Isoquinolin-3-yl carboxamides and preparation and use thereof
Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an isoquinoline compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, 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 a pharmaceutically acceptable salt thereof, of Formula I:
wherein:
R 1 , R 2 , R 4 , and R 5 are H;
R 3 is
R 6 is -pyridinyl substituted with one R 37 ;
R 7 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), and -carbocyclyl;
R 37 is independently selected from the group consisting of —XR 42 and -heterocyclyl optionally substituted with 1-3 R 43 ;
R 42 is -heterocyclyl optionally substituted with 1-3 R 43 ;
each R 43 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —OH, —N(R 50 ) 2 , and -carbocyclyl;
R 48 is independently selected from the group consisting of H and Me;
each R 50 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);
and X is selected from the group consisting of O, S, and NR 48 .
2. The compound of claim 1 , wherein R 7 is —(C 1-3 alkyl).
3. The compound of claim 2 , wherein R 7 is methyl.
4. The compound of claim 3 , wherein R 6 is -pyridin-3-yl substituted with one R 37 .
5. The compound of claim 3 , wherein R 6 is -pyridin-4-yl substituted with one R 37 .
6. The compound of claim 4 , wherein R 37 is selected from the group consisting of -heterocyclyl optionally substituted with one R 43 , —Oheterocyclyl optionally substituted with one R 43 , and —NHheterocyclyl optionally substituted with one R 43 .
7. The compound of claim 5 , wherein R 37 is selected from the group consisting of -heterocyclyl optionally substituted with one R 43 , —Oheterocyclyl optionally substituted with one R 43 , and —NHheterocyclyl optionally substituted with one R 43 .
8. The compound of claim 7 , wherein R 37 is -heterocyclyl substituted with one R 43 .
9. The compound of claim 8 , wherein the -heterocyclyl is selected from the group consisting of azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[3.5]nonanyl, and morpholinyl.
10. The compound of claim 9 , wherein R 43 is selected from the group consisting of —(C 1-3 alkyl), —NMe 2 , and -carbocyclyl.
11. The compound of claim 10 , wherein the -heterocyclyl is piperazinyl.
12. The compound of claim 10 , wherein the -heterocyclyl is piperidinyl.
13. The compound of claim 11 , wherein R 43 is methyl.
14. The compound of claim 12 , wherein R 43 is methyl.
15. The compound of claim 12 , wherein R 43 is —NMe 2 .
16. A compound of Formula I selected from the group consisting of:
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure selected from the group consisting of:
thereof, and a pharmaceutically acceptable carrier.
20. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 16 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.