Indazole inhibitors of the Wnt signal pathway 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; 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 associated with neuro-degenerative disorders, 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 or pharmaceutically acceptable salt thereof having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is heteroarylR 3 R 4 ;

R 2 is selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6 and -arylR 7 ;

R 3 is selected from the group consisting of H, -heterocyclylR 8 , —NHC(═O)R 9 , —NHSO 2 R 10 , —NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;

with the proviso that R 2 and R 3 are not both H;

R 4 is 1-3 substituents each selected from the group consisting of H, halide, —CF 3 , —CN, OR 13 and amino;

each R 5 is independently 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , —C(═O)R 11 , amino and —(C 1-6 alkyl)NR 11 R 12 ;

each R 6 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;

each R 7 is independently 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 , amino, —(C 1-6 alkyl)NHSO 2 R 11 , —NR 12 (C 1-6 alkyl)NR 11 R 12 and —(C 1-6 alkyl)NR 11 R 12 ;

R 8 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino;

R 9 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 and —CH 2 carbocyclyl;

R 10 is selected from the group consisting of C 1-9 alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 , and -carbocyclylR 14 ;

each R 11 is independently selected from C 1-6 alkyl;

each R 12 is independently selected from the group consisting of H and C 1-6 alkyl;

each R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring;

each R 13 is independently selected from the group consisting of H and C 1-6 alkyl;

R 14 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —CN, OR 13 and amino; and

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

2. The method of claim 1 wherein R 1 is pyridineR 3 R 4 .

3. The method of claim 2 wherein R 1 is pyridin-3-ylR 3 R 4 .

4. The method of claim 3 wherein R 3 is —(C 1-6 alkyl)NR 11 R 12 .

5. The method of claim 4 wherein R 3 is —(C 1-2 alkyl)NR 11 R 12 , R 11 is —(C 1-2 alkyl), R 12 is —(C 1-2 alkyl) and R 4 is H.

6. The method of claim 4 wherein R 11 and R 12 are optionally linked to form a five or six membered heterocyclyl ring and R 4 is H.

7. The method of claim 6 wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.

8. The method of claim 3 wherein R 3 is —NHC(═O)R 9 .

9. The method of claim 8 wherein R 4 is H and R 9 is selected from the group consisting of —(C 2-5 alkyl), phenyl, -carbocyclyl and —CH 2 carbocyclyl.

10. The method of claim 3 wherein R 3 is —NHSO 2 R 10 .

11. The method of claim 10 wherein R 4 is H and R 10 is selected from the group consisting of —(C 1-4 alkyl) and phenyl.

12. The method of claim 3 wherein R 3 is -heterocyclylR 8 .

13. The method of claim 12 wherein R 4 is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.

14. The method of claim 3 wherein R 3 is H and R 4 is amino.

15. The method of claim 3 , in which R 2 is -heteroarylR 5 .

16. The method of claim 15 , in which R 2 is -pyridin-3-ylR 5 .

17. The method of claim 16 , in which R 2 is -pyridin-3-ylR 5 and R 5 is 1-2 fluorine atoms.

18. The method of claim 15 , in which R 2 is thiopheneR 5 .

19. The method of claim 3 , in which R 2 is -heterocyclyR 6 .

20. The method of claim 19 , in which R 2 is -heterocyclylR 6 , in which R 6 is selected from the group consisting of H, F and —(C 1-4 alkyl), and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine.

21. The method of claim 3 , in which R 2 is -aryR 7 .

22. The method of claim 21 , in which R 2 is -phenylR 7 and R 7 is 1-2 fluorine atoms.

23. The method of claim 21 , in which R 2 is -phenylR 7 and R 7 is 2 substituents consisting of 1 fluorine atom and either —NR 12 (C 1-6 alkyl)NR 11 R 12 or —(C 1-6 alkyl)NHSO 2 R 11 .

24. The method of claim 1 having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

34. The method of claim 1 , wherein the disorder is fibrosis-associated with neuro-degenerative disorders, and wherein the neuro-degenerative disorders are selected from the group consisting of Alzheimer's Disease and multiple sclerosis.

35. The method of claim 1 , wherein the disorder is central nervous system fibrosis, and wherein the central nervous system fibrosis is fibrosis following stroke.

36. The method of claim 1 , wherein the disorder is adhesions, and wherein the adhesions occur in the abdomen, pelvis, spine or tendons.