Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases due to mutations in Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
1. A method of treating fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 , R 2 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 3 is selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 , and -heteroarylR 14 R 15 ;
alternatively, one of each of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , 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 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 10 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;
each R 11 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 12 is independently selected from the group consisting of —OR 10 and R 10 ;
each R 13 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 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 14 is selected from the group consisting of —NR 10 C(=A)R 10 , —NR 10 S(═O)R 11 , —NR 10 SO 2 R 10 , —NR 10 C(═O)N(R 16 ) 2 , —NR 10 C(═S)N(R 10 ) 2 , —NR 10 C(═NR 12 )N(R 10 ) 2 , —N(R 16 ) 2 , —C(═O)NR 10 R 17 , —C(═S)N(R 10 ) 2 , —C(═NR 12 )N(R 10 ) 2 , —OC(=A)R 10 , —C(=A)R 10 , —NR 10 C(=A)OR 10 , and —OC(=A)NR 10 R 10 ;
R 15 is 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclylR 13 , heterocyclylR 13 , arylR 13 , heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 16 is —C 1-9 alkyl;
each R 17 is independently selected from the group consisting of -heterocyclylR 13 , —(C 1-9 alkyl)heterocyclylR 13 , and —(C 1-9 alkyl)carbocyclylR 13 ;
R 18 and R 19 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
alternatively, R 18 and R 19 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 12 ;
Y 1 , Y 2 , and Y 4 are C;
Y 3 is nitrogen and R 8 is absent; and
each n is 0 or 1.
2. The method of claim 1 , wherein n is 0.
3. The method of claim 1 , wherein n is 1.
4. The method of claim 1 , wherein A is O.
5. The method of claim 1 , wherein R 1 , R 2 and R 4 are H and R 3 is independently selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 .
6. The method of claim 5 , wherein R 3 is —(C 1-9 alkyl)R 14 .
7. The method of claim 5 , wherein R 3 is -carbocyclylR 14 R 15 .
8. The method of claim 5 , wherein R 3 is -heterocyclylR 14 R 15 .
9. The method of claim 5 , wherein R 3 is -arylR 14 R 15 .
10. The method of claim 5 , wherein R 3 is -heteroarylR 14 R 15 .
11. The method of claim 10 , wherein R 14 is —NR 10 C(=A)R 10 and A is O.
12. The method of claim 10 , wherein R 14 is —C(═O)NR 10 R 17 .
13. The method of claim 10 , in which the heteroaryl is a pyridine.
14. The method of claim 10 , in which R 14 is —NHC(═O)R 10 and R 10 is selected from the group consisting of —C 1-9 alkyl, carbocyclyl, aryl and —(C 1-9 alkyl)aryl.
15. The method of claim 10 , in which R 14 is —C(═O)NHR 17 , R 17 is —(C 1-9 alkyl)carbocyclylR 13 and R 13 is H.
16. The method of claim 1 , wherein R 6 is —(C 1-9 alkyl) n heteroarylR 13 , n is 0 and R 13 is H.
17. The method of claim 1 , wherein R 1 , R 2 , R 4 , R 7 , and R 9 are H; R 3 is heteroarylR 14 R 15 ; and R 6 is —(C 1-9 alkyl) n arylR 13 .
18. The method of claim 17 , wherein R 13 is halide.
19. The method of claim 18 , wherein the halide is fluoro.
20. The method of claim 1 , wherein the compound of Formula Ia is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound of Formula Ia is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the disorder associated with fibrosis is pulmonary fibrosis.
