1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof

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

wherein:

R 1 is H;

R 2 is independently selected from the group consisting of —(CH 2 )heterocyclyl(R 8 ) q and —NHC(═O)R 11 ;

R 3 is H;

R 4 is independently selected from the group consisting of H, -aryl(R 13 ) q , -heterocyclyl(R 14 ) q , and -heteroaryl(R 15 ) q ;

R 5 is H;

each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H and halide;

each R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, and —C 1-4 alkyl;

each R 9 is independently selected from the group consisting of H, —C 1-9 alkyl, —(C 1-3 alkyl) n carbocyclyl and —(C 1-9 alkyl)N(R 16 ) 2 ;

R 11 is selected from the group consisting of —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl, —C 1-9 alkyl and —CF 3 ;

each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, —CF 3 , CN, —(C 1-2 alkyl)heterocyclyl(R 8 ) q , —(C 1-2 alkyl) n N(R 9 ) 2 and —(C 1-2 alkyl) n NHSO 2 R 18 ;

each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 and CN;

each R 15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 , CN, —C(═O)(C 1-3 alkyl), —(C 1-2 alkyl) n N(R 9 ) 2 and —(C 1-2 alkyl) n NHSO 2 R 18 ;

each R 16 is independently selected from the group consisting of H and lower alkyl;

each R 18 is a lower alkyl;

A is C;

each q is an integer of 1 to 3;

each n is an integer of 0 or 1; and

with the proviso that Formula I is not a structure selected from the group consisting of:

2. The compound of claim 1 , wherein aryl is phenyl.

3. The compound of claim 1 , wherein heteroaryl is pyridinyl.

4. The compound of claim 1 , wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

5. The compound of claim 1 , wherein R 2 is —(CH 2 )heterocyclyl(R 8 ) q .

6. The compound of claim 1 , wherein R 2 is —NHC(═O)R 11 .

7. The compound of claim 5 , wherein R 8 is independently selected from the group consisting of H, Me, and halide; and q is 1-2.

8. The compound of claim 6 , wherein R 11 is selected from the group consisting of —C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) q , and —CH 2 phenyl(R 6 ) q .

9. The compound of claim 5 , wherein R 4 is phenyl(R 13 ) q .

10. The compound of claim 6 , wherein R 4 is phenyl(R 13 ) q .

11. The compound of claim 7 , wherein R 4 is phenyl(R 13 ) q .

12. The compound of claim 8 , wherein R 4 is phenyl(R 13 ) q .

13. The compound of claim 5 , wherein R 4 is -heterocyclyl(R 14 ) q .

14. The compound of claim 6 , wherein R 4 is -heterocyclyl(R 14 ) q .

15. The compound of claim 7 , wherein R 4 is -heterocyclyl(R 14 ) q .

16. The compound of claim 8 , wherein R 4 is -heterocyclyl(R 14 ) q .

17. The compound of claim 5 , wherein R 4 is -heteroaryl(R 15 ) q .

18. The compound of claim 6 , wherein R 4 is -heteroaryl(R 15 ) q .

19. The compound of claim 7 , wherein R 4 is -heteroaryl(R 15 ) q .

20. The compound of claim 8 , wherein R 4 is -heteroaryl(R 15 ) q .

21. The compound of claim 9 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

22. The compound of claim 10 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

23. The compound of claim 11 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

24. The compound of claim 12 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

25. The compound of claim 9 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

26. The compound of claim 10 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

27. The compound of claim 11 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

28. The compound of claim 11 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

29. The compound of claim 13 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

30. The compound of claim 14 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

31. The compound of claim 15 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

32. The compound of claim 16 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

33. The compound of claim 17 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

34. The compound of claim 18 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

35. The compound of claim 19 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

36. The compound of claim 20 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

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

pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R 1 is H;

R 2 is independently selected from the group consisting of —(CH 2 )heterocyclyl(R 8 ) q and —NHC(═O)R 11 ;

R 3 is H;

R 4 is independently selected from the group consisting of H, -aryl(R 13 ) q , -heterocyclyl(R 14 ) q , and -heteroaryl(R 15 ) q ;

R 5 is H;

each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H and halide;

each R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, and —C 1-4 alkyl;

each R 9 is independently selected from the group consisting of H, —C 1-9 alkyl, —(C 1-3 alkyl) n carbocyclyl and —(C 1-9 alkyl)N(R 16 ) 2 ;

