Isoquinolin-3-yl carboxamides and preparation and use thereof
Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure 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, Alzheimer's disease, lung disease, inflammation, auto-immune diseases and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
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 selected from the group consisting of
and
R 6 is selected from the group consisting of -heterocyclyl optionally substituted with 1-3 R 36 ;
R 7 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), and -carbocyclyl;
each R 36 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene)OR 42 , -heterocyclyl optionally substituted with 1-2 R 43 , and —SO 2 (R 52 ); wherein —(C 1-4 alkylene) is optionally substituted with one or more halides;
each R 42 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);
each R 43 is independently selected from the group consisting of halide and unsubstituted —(C 1-5 alkyl); and
R 52 is selected from the group consisting of unsubstituted —(C 1-5 alkyl) and -aryl optionally substituted with one or more halides;
wherein one or more H are optionally replaced by D;
wherein each heterocyclyl is independently a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone.
2. The compound of claim 1 , wherein R 3 is
3. The compound of claim 1 , wherein R 3 is
4. The compound of claim 2 , wherein R 7 is —(C 1-3 alkyl).
5. The compound of claim 3 , wherein R 7 is —(C 1-3 alkyl).
6. The compound of claim 2 , wherein R 7 is H.
7. The compound of claim 2 , wherein R 7 is Me.
8. The compound of claim 3 , wherein R 7 is Me.
9. The compound of claim 7 , wherein R 6 is selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, 7-azaspiro[3.5]nonanyl, and 2-azaspiro[3.3]heptanyl, all optionally substituted with 1-2 R 36 .
10. The compound of claim 8 , wherein R 6 is selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, 7-azaspiro[3.5]nonanyl, and 2-azaspiro[3.3]heptanyl, all optionally substituted with 1-2 R 36 .
11. The compound of claim 9 , wherein R 6 is a piperidinyl substituted with one —(C 1-5 alkyl).
12. The compound of claim 9 , wherein R 6 is a piperidinyl substituted with one —(C 1-4 haloalkyl).
13. The compound of claim 9 , wherein R 6 is a piperidinyl substituted with one —SO 2 Me.
14. The compound of claim 10 , wherein R 6 is a piperidinyl substituted with one —(C 1-5 alkyl).
15. The compound of claim 10 , wherein R 6 is a piperidinyl substituted with one —(C 1-4 haloalkyl).
16. The compound of claim 10 , wherein R 6 is a piperidinyl substituted with one —SO 2 Me.
17. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 17 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. 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.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 17 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.