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 compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:
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 compound of claim 1 , wherein R 1 is pyridinylR 3 R 4 .
3. The compound of claim 2 , wherein R 1 is pyridin-3-ylR 3 R 4 .
4. The compound of claim 2 , wherein R 9 is —(C 1-6 alkyl).
5. The compound of claim 2 , wherein R 9 is —(C 2-5 alkyl).
6. The compound of claim 2 , wherein R 9 is carbocyclyl.
7. The compound of claim 2 , wherein R 9 is —CH 2 -carbocyclyl.
8. The compound of claim 2 , wherein R 9 is phenyl.
9. The compound of claim 5 , wherein R 7 is halide.
10. The compound of claim 9 , wherein R 7 is fluorine.
11. The compound 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 compound of claim 11 , wherein R 11 and R 12 are both —(C 1-2 alkyl).
13. The compound of claim 11 , wherein R 11 and R 12 are linked to form an azetidine ring.
14. The compound of claim 11 , wherein R 11 and R 12 are linked to form a pyrrolidine ring.
15. The compound of claim 11 , wherein R 11 and R 12 are linked to form a piperidine ring.
16. The compound 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 compound 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 compound of claim 17 , wherein R 11 and R 12 are both —(C 1-2 alkyl).
19. The compound 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 compound of claim 19 , wherein R 7 is 2 substituents consisting of a fluorine atom and —CH 2 NHSO 2 R 11 .
21. The compound of claim 20 , wherein R 11 is —(C 1-2 alkyl).
22. The compound of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:
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 compound of claim 23 , wherein R 9 is —(C 2-5 alkyl).
25. The compound of claim 23 , wherein R 9 is carbocyclyl.
26. The compound of claim 24 , wherein R 7 is one fluorine.
27. The compound 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. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29. The compound of claim 1 , having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.