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

1. A method of treating a disorder selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; muscle fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver; liver fibrosis; adhesions occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; idiopathic pulmonary fibrosis (IPF); fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis; fibrosis following stroke; fibrosis associated with neuro-degenerative disorders selected from the group consisting of Alzheimer's Disease and multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease; and radiation fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is H;

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

R 3 is H;

R 4 is independently selected from the group consisting of -aryl(R 13 ) q , -furyl(R 15 ) q , and -thiophenyl(R 15 ) q ;

R 5 is H;

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 ;

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

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, and —C(═O)(C 1-3 alkyl);

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 independently an integer of 1 or 2; and

each n is independently an integer of 0 or 1.

2. The method of claim 1 , wherein the R 4 aryl is phenyl.

3. The method of claim 1 , wherein the R 13 heterocyclyl is selected from the group consisting of azetidinyl(R 8 ) q , pyrrolidinyl(R 8 ) q , piperidinyl(R 8 ) q , piperazinyl(R 8 ) q , and morpholinyl(R 8 ) q .

4. The method of claim 1 , wherein R 2 is H.

5. The method of claim 1 , wherein R 2 is —(C 1-9 alkyl) n N(R 9 ) 2 .

6. The method of claim 5 , wherein R 2 is —CH 2 N(R 9 ) 2 or —N(R 9 ) 2 .

7. The method of claim 6 , wherein R 9 is independently selected from the group consisting of H, Me, Et, n-propyl, isopropyl, and —CH 2 carbocyclyl.

8. The method of claim 7 , wherein R 4 is phenyl(R 13 ) q .

9. The method of claim 7 , wherein R 4 is -furyl(R 15 ) q .

10. The method of claim 7 , wherein R 4 is -thiophenyl(R 15 ) q .

11. The method of claim 8 , wherein R 13 is one substituent attached to the phenyl ring and the substituent is a fluorine atom.

12. The method of claim 8 , wherein R 13 is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and —N(R 9 ) 2 , wherein R 9 is independently selected from the group consisting of H and —CH 2 CH 2 N(R 16 ) 2 , and wherein R 16 is is independently selected from the group consisting of H, Me, and Et.

13. The method of claim 8 , wherein R 13 is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and —(CH 2 ) n NHSO 2 R 18 , wherein R 9 is independently selected from the group consisting of Me and Et.

14. The method of claim 10 , wherein R 15 is one substituent attached to the thiophenyl ring and the substituents are selected from the group consisting of H, F, Me, and —C(═O)Me.

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

or a pharmaceutically acceptable salt thereof.

16. The method having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the fibrotic disorder is a skin fibrosis.

18. The method of claim 1 , wherein the fibrotic disorder is scleroderma.

19. The method of claim 1 , wherein the fibrotic disorder is pulmonary fibrosis.

20. The method of claim 1 , wherein the fibrotic disorder is renal fibrosis.

21. The method of claim 1 , wherein the fibrotic disorder is idiopathic pulmonary fibrosis (IPF).

22. The method of claim 1 , wherein the fibrotic disorder is cirrhosis of the liver.

23. The method of claim 1 , wherein the fibrotic disorder is liver fibrosis.

24. The method of claim 1 , wherein the subject is a human.

25. A method of treating idiopathic pulmonary fibrosis (IPF) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

26. A method of treating renal fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

27. A method of treating cirrhosis of the liver in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

28. A method of treating liver fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.