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 selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6 and -arylR 7 ;
R 3 is selected from the group consisting of H, -heterocyclylR 8 , —NHC(═O)R 9 , —NHSO 2 R 10 , —NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;
with the proviso that R 2 and R 3 are not both H;
R 4 is 1-3 substituents each selected from the group consisting of H, halide, —CF 3 , —CN, OR 13 and amino;
each R 5 is independently 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , —C(═O)R 11 , amino and —(C 1-6 alkyl)NR 11 R 12 ;
each R 6 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
each R 7 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , amino, -(C 1-6 alkyl)NHSO 2 R 11 , —NR 12 (C 1-6 alkyl)NR 11 R 12 and -(C 1-6 alkyl)NR 11 R 12 ;
R 8 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
R 9 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 and —CH 2 -carbocyclyl;
R 10 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 , and -carbocyclylR 14 ;
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;
each R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring;
each R 13 is independently selected from the group consisting of H and C 1-6 alkyl;
R 14 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;
with the proviso that Formula I is not a structure selected from the group consisting of:
2. The compound of claim 1 wherein R 1 is pyridineR 3 R 4 .
3. The compound of claim 2 wherein R 1 is pyridin-3-ylR 3 R 4 .
4. The compound of claim 3 wherein R 3 is —(C 1-6 alkyl)NR 11 R 12 .
5. The compound of claim 4 wherein R 3 is —(C 1-2 alkyl)NR 11 R 12 , R 11 is —(C 1-2 alkyl), R 12 is —(C 1-2 alkyl) and R 4 is H.
6. The compound of claim 4 wherein R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring and R 4 is H.
7. The compound of claim 6 wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.
8. The compound of claim 3 wherein R 3 is —NHC(═O)R 9 .
9. The compound of claim 8 wherein R 4 is H and R 9 is selected from the group consisting of —(C 2-5 alkyl), phenyl, -carbocyclyl and —CH 2 -carbocyclyl.
10. The compound of claim 3 wherein R 3 is —NHSO 2 R 10 .
11. The compound of claim 10 wherein R 4 is H and R 10 is selected from the group consisting of -(C 1-4 alkyl) and phenyl.
12. The compound of claim 3 wherein R 3 is -heterocyclylR 8 .
13. The compound of claim 12 wherein R 4 is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
14. The compound of claim 3 wherein R 3 is H and R 4 is amino.
15. The compound as in any of claims 3 - 14 , in which R 2 is -heteroarylR 5 .
16. The compound as in any of claims 3 - 14 , in which R 2 is -pyridin-3-ylR 5 .
17. The compound as in any of claims 3 - 14 , in which R 2 is -pyridin-3-ylR 5 and R 5 is 1-2 fluorine atoms.
18. The compound as in any of claims 3 - 14 , in which R 2 is thiopheneR 5 .
19. The compound as in any of claims 3 - 14 , in which R 2 is -heterocyclylR 6 .
20. The compound as in any of claims 3 - 14 , in which R 2 is -heterocyclylR 6 , in which R 6 is selected from the group consisting of H, F and -(C 1-4 alkyl), and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.
21. The compound as in any of claims 3 - 14 , in which R 2 is -arylR 7 .
22. The compound as in any of claims 3 - 14 , in which R 2 is -phenylR 7 and R 7 is 1-2 fluorine atoms.
23. The compound as in any of claims 3 - 14 , in which R 2 is -phenylR 7 and R 7 is 2 substituents consisting of 1 fluorine atom and either —NR 12 (C 1-6 alkyl)NR 11 R 12 or -(C 1-6 alkyl)NHSO 2 R 11 .
24. The compound of claim 1 having a structure selected from the group consisting of:
25. The compound of claim 1 having a structure selected from the group consisting of:
26. The compound of claim 1 having a structure selected from the group consisting of:
27. 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 excipient.
28. A compound or pharmaceutically acceptable salt thereof having a structure selected from the group consisting of: