6-(5-membered heteroaryl)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 independently selected from the group consisting of H and halide;

R 3 is a 5-membered heteroaryl substituted with 1-4 R 26 ;

with the proviso that R 3 is not

R 6 is selected from the group consisting of —CH 2 phenyl substituted with 1-5 R 41 , —CH═CHphenyl optionally substituted with halide, —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-5 R 27 , -carbocyclyl substituted with 1-5 R 28 , and

wherein —(C 1-4 alkylene) is, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl); wherein n is 1-4, m is 0-2 and each Z is independently selected from the group consisting of CR 32 and N;

each R 26 is independently unsubstituted —(C 1-5 alkyl);

each R 27 is independently selected from the group consisting of halide and —N(R 43 )(R 44 ), with the proviso that if one or more R 27 is halide, at least one R 27 is —N(R 43 )(R 44 );

each R 28 is independently —N(R 33 )(R 34 );

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

R 33 is attached to the nitrogen and selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

R 34 is attached to the nitrogen and is selected from the group consisting of unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 , —(C 1-4 alkylene)OR 35 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 35 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);

each R 38 is independently selected from the group consisting of halide and unsubstituted —(C 1-5 alkyl);

each R 39 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), —CN, and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 40 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 40 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), and —CN;

each R 41 is halide;

each R 43 is attached to the nitrogen and selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

each R 44 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 , and —(C 1-4 alkylene)OR 35 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

2. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and halide;

R 3 is selected from the group consisting of:

wherein each of R 7 -R 25 is, independently, a substituent or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R 11 -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, and only one of R 24 -R 25 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R 7 , R 11 , R 15 , or R 18 can serve as the point of attachment of R 3 to the isoquinoline ring; likewise, any one of the carbon atoms attached to R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 can serve as the point of attachment of R 3 to the isoquinoline ring; so that:

when the nitrogen atom to which R 7 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 7 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 8 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 8 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 9 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 9 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 10 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 10 is a single bond connecting R 3 to the isoquinoline ring;

when the nitrogen atom to which R 11 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 11 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 12 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 12 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 13 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 13 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 14 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 14 is a single bond connecting R 3 to the isoquinoline ring;

when the nitrogen atom to which R 15 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 15 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 16 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 16 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 17 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 17 is a single bond connecting R 3 to the isoquinoline ring;

when the nitrogen atom to which R 18 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 18 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 19 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 19 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 26 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 20 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 21 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 21 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 22 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 22 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 23 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 23 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 24 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 24 is a single bond connecting R 3 to the isoquinoline ring;

when the carbon atom to which R 25 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 25 is a single bond connecting R 3 to the isoquinoline ring;

R 6 is selected from the group consisting of —CH 2 phenyl substituted with 1-5 R 41 , —CH═CHphenyl optionally substituted with halide, —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-5 R 27 , -carbocyclyl substituted with 1-5 R 28 , and

wherein —(C 1-4 alkylene) is, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl); wherein n is 1-4, m is 0-2 and each Z is independently selected from the group consisting of CR 32 and N;

R 7 is selected from the group consisting of a single bond and unsubstituted —(C 1-5 alkyl);

R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 11 is selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 15 is selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 16 and R 17 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 18 is selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 19 and R 20 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 21 , R 22 , and R 23 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

R 24 and R 25 are independently selected from the group consisting of a single bond, H, and unsubstituted —(C 1-5 alkyl);

each R 27 is independently selected from the group consisting of halide, and —N(R 43 )(R 44 ), with the proviso that if one or more R 27 is halide, at least one R 27 is —N(R 43 )(R 44 );

each R 28 is independently —N(R 33 )(R 34 );

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

R 33 is attached to the nitrogen and selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

R 34 is attached to the nitrogen and is selected from the group consisting of unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 , —(C 1-4 alkylene)OR 35 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or unsubstituted —(C 1-3 alkyl);

each R 35 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);

each R 38 is independently selected from the group consisting of halide and unsubstituted —(C 1-5 alkyl);

each R 39 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), —CN, and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 40 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 40 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), and —CN;

each R 41 is halide;

each R 43 is attached to the nitrogen and selected from the group consisting of H, unsubstituted -(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

each R 44 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 , and —(C 1-4 alkylene)OR 35 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each X is 0 or S;

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

3. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and halide;

R 3 is a 5-membered heteroaryl substituted with 1-4 R 26 ;

with the proviso that R 3 is not

R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-5 R 27 , -carbocyclyl optionally substituted with 1-5 R 28 , and —N(R 30 )(R 31 ); wherein —(C 1-4 alkylene) is, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 26 is independently unsubstituted —(C 1-5 alkyl);

each R 27 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 1-9 haloalkyl), —OR 35 , and —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-5 R 36 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

each R 28 is independently selected from the group consisting of —N(R 33 ) 2 , —(C 1-4 alkylene)OR 35 , —C(═O)(R 37 ), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-5 R 36 ; wherein each —(C 1-4 alkylene) is independently, optionally substituted with one or more halides or one or more unsubstituted —(C 1-3 alkyl);

