Isoquinolin-3-YL carboxamides and preparation and use thereof

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 selected from the group consisting of —(C 1-2 alkylene) p heterocyclyl optionally substituted with 1-3 R 36. ; wherein —(C 1-4 alkylene) is optionally substituted with one or more halides;

R 32 is selected from the group consisting of H, halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —N(R 53 ) 2 ;

each R 36 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), —(C 1-4 alkylene)OR 42 , —(C 1-2 alkylene) p heterocyclyl optionally substituted with 1-2 R 43 , —(C 1-2 alkylene) p carbocyclyl optionally substituted with 1-2 R 44 , and —SO 2 (R 52 ); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides;

each R 42 is independently selected from the group consisting of H and unsubstituted —(C 1-3 alkyl);

each R 43 is independently selected from the group consisting of halide and unsubstituted —(C 1-3 alkyl);

each R 44 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), and unsubstituted —(C 1-5 haloalkyl);

each R 52 is selected from the group consisting of unsubstituted —(C 1-3 alkyl) and -aryl optionally substituted with one or more halides;

each R 53 is independently selected from the group consisting of H and unsubstituted —(C 1-2 alkyl);

X is O or S; and

each p is independently 0 or 1;

wherein one or more H are optionally replaced by D;

wherein each heterocyclyl is independently a nonaromatic cyclic ring system comprising at least one hetereoatom 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 32 is —(C 1-3 alkyl).

5. The compound of claim 3 , wherein R 32 is —(C 1-3 alkyl).

6. The compound of claim 2 , wherein R 32 is Me.

7. The compound of claim 3 , wherein R 32 is Me.

8. The compound of claim 6 , wherein R 6 is —(CH 2 )heterocyclyl optionally substituted with 1-2 R 36 .

9. The compound of claim 7 , wherein R 6 is —(CH 2 )heterocyclyl optionally substituted with 1-2 R 36 .

10. The compound of claim 8 , wherein the R 6 heterocyclyl is selected from the group consisting of piperidinyl, pyrrolidinyl, 1,4-oxazepanyl, piperazinyl, morpholinyl, and 2-oxa-5-azabicyclo[2.2.1]heptanyl, all optionally substituted with one R 36 .

11. The compound of claim 9 , wherein the R 6 heterocyclyl is selected from the group consisting of piperidinyl, pyrrolidinyl, 1,4-oxazepanyl, piperazinyl, morpholinyl, and 2-oxa-5-azabicyclo[2.2.1]heptanyl, all optionally substituted with one R 36 .

12. The compound of claim 10 , wherein R 6 is a —(CH 2 )piperidinyl optionally substituted with one R 36 ; wherein R 36 is selected from the group consisting of F, Cl, Me, CHF 2 , CF 3 , and cyclopropyl.

13. The compound of claim 10 , wherein R 6 is a —(CH 2 )pyrrolidinyl optionally substituted with one R 36 ; wherein R 36 is selected from the group consisting of F, Cl, and Me.

14. The compound of claim 10 , wherein R 6 is a —(CH 2 )morpholinyl optionally substituted with one Me.

15. The compound of claim 11 , wherein R 6 is a —(CH 2 )piperidinyl optionally substituted with one R 36 ; wherein R 36 is selected from the group consisting of F, Cl, Me, CHF 2 , CF 3 , and cyclopropyl.

16. The compound of claim 11 , wherein R 6 is a —(CH 2 )pyrrolidinyl optionally substituted with one R 36 ; wherein R 36 is selected from the group consisting of F, Cl, and Me.

17. The compound of claim 11 , wherein R 6 is a —(CH 2 )morpholinyl optionally substituted with one Me.

18. The compound of claim 1 , 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 18 , 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 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 18 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.