Methods of using indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors
This disclosure features the use of one or more indazole-3-carboxamide compounds or salts or analogs thereof, in the treatment of one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease; and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3-carboxamide compounds or salts or analogs thereof as described anywhere herein.
1. A method of treating tendinosis the method comprising administering to a subject a compound or pharmaceutically acceptable salt thereof having the structure of Formula I:
wherein:
R 1 , R 2 and R 4 are independently selected from the group consisting of H, C 1-9 alkyl, halide, —N(R 10 ) 2 , —XR 10 , CN, —OCF 3 and —CF 3 ;
R 3 is selected from the group consisting of carbocyclylR 6 , heterocyclylR 6 , arylR 6 and heteroarylR 6 ;
R 5 is selected from the group consisting of —(C 1-9 alkyl) n carbocyclylR 7 , —(C 1-9 alkyl) n heterocyclylR 7 , —(C 1-9 alkyl) n arylR 7 and —(C 1-9 alkyl) n heteroarylR 7 ;
each R 6 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, amino, —OCF 3 , —CF 3 , —CN, —XR 10 , —(C 1-9 alkyl) n carbocyclylR 8 , —(C 1-9 alkyl) n heterocyclylR 8 , —(C 1-9 alkyl) n arylR 8 , —(C 1-9 alkyl) n heteroarylR 8 , —C(═O)R 11 , —N(R 10 )C(═O)R 11 , —(C 1-9 )alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 11 and —SO 2 R 11 ;
each R 7 is 1-5 substituents each selected from the group consisting of H, C 1-9 alkyl, halide, amino, —OCF 3 , —CF 3 , —CN, —XR 10 , —(C 1-9 alkyl) n carbocyclylR 9 , —(C 1-9 alkyl) n heterocyclylR 9 , —(C 1-9 alkyl) n arylR 9 , —(C 1-9 alkyl) n heteroarylR 9 , —C(═O)R 11 , —N(R 10 )C(═O)R 11 , —(C 1-9 )alkyl) n N(R 10 ) 2 , —(C 1-9 )alkyl) n N(R 10 )SO 2 R 11 and —SO 2 R 11 ;
each R 8 is 1-5 substituents each selected from the group consisting of H, C 1-3 alkyl, halide, amino, OCF 3 , —CF 3 —CN, —XR 12 , —C(═O)R 13 , —N(R 12 )C(═O)R 13 , —(C 1-9 alkyl) n N(R 12 ) 2 , —(C 1-9 alkyl) n N(R 12 )SO 2 R 13 and —SO 2 R 13 ;
each R 9 is 1-5 substituents each selected from the group consisting of H, C 1-3 alkyl, halide, amino, —OCF 3 , —CF 3 —CN, —XR 12 , —C(═O)R 13 , —N(R 12 )C(═O)R 13 , —(C 1-9 alkyl) n N(R 12 ) 2 , —(C 1-9 alkyl) n N(R 12 )SO 2 R 13 and —SO 2 R 13 ;
each R 10 is independently selected from the group consisting of H, C 1-9 alkyl, —(C 1-9 alkyl) n N(R 14 ) 2 , —(C 1-9 alkyl) n carbocyclylR 8 , —(C 1-9 alkyl) n heterocyclylR 8 , —(C 1-9 alkyl) n arylR 8 and —(C 1-9 alkyl) n heteroarylR 8 ;
each R 11 is independently selected from the group consisting of C 1-9 alkyl, —N(R 14 ) 2 , —(C 1-9 alkyl) n carbocyclylR 8 , —(C 1-9 alkyl) n heterocyclylR 8 , —(C 1-9 alkyl) n arylR 8 and —(C 1-9 alkyl) n heteroarylR 8 ;
each R 12 is independently selected from the group consisting of H, C 1-9 alkyl, —(C 1-9 alkyl) n N(R 14 ) 2 , —(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 13 is independently selected from the group consisting of C 1-9 alkyl, —N(R 14 ) 2 , —(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 14 is independently selected from the group consisting of H, C 1-3 alkyl, carbocyclyl and aryl;
each X is selected from the group consisting of a bond, —O— and —S—; and
each n is 0 or 1.
