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

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

wherein:

R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;

one of each R 1 and R 2 , R 2 and R 3 , R 5 and R 6 , or R 6 and R 7 are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 9 is independently selected from the group consisting of H, C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

alternatively, two adjacent R 9 , may be taken together with the atoms to which they are attached to form a carbocyclyl or heterocyclyl;

each R 10 is independently selected from the group consisting of C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 11 is independently selected from the group consisting of —OR 9 and R 9 ;

each R 12 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1- 9 alkyl) n C(═A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;

R 14 and R 15 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1 -9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;

alternatively, R 14 and R 15 are taken together to form a ring which is selected from the group consisting of benzene and pyridine;

each A is independently selected from O, S and NR 11 ;

Y 1 , Y 2 and Y 3 are carbon;

Y 4 is nitrogen;

R 8 is absent; and

each n is 0 or 1.

2. The compound of claim 1 , wherein n is 0.

3. The compound of claim 1 , wherein n is 1.

4. The compound of claim 1 , wherein A is O.

5. The compound of claim 1 , wherein R 1 and R 3 are H and R 2 is selected from the group consisting of -carbocyclylR 12 , -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .

6. The compound of claim 5 , wherein R 2 is -heteroarylR 12 .

7. The compound of claim 5 , wherein the heteroaryl is pyridine.

8. The compound of claim 5 , wherein R 12 is selected from the group consisting of —NHC(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —NHC(═O)R 9 , —NHC(═O)CH(R 9 ) 2 and —NHSO 2 R 9 .

9. The compound of claim 8 , wherein R 9 is selected from the group consisting of H, —C 1-4 alkyl, carbocyclyl and -heterocyclyl.

10. The compound as in any of claims 5 - 9 , wherein R 6 and R 7 are H and R 5 is selected from the group consisting of H, -heterocyclylR 12 , —arylR 12 , -heteroarylR 12 , N(R 9 )C(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)CH(R 9 ) 2 , —CN, —CO 2 R 9 and —C(═O)R 9 .

11. The compound of claim 10 , wherein R 5 is selected from the group consisting of -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .

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

13. The compound of claim 11 , wherein R 5 is -heteroarylR 12 and the heteroaryl is pyridine.

14. The compound of claim 10 , wherein R 5 is selected from the group consisting of H, —C(═O)N(R 9 ) 2 and —CN.

15. The compound of claim 14 , wherein R 9 is selected from the group consisting of H and —C 1-4 alkyl, alternatively, R 9 is taken together to form a fused ring with the nitrogen.

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

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula Ib:

wherein:

R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl)carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl)heteroarylR 12 , —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and -(C 1-9 alkyl) n C(=A)R 9 ;

one of each R 1 and R 2 , R 2 and R 3 , R 5 and R 6 , or R 6 and R 7 are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 9 is independently selected from the group consisting of H, C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl)heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

alternatively, two adjacent R 9 , may be taken together with the atoms to which they are attached to form a carbocyclyl or heterocyclyl;

each R 10 is independently selected from the group consisting of C 1-9 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, —(C 1-9 alkyl) n heterocyclyl, —(C 1-9 alkyl) n aryl and —(C 1-9 alkyl) n heteroaryl;

each R 11 is independently selected from the group consisting of —OR 9 and R 9 ;

each R 12 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C 1-9 alkyl) n OR 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and -(C 1-9 alkyl)C(=A)R 9 ;

R 14 and R 15 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 12 , —(C 1-9 alkyl) n heterocyclylR 12 , —(C 1-9 alkyl) n arylR 12 , —(C 1-9 alkyl) n heteroarylR 12 , —(C 1-9 alkyl) n 0 R 9 , —(C 1-9 alkyl) n SR 9 , —(C 1-9 alkyl) n S(═O)R 10 , —(C 1-9 alkyl) n SO 2 R 9 , —(C 1-9 alkyl) n N(R 9 )SO 2 R 9 , —(C 1-9 alkyl) n SO 2 N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 9 ) 2 , —(C 1-9 alkyl) n N(R 9 )C(=A)R 9 , —(C 1-9 alkyl) n N(R 9 )C(=A)CH(R 9 ) 2 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 9 and —(C 1-9 alkyl) n C(=A)R 9 ;

alternatively, R 14 and R 15 are taken together to form a ring which is selected from the group consisting of benzene and pyridine;

each A is independently selected from O, S and NR 11 ;

Y 1 , Y 2 and Y 3 are carbon;

Y 4 is nitrogen;

R 8 is absent;

each n is 0 or 1; and

a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17 , wherein n is 0.

19. The pharmaceutical composition of claim 17 , wherein n is 1.

20. The pharmaceutical composition of claim 17 , wherein A is O.

21. The pharmaceutical composition of claim 17 , wherein R 1 and R 3 are H and R 2 is selected from the group consisting of -carbocyclylR 12 , -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .

22. The pharmaceutical composition of claim 21 , wherein R 2 is -heteroarylR 12 .

23. The pharmaceutical composition of claim 21 , wherein the heteroaryl is pyridine.

24. The pharmaceutical composition of claim 21 , wherein R 12 is selected from the group consisting of —NHC(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —NHC(═O)R 9 , —NHC(═O)CH(R 9 ) 2 and —NHSO 2 R 9 .

25. The pharmaceutical composition of claim 24 , wherein R 9 is selected from the group consisting of H, —C 1-4 alkyl, carbocyclyl and -heterocyclyl.

26. The pharmaceutical composition as in any of claims 21 - 25 , wherein R 6 and R 7 are H and R 5 is selected from the group consisting of H, -heterocyclylR 12 , -arylR 12 , -heteroarylR 12 , —N(R 9 )C(═O)N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)CH(R 9 ) 2 , —CN, —CO 2 R 9 and —C(═O)R 9 .

27. The pharmaceutical composition of claim 26 , wherein R 5 is selected from the group consisting of -heterocyclylR 12 , -arylR 12 and -heteroarylR 12 .

28. The pharmaceutical composition of claim 27 , wherein R 12 is selected from the group consisting of H and halide.

29. The pharmaceutical composition of claim 27 , wherein R 5 is -heteroarylR 12 and the heteroaryl is pyridine.

30. The pharmaceutical composition of claim 26 , wherein R 5 is selected from the group consisting of H, —C(═O)N(R 9 ) 2 and —CN.

31. The pharmaceutical composition of claim 30 , wherein R 9 is selected from the group consisting of H and —C 1-4 alkyl, alternatively, R 9 is taken together to form a fused ring with the nitrogen.

32. The pharmaceutical composition of claim 17 , wherein the compound of Formula Ib is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.