R 11 is selected from the group consisting of —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl, —C 1-9 alkyl and —CF 3 ;

each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, —CF 3 , CN, —(C 1-2 alkyl)heterocyclyl(R 8 ) q , —(C 1-2 alkyl) n N(R 9 ) 2 and —(C 1-2 alkyl) n NHSO 2 R 18 ;

each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 and CN;

each R 15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 , CN, —C(═O)(C 1-3 alkyl), —(C 1-2 alkyl) n N(R 9 ) 2 and —(C 1-2 alkyl) n NHSO 2 R 18 ;

each R 16 is independently selected from the group consisting of H and lower alkyl;

each R 18 is a lower alkyl;

A is C;

each q is an integer of 1 to 3;

each n is an integer of 0 or 1; and

with the proviso that Formula I is not a structure selected from the group consisting of:

and

a pharmaceutically acceptable carrier.

40. The pharmaceutical composition of claim 39 , wherein aryl is phenyl.

41. The pharmaceutical composition of claim 39 , wherein heteroaryl is pyridinyl.

42. The pharmaceutical composition of claim 39 , wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

43. The pharmaceutical composition of claim 39 , wherein R 2 is —(CH 2 )heterocyclyl(R 8 ) q .

44. The pharmaceutical composition of claim 39 , wherein R 2 is —NHC(═O)R 11 .

45. The pharmaceutical composition of claim 43 , wherein R 8 is independently selected from the group consisting of H, Me, and halide; and q is 1-2.

46. The pharmaceutical composition of claim 44 , wherein R 11 is selected from the group consisting of —C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) q , and —CH 2 phenyl(R 6 ) q .

47. The pharmaceutical composition of claim 43 , wherein R 4 is phenyl(R 13 ) q .

48. The pharmaceutical composition of claim 44 , wherein R 4 is phenyl(R 13 ) q .

49. The pharmaceutical composition of claim 45 , wherein R 4 is phenyl(R 13 ) q .

50. The pharmaceutical composition of claim 46 , wherein R 4 is phenyl(R 13 ) q .

51. The pharmaceutical composition of claim 43 , wherein R 4 is -heterocyclyl(R 14 ) q .

52. The pharmaceutical composition of claim 44 , wherein R 4 is -heterocyclyl(R 14 ) q .

53. The pharmaceutical composition of claim 45 , wherein R 4 is -heterocyclyl(R 14 ) q .

54. The pharmaceutical composition of claim 46 , wherein R 4 is -heterocyclyl(R 14 ) q .

55. The pharmaceutical composition of claim 43 , wherein R 4 is -heteroaryl(R 15 ) q .

56. The pharmaceutical composition of claim 44 , wherein R 4 is -heteroaryl(R 15 ) q .

57. The pharmaceutical composition of claim 45 , wherein R 4 is -heteroaryl(R 15 ) q .

58. The pharmaceutical composition of claim 46 , wherein R 4 is -heteroaryl(R 15 ) q .

59. The pharmaceutical composition of claim 47 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

60. The pharmaceutical composition of claim 48 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

61. The pharmaceutical composition of claim 49 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

62. The pharmaceutical composition of claim 50 , wherein R 13 is one substituent attached to the phenyl comprising a fluorine atom.

63. The pharmaceutical composition of claim 47 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

64. The pharmaceutical composition of claim 48 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

65. The pharmaceutical composition of claim 49 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

66. The pharmaceutical composition of claim 50 , wherein R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a —(CH 2 )N(R 5 ) 2 or a —(CH 2 )NHSO 2 R 18 .

67. The pharmaceutical composition of claim 51 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

68. The pharmaceutical composition of claim 52 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

69. The pharmaceutical composition of claim 53 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

70. The pharmaceutical composition of claim 54 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; q is 1 and the R 14 is H or Me.

71. The pharmaceutical composition of claim 55 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

72. The pharmaceutical composition of claim 56 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and R 15 is selected from the group consisting of H, lower alkyl or halide.

73. The pharmaceutical composition of claim 57 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and V is selected from the group consisting of H, lower alkyl or halide.

74. The pharmaceutical composition of claim 58 , wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; q is 1-2 and V is selected from the group consisting of H, lower alkyl or halide.

75. The pharmaceutical composition of claim 39 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

76. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

77. A pharmaceutical composition comprising a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.