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, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
1. A method of treating a neurological disorder in a subject, wherein the neurological disorder is selected from: Alzheimer's disease, autism, schizophrenia, Williams Syndrome, bipolar disorder, Parkinson's disease, multiple sclerosis, and neural tube defects, 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:
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 -heterocyclylR 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 -arylR 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 , wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula I having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 1 , wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula I having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 1 , wherein the neurological disorder is Alzheimer's disease.
27. The method of claim 1 , wherein the neurological disorder is schizophrenia.
28. The method of claim 1 , wherein the neurological disorder is bipolar disorder.
29. The method of claim 1 , wherein the neurological disorder is Parkinson's disease.
30. The method of claim 1 , wherein the neurological disorder is multiple sclerosis.
31. The method of claim 1 , wherein the subject is a human.