23. The method of claim 1 , wherein the disorder associated with fibrosis is cystic fibrosis.
24. The method of claim 1 , wherein the disorder associated with fibrosis is myocardial infarction.
25. The method of claim 1 , wherein the subject is a human.
26. A method of treating pulmonary fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 , R 2 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 3 is selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 , and -heteroarylR 14 R 15 ;
alternatively, one of each of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , 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 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 10 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;
each R 11 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 12 is independently selected from the group consisting of —OR 10 and R 10 ;
each R 13 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 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 14 is selected from the group consisting of —NR 10 C(=A)R 10 , —NR 10 S(═C)R 11 , —NR 10 SO 2 R 10 , —NR 10 C(═O)N(R 16 ) 2 , —NR 10 C(═S)N(R 10 ) 2 , —NR 10 C(═NR 12 )N(R 10 ) 2 , —N(R 16 ) 2 , —C(═O)NR 10 R 17 , —C(═S)N(R 10 ) 2 , —C(═NR 12 )N(R 10 ) 2 , —OC(=A)R 10 , —C(=A)R 10 , —NR 10 C(=A)OR 10 , and —OC(=A)NR 10 R 10 ;
R 15 is 1-4 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, —CF 3 , carbocyclylR 13 , heterocyclylR 13 , arylR 13 , heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
R 16 is —C 1-9 alkyl;
each R 17 is independently selected from the group consisting of -heterocyclylR 13 , —(C 1-9 alkyl)heterocyclylR 13 , and —(C 1-9 alkyl)carbocyclylR 13 ;
R 18 and R 19 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —(C 1-9 alkyl) n carbocyclylR 13 , —(C 1-9 alkyl) n heterocyclylR 13 , —(C 1-9 alkyl) n arylR 13 , —(C 1-9 alkyl) n heteroarylR 13 , —(C 1-9 alkyl) n OR 10 , —(C 1-9 alkyl) n SR 10 , —(C 1-9 alkyl) n S(═O)R 11 , —(C 1-9 alkyl) n SO 2 R 10 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9 alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9 alkyl) n CO 2 R 10 , and —(C 1-9 alkyl) n C(=A)R 10 ;
alternatively, R 18 and R 19 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 12 ;
Y 1 , Y 2 , and Y 4 are C;
Y 3 is nitrogen and R 8 is absent; and
each n is 0 or 1.
27. The method of claim 26 , wherein n is 0.
28. The method of claim 26 , wherein n is 1.
29. The method of claim 26 , wherein A is O.
30. The method of claim 26 , wherein R 1 , R 2 and R 4 are H and R 3 is independently selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15 and -heteroarylR 14 R 15 .
31. The method of claim 30 , wherein R 3 is —(C 1-9 alkyl)R 14 .
32. The method of claim 30 , wherein R 3 is -carbocyclylR 14 R 15 .
33. The method of claim 30 , wherein R 3 is -heterocyclylR 14 R 15 .
34. The method of claim 30 , wherein R 3 is -arylR 14 R 15 .
35. The method of claim 30 , wherein R 3 is -heteroarylR 14 R 15 .
36. The method of claim 35 , wherein R 14 is —NR 10 C(=A)R 10 and A is O.
37. The method of claim 35 , wherein R 14 is —C(═O)NR 10 R 17 .
38. The method of claim 35 , in which the heteroaryl is a pyridine.
39. The method of claim 35 , in which R 14 is —NHC(═O)R 10 and R 10 is selected from the group consisting of —C 1-9 alkyl, carbocyclyl, aryl and —(C 1-9 alkyl)aryl.
40. The method of claim 35 , in which R 14 is —C(═O)NHR 17 , R 17 is —(C 1-9 alkyl)carbocyclylR 13 and R 13 is H.
41. The method of claim 26 , wherein R 6 is —(C 1-9 alkyl) n heteroarylR 13 , n is 0 and R 13 is H.
42. The method of claim 26 , wherein R 1 , R 2 , R 4 , R 7 , and R 9 are H; R 3 is heteroarylR 14 R 15 ; and R 6 is —(C 1-9 alkyl) n arylR 13 .
43. The method of claim 42 , wherein R 13 is halide.
44. The method of claim 43 , wherein the halide is fluoro.
45. The method of claim 26 , wherein the compound of Formula Ia is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
46. The method of claim 26 , wherein the compound of Formula Ia is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
47. The method of claim 26 , wherein the subject is a human.