2. The method of claim 1 , wherein R 1 , R 2 and R 4 are H.
3. The method of claim 2 , wherein R 3 is 3-pyridylR 6 .
4. The method of claim 2 , wherein R 3 is 5-pyrimidinylR 6 .
5. The method of claim 2 , wherein R 3 is 4-pyridazinylR 6 .
6. The method of claim 3 , wherein R 6 is one substituent and is —N(R 9 )C(═O)R 10 .
7. The method of claim 3 , wherein R 6 is one substituent and is —(CH 2 )heterocyclylR 8 .
8. The method of claim 7 , wherein the R 6 heterocyclyl is independently selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 .
9. The method of claim 2 , wherein R 5 is 3-pyridylR 7 .
10. The method of claim 3 , wherein R 5 is 3-pyridylR 7 .
11. The method of claim 2 , wherein R 5 is 5-pyrimidinylR 7 .
12. The method of claim 2 , wherein R 5 is 4-pyridazinylR 7 .
13. The method of claim 9 , wherein R 7 is one substituent and is selected from the group consisting of halide, —OCF 3 , —CF 3 , —(C 1-9 )alkyl) n N(R 10 ) 2 , —(C 1-9 ) alkyl) n N(R 10 )SO 2 R 11 and —N(R 10 )C(═O)R 11 .
14. The method of claim 10 , wherein R 7 is one substituent and is selected from the group consisting of halide, —OCF 3 , —CF 3 , —(C 1-9 alkyl) n N(R 10 ) 2 , —(C 1-9 alkyl) n N(R 10 )SO 2 R 11 and —N(R 10 )C(═O)R 11 .
15. The method of claim 9 , wherein R 7 is one substituent and is selected from the group consisting of —OR 10 and —C(═O)R 11 where R 11 is —N(R 10 ) 2 , and each R 10 is independently selected from the group consisting of H, methyl and —(C 1-9 alkyl) n carbocyclylR 8 where n is 0 and each R 8 is 1-2 substituents independently selected from H or halide.
16. The method of claim 10 , wherein R 7 is one substituent and is selected from the group consisting of —OR 10 and —C(═O)R 11 where R 11 is —N(R 10 ) 2 , and each R 10 is independently selected from the group consisting of H, methyl and —(C 1-9 alkyl) n carbocyclylR 8 where n is 0 and each R 8 is 1-2 substituents independently selected from H or halide.
17. The method of claim 1 , the compound having a structure selected from the group consisting of:
and or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 17 , the compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
26. A method of treating tendinosis the method comprising administering to a subject a compound or pharmaceutically acceptable salt thereof having the structure of Formula Ia:
wherein:
R 3 is 3-pyridylR 6 ;
R 5 is selected from the group consisting of pyridylR 7 , -pyrimidinylR 7 , and -pyridazinylR 7 ;
R 6 is —CH 2 heterocyclylR 8 ;
R 7 is 1-2 substituents each independently selected from the group consisting of H, F, methyl, —NH 2 , —CF 3 , —CN, —OMe, —SO 2 Me,
and
R 8 is 1-2 substituents each independently selected from the group consisting of H and halide.
27. The method of claim 26 , wherein the R 6 heterocyclyl is selected from the group consisting of azetidinylR 8 , pyrrolidinylR 8 , piperidinylR 8 , piperazinylR 8 , and morpholinylR 8 .
28. The method of claim 26 , wherein R 6 is —CH 2 piperidinylR 8 .
29. The method of claim 26 , wherein R 7 is selected from the group consisting of H, —CF 3 , —OMe, —CN,
30. The method of claim 27 , wherein R 8 is H.
31. The method of claim 28 , wherein R 8 is H.