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 pyridinylR 6 , pyrimidinylR 6 , pyridazinylR 6 , and pyrazinylR 6 ;
R 5 is selected from the group consisting of -piperazinylR 7 , -tetrahydropyranylR 7 , -piperidinylR 7 , pyrazolylR 7 , pyrimidinylR 7 , pyridazinylR 7 , benzo[d][1,3]dioxolylR 7 , 2,3-dihydrobenzo[b][1,4]dioxinylR 7 , pyrazinylR 7 , and 3-pyridylR 7 ;
each R 6 is 1-2 substituents each selected from the group consisting of (C 1-2 alkyl)heterocyclylR 8 , -heterocyclylR 8 , -(C 1-2 alkyl)arylR 8 , —N(R 10 )C(═O)R 11 and —(C 1-2 alkyl)N(R 10 ) 2 ;
each R 7 is 1-2 substituents each selected from the group consisting of unsubstituted C 1-3 alkyl, halide, amino, —OCF 3 , —CF 3 , —CN, —OR 10 , —C(═O)R 11 , —N(R 10 )C(═O)R 11 , —N(R 10 ) 2 , —(C 1-2 alkyl)N(R 10 ) 2 , and —N(R 10 )SO 2 R 11 ;
each R 8 is 1-2 substituents each selected from the group consisting of H, C 1-3 alkyl, halide, amino, OCF 3 , —CF 3 —CN and —OR 12 ;
each R 10 is independently selected from the group consisting of H, C 1-3 alkyl, —(C 1-3 alkyl)N(R 14 ) 2 and -arylR 8 ;
each R H is independently selected from the group consisting of C 1-3 alkyl, —N(R 14 ) 2 , -carbocyclylR 8 and -heterocyclylR 8 ; and
each R 12 is independently selected from the group consisting of H and C 1-3 alkyl;
each R 14 is independently selected from the group consisting of H, C 1-3 alkyl and carbocyclyl.
2. The compound of claim 1 , wherein R 6 is one substituent and is (CH 2 )heterocyclylR 8 .
3. The compound of claim 2 , wherein R 5 is 3-pyridylR 7 .
4. The compound of claim 3 , wherein R 7 is one substituent and is selected from the group consisting of —XR 10 where X is O, and —C(═O)R 11 where R 11 is —N(R 10 ) 2 , and each R 10 is independently selected from the group consisting of H, methyl and —(C 1-9 alkyl) n carbocyclylR 8 where n is 0 and each R 8 is 1-2 substituents independently selected from H or halide.
5. The compound of claim 1 , wherein R 3 is 3-pyridylR 6 .
6. The compound of claim 1 , wherein R 3 is 5-pyrimidinylR 6 .
7. The compound of claim 1 , wherein R 3 is 4-pyridazinylR 6 .
8. The compound of any one of claim 5 - 7 wherein R 6 is one substituent and is N(R 9 )C(═O)R 10 .
9. The compound of claim 1 , wherein R 5 is 3-pyridylR 7 .
10. The compound of claim 1 , wherein R 5 is 5-pyrimidinylR 7 .
11. The compound of claim 1 wherein R 5 is 4-pyridazinylR 7 .
12. The compound of any one of claims 9 - 11 , wherein R 7 is one substituent and is selected from the group consisting of halide, —OCF 3 , —CF 3 , (C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 11 and —N(R 10 )C(═O)R 11 .
13. The compound of claim 1 having a structure selected from the group consisting of:
14. The compound of claim 13 having a structure selected from the group consisting of:
15. The compound of claim 13 having a structure selected from the group consisting of:
16. The compound of claim 13 having a structure selected from the group consisting of:
17. The compound of claim 13 having a structure selected from the group consisting of:
18. The compound of claim 13 having a structure selected from the group consisting of:
19. The compound of claim 13 having a structure selected from the group consisting of:
20. The compound of claim 13 having a structure selected from the group consisting of:
21. The compound of claim 13 having a structure selected from the group consisting of:
22. A compound selected from the group consisting of:
23. The compound of claim 22 having a structure selected from the group consisting of:
24. The compound of claim 22 having a structure selected from the group consisting of:
25. The compound of claim 22 having a structure selected from the group consisting of:
26. The compound of claim 22 having a structure selected from the group consisting of:
27. The compound of claim 22 having a structure selected from the group consisting of:
28. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.