 is independently 1-2 substituents each selected from the group consisting of fluorine, —CH 2 NHSO 2 R 11 , —(C 1-6 alkyl)NR 11 R 12 ; and —NHCH 2 CH 2 NR 11 R 12 ;
R 9 is selected from the group consisting of —(C 2-5 alkyl), -phenyl, - carbocyclyl, and —CH 2 carbocyclyl;
each R 11 is independently selected from —(C 1-2 alkyl);
each R 12 is independently selected from the group consisting of H and —(C 1-2 alkyl); and
each R 11 and R 12 are optionally linked to form a four to six membered heterocyclyl ring.
24. The method of claim 23 , wherein R 9 is —(C 2-5 alkyl).
25. The method of claim 23 , wherein R 9 is carbocyclyl.
26. The method of claim 24 , wherein R 7 is one fluorine.
27. The method of claim 24 , wherein R 7 is 2 substituents consisting of a fluorine atom and —CH 2 NHSO 2 R 11 , and R 11 is —(C 1-2 alkyl).
28. The method of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
29. The method of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
30. The method of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
31. The method of claim 1 , wherein the bone or cartilage disease is osteoarthritis.
32. The method of claim 23 , wherein the bone or cartilage disease is osteoarthritis.
33. The method of claim 1 , wherein the bone or cartilage disease is osteochondrodysplasia.
34. The method of claim 23 , wherein the bone or cartilage disease is osteochondrodysplasia.
35. The method of claim 1 , wherein the subject is a human.
36. The method of claim 23 , wherein the subject is a human.
37. The method of claim 1 , wherein the subject is a non-human mammal.
38. The method of claim 23 , wherein the subject is a non-human mammal.