5-heteroaryl substituted indazole-3-carboxamides and preparation and use thereof

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

wherein:

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

R 3 is a 5-membered heteroaryl ring optionally substituted with from 1-4 R 42 ;

R 5 is aryl optionally substituted with 1-5 R 29 ;

each R 29 is independently selected from the group consisting of halide, —OR 38 , unsubstituted —(C 1 -9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 39 , —NHheterocyclyl optionally substituted with 1-10 R 40 , and —O(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 40 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

each R 38 is independently selected from the group consisting of H, unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), and unsubstituted —(C 1-4 haloalkyl);

each R 39 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 40 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 42 is independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p OH, —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 43 , and -carbocyclyl optionally substituted with 1-12 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

alternatively, two adjacent R 42 groups are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 45 and -carbocyclyl optionally substituted with 1-12 R 46 ;

each R 43 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 44 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 45 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 46 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN; and

each p is independently 0 or 1.

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

wherein:

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

R 3 is selected from the group consisting of:

wherein each of R 6 -R 25 is, independently, a substituent as defined below or a single bond connecting R 3 to the indazole ring; wherein only one of R 6 -R 9 (when present) is a bond, only one of R 10 -R 13 (when present) is a bond, only one of R 14 -R 16 (when present) is a bond, only one of R 17 -R 19 (when present) is a bond, only one of R 20 -R 22 is a bond, and only one of R 23 -R 25 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R 6 , R 10 , R 14 , or R 17 can serve as the point of attachment of R 3 to the indazole ring; likewise, any one of the carbon atoms attached to R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 can serve as the point of attachment of R 3 to the indazole ring; accordingly:

when the nitrogen atom to which R 6 is attached serves as the point of attachment of R 3 to the indazole ring, then R 6 is a single bond connecting R 3 to the indazole ring;

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

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

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

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

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

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

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

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

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

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

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

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

when the carbon atom to which R 19 is attached is instead attached to the indazole ring then R 19 is a single bond connecting R 3 to the indazole ring;

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

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

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

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

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

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

R 5 is aryl optionally substituted with 1-5 R 29 ;

R 6 is independently selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 30 , and -carbocyclyl optionally substituted with 1-12 R 31 ; wherein —(C 1-4 alkylene) is, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

R 7 , R 8 , and R 9 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p OH, and —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 27 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

alternatively, one of R 6 and R 7 , R 7 and R 8 , or R 8 and R 9 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 32 and -carbocyclyl optionally substituted with 1-12 R 33 ;

R 10 is independently selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 30 , and -carbocyclyl optionally substituted with 1-12 R 31 ; wherein —(C 1-4 alkylene) is, optionally substituted with a substituent as defined anywhere herein 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

R 11 , R 12 , and R 13 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

alternatively, one of R 10 and R 11 , R 11 and R 12 , or R 13 and R 10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 32 and -carbocyclyl optionally substituted with 1-12 R 33 ;

R 14 is independently selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 30 , and -carbocyclyl optionally substituted with 1-12 R 31 ; wherein —(C 1-4 alkylene) is, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

R 15 and R 16 are independently selected from the group consisting of H, halide, unsubstituted 9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

alternatively, one of R 14 and R 15 or R 16 and R 14 are taken together to form a heterocyclyl optionally substituted with 1-10 R 32 ;

R 17 is independently selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 30 , and -carbocyclyl optionally substituted with 1-12 R 31 ; wherein —(C 1-4 alkylene) is, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

R 18 and R 19 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

alternatively, R 18 and R 19 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 32 and -carbocyclyl optionally substituted with 1-12 R 33 ;

R 20 , R 21 , and R 22 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

alternatively, one of R 20 and R 21 or R 21 and R 22 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 32 and -carbocyclyl optionally substituted with 1-12 R 33 ;

R 23 , R 24 , and R 25 are independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), and unsubstituted —(C 1-9 haloalkyl);

alternatively, R 23 and R 24 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 32 and -carbocyclyl optionally substituted with 1-12 R 33 ;

each R 29 is independently selected from the group consisting of halide, —OR 38 , unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 39 , —NHheterocyclyl optionally substituted with 1-10 R 40 , and —O(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 40 ; wherein —(C 1-4 alkylene) is, optionally substituted with 1-5 halo or 1-5 unsubstituted —(C 1-3 alkyl);

each R 30 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 31 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 32 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 33 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 38 is independently selected from the group consisting of H, unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), and unsubstituted —(C 1-4 haloalkyl);

each R 39 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 40 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each R 46 is independently selected from the group consisting of unsubstituted —(C 1-4 alkyl), unsubstituted —(C 2-4 alkenyl), unsubstituted —(C 2-4 alkynyl), unsubstituted —(C 1-4 haloalkyl), halide, and —CN;

each X is O or S; and

each p is independently 0 or 1.

3. The compound of claim 1 , wherein R 1 , R 2 and R 4 are H.

4. The compound of claim 2 , wherein R 1 , R 2 and R 4 are H.

5. The compound of claim 4 , wherein R 3 is

6. The compound of claim 5 , wherein R 6 is selected from the group consisting of H, unsubstituted —(C 1-3 alkyl), unsubstituted —(C 1-2 haloalkyl), and —(C 3-4 carbocyclyl) optionally substituted with 1-2 R 31 .

7. The compound of claim 5 , wherein R 7 is selected from the group consisting of H, halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

8. The compound of claim 5 , wherein R 9 is selected from the group consisting of H and halide.

9. The compound of claim 4 , wherein R 3 is

10. The compound of claim 9 , wherein R 10 is selected from the group consisting of H, unsubstituted —(C 1-3 alkyl), unsubstituted —(C 1-2 haloalkyl), and —(C 3-4 carbocyclyl) optionally substituted with 1-2 R 31 .

11. The compound of claim 9 , wherein R 12 is selected from the group consisting of H and halide.

12. The compound of claim 9 , wherein R 13 is selected from the group consisting of H, halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

13. The compound of claim 4 , wherein R 3 is

14. The compound of claim 13 , wherein R 24 is selected from the group consisting of H and halide.

15. The compound of claim 13 , wherein R 25 is selected from the group consisting of H, halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

16. The compound of claim 4 , wherein R 3 is

17. The compound of claim 16 , wherein R 14 is selected from the group consisting of H, unsubstituted —(C 1-3 alkyl), unsubstituted —(C 1-2 haloalkyl), and —(C 3-4 carbocyclyl) optionally substituted with 1-2 R 31 .

18. The compound of claim 16 , wherein R 16 is selected from the group consisting of H, halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

19. The compound of claim 4 , wherein R 5 is aryl optionally substituted with 1-2 R 29 .

20. The compound of claim 19 , wherein R 5 is -phenyl substituted with 1-2 R 29 .

21. The compound of claim 20 , wherein R 29 is independently selected from the group consisting of F, —OH, —OCHF 2 , —OCF 3 , methyl, —CF 3 ,

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

or a pharmaceutically acceptable salt thereof.

23. 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.

24. 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.