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 compound or pharmaceutically acceptable salt thereof having the structure of Formula Ia:
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 compound of claim 1 , wherein R 3 is 3-pyridylR 6 .
3. The compound of claim 2 , wherein R 6 is —(C 1-2 alkyl)heterocyclylR 8 .
4. The compound of claim 2 , wherein R 6 is -heterocyclylR 8 .
5. The compound 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 compound 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 compound 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 compound of claim 7 , wherein R 6 is —CH 2 piperidinylR 8 .
9. The compound of claim 7 , wherein R 6 is —CH 2 pyrrolidinylR 8 .
10. The compound of claim 7 , wherein R 6 is —CH 2 morpholinylR 8 .
11. The compound of claim 7 , wherein R 8 is 1-2 substituents each independently selected from the group consisting of H and F.
12. The compound of claim 11 , wherein R 5 is selected from the group consisting of -pyridylR 7 , -pyrimidinylR 7 , -pyridazinylR 7 , and -pyrazinylR 7 .
13. The compound of claim 12 , wherein R 5 is -3-pyridylR 7 .
14. The compound 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 compound 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 compound of claim 15 , wherein R 7 is selected from the group consisting of H, —NH 2 , —CF 3 , —CN, —OMe, —OEt, —OiPr,
17. The compound 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 compound 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. A compound or pharmaceutically acceptable salt thereof having the structure of Formula Ia:
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.
20. The compound of claim 19 , wherein the R 6 heterocyclyl is selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 .
21. The compound of claim 19 , wherein R 6 is —CH 2 piperidinylR 8 .
22. The compound of claim 21 , wherein R 7 is selected from the group consisting of H, —CF 3 , —OMe, —CN,
23. The compound of claim 22 , wherein R 8 is H.