3-(benzoimidazol-2-YL)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure 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, of Formula I:
wherein:
R 1 is -pyridinylR 3 R 4 ;
R 2 is -thiophenylR 5 ;
R 3 is 1 substituent attached to the heteroaryl ring and is selected from the group consisting of H, C 1-3 alkyl, —CF 3 , —NR 9 R 10 , —NHC(═O)R 8 , and —(C 1-3 alkyl)NR 9 R 10 ;
R 4 is 1 substituent attached to the pyridinyl ring and is selected from the group consisting of H, C 1-3 alkyl, —CF 3 , halide, —CN, —OR 8 , —OH, —(C 1-3 alkyl)OR 8 , —NR 9 R 10 , —(C 1-3 alkyl)NR 9 R 10 and —OCF 3 ;
R 5 is 1-3 substituents attached to the pyridinyl ring and each is independently selected from the group consisting of H, C 1-3 alkyl, —CF 3 , halide, —CN, —OR 8 , —OH, —(C 1-3 alkyl)OR 8 , —NR 9 R 10 , —(C 1-3 alkyl)NR 9 R 10 and —OCF 3 ;
each R 8 is independently selected from the group consisting of C 1-9 alkyl, -arylR 14 , carbocyclylR 11 , —(C 1-3 alkyl)arylR 14 and —(C 1-3 alkyl)carbocyclylR 11 ;
each R 9 is independently selected from the group consisting of H, C 1-6 alkyl, -arylR 14 , carbocyclylR 1 , —(C 1-3 alkyl)arylR 14 and —(C 1-3 alkyl)carbocyclylR 11 ;
each R 10 is independently selected from the group consisting of H and C 1-6 alkyl;
R 11 is 1-3 substituents attached to the carbocyclyl ring and each independently selected from the group consisting of H, C 1-3 alkyl, —CF 3 , halide, —CN, —O(R 10 ), —(C 1-3 alkyl)OR 10 , —N(R 10 ) 2 , —(C 1-3 alkyl)N(R 10 ) 2 and —OCF 3 ; and
R 14 is 1-3 substituents attached to the aryl ring and each is independently selected from the group consisting of H, C 1-3 alkyl, —CF 3 , halide, —CN, —O(R 10 ), —(C 1-3 alkyl)OR 10 , —N(R 10 ) 2 , —(C 1-3 alkyl)N(R 10 ) 2 and —OCF 3 .
2. The compound of claim 1 , wherein R 1 is pyridin-3-ylR 3 R 4 .
3. The compound of claim 2 , wherein R 3 and R 4 are both H.
4. The compound of claim 2 , wherein R 3 is —C 1-2 alkyl and R 4 is H.
5. The compound of claim 2 , wherein R 3 is —CH 2 NR 9 R 10 .
6. The compound of claim 5 , wherein R 9 is —C 1-2 alkyl; R 10 is —(C 1-2 alkyl); and R 4 is H.
7. The compound of claim 5 , wherein R 4 and R 10 are both H; and R 9 is selected from the group consisting of —C 1-2 alkyl, —CH 2 phenyl and —CH 2 carbocyclyl.
8. The compound of claim 2 , wherein R 3 is —NHC(═O)R 8 .
9. The compound of claim 8 , wherein R 4 is H and R 8 is selected from the group consisting of —C 1-5 alkyl, —CH 2 phenyl, phenyl and -carbocyclyl.
10. The compound of claim 2 , wherein R 3 is —NR 9 R 10 .
11. The compound of claim 2 , wherein R 3 is —NH 2 and R 4 is H.
12. The compound of claim 10 , wherein R 9 is —C 1-2 alkyl; R 10 is —C 1-2 alkyl; and R 4 is H.
13. The compound of claim 10 , wherein R 4 and R 9 are both H; and R 10 is —C 1-4 alkyl.
14. The compound of claim 2 , wherein R 3 is selected from the group consisting of:
15. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. 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.