R 30 is attached to the nitrogen and is selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);

R 31 is attached to the nitrogen and is heterocyclyl optionally substituted with 1-5 R 38 ;

R 33 is attached to the nitrogen and selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), and unsubstituted —(C 2-5 alkynyl);

each R 35 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);

each R 36 is selected from the group consisting of unsubstituted —(C 1-5 alkyl) and unsubstituted —(C 1-5 haloalkyl);

R 37 is -heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl);

each R 38 is independently selected from the group consisting of halide and unsubstituted —(C 1-5 alkyl);

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

5. The compound of claim 4 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and halide;

R 3 is a 5-membered heteroaryl optionally substituted with 1-4 R 26 ;

R 6 is a selected from the group consisting of -phenyl substituted with 1-5 R 42 and 6-membered heteroaryl optionally substituted with 1-6 R 29 ;

each R 26 is independently unsubstituted —(C 1-5 alkyl);

each R 29 is independently selected from the group consisting of unsubstituted —(C 1-5 alkyl) and heterocyclyl optionally substituted with 1-5 R 36 ;

each R 36 is independently unsubstituted (C 1-5 alkyl);

each R 42 is independently selected from the group consisting of halide, —OMe, and unsubstituted —(C 1-5 alkyl); and

wherein one or more H are optionally replaced by D.

7. The compound of claim 6 , wherein the compound of Formula I is selected from the group consisting of:

and or a pharmaceutically acceptable salt thereof.

8. 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.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. The compound of claim 2 , wherein R 3 is selected from the group consisting of:

and X is O or S.

13. The compound of claim 12 , wherein R 3 is selected from the group consisting of:

wherein R 7 is —(C 1-2 alkyl), and R 11 , R 14 , R 23 , and R 24 are independently selected from the group consisting of H and —(C 1-2 alkyl).

14. The compound of claim 13 , wherein R 6 is a -heterocyclyl optionally substituted with 1-2 R 27 .

15. The compound of claim 13 , wherein R 6 is a —CH 2 heterocyclyl optionally substituted with 1-2 R 27 .

16. The compound of claim 14 , wherein R 6 is either a piperidinyl or a pyrrolidinyl both optionally substituted with 1-2 R 27 .

17. The compound of claim 13 , wherein R 6 is selected from the group consisting of

and q is 1.

18. The compound of claim 16 , wherein R 6 is a piperidinyl substituted with one —N(R 43 )(R 44 ).

19. The compound of claim 17 , wherein R 43 is H or Me and R 44 is —C 1-4 haloalkyl.

20. The compound of claim 13 , wherein R 6 is —carbocyclyl substituted with 1-2 R 28 .

21. The compound of claim 4 , wherein R 3 is selected from the group consisting of a pyrazolyl substituted with one —(C 12 alkyl), imidazolyl substituted with 1-2 —(C 12 alkyl), oxazolyl substituted with one —(C 1-2 alkyl), and thiadiazolyl substituted with one —(C 1-2 alkyl).

22. The compound of claim 21 , wherein R 6 is -heterocyclyl optionally substituted with 1-2 R 27 .

23. The compound of claim 22 , wherein R 6 is selected from the group consisting of

and q is 1.

24. A method of inhibiting one or more proteins in the Wnt pathway, the method comprising contacting a cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.

25. A method of inhibiting one or more proteins in the Wnt pathway, the method comprising contacting a cell with an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.

26. A method of inhibiting one or more proteins in the Wnt pathway, the method comprising contacting a cell with an effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.

27. A method of inhibiting one or more proteins in the Wnt pathway, the method comprising contacting a cell with an effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.

28. The method of claim 24 , wherein the cell is a human cancerous cell.

29. The method of claim 25 , wherein the cell is a human cancerous cell.

30. The method of claim 26 , wherein the cell is a human cancerous cell.

31. The method of claim 27 , wherein the cell is a human cancerous cell.

32. The method of claim 24 , wherein the protein is a kinase and the kinase is selected from the group consisting of DYRK or GSK families of kinases.

33. The method of claim 25 , wherein the protein is a kinase and the kinase is selected from the group consisting of DYRK or GSK families of kinases.

34. The method of claim 26 , wherein the protein is a kinase and the kinase is selected from the group consisting of DYRK or GSK families of kinases.

35. The method of claim 27 , wherein the protein is a kinase and the kinase is selected from the group consisting of DYRK or GSK families of kinases.