Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
1. A compound according to Formula I:
wherein:
X is CH or N;
n is 0, 1 or 2;
R 1 is independently OH, halo or (C 1-4 )alkyl;
R 2 is independently OH, halo, (C 1-4 )alkyl, CH 2 F, CHF 2 or CF 3 ; and
R 3 is CH 2 F, CHF 2 or CF 3 ;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein the compound is represented by Formula
wherein:
X is CH or N;
n is 1 or 2;
R 2 is independently OH, halo, (C 1-4 )alkyl, CH 2 F, CHF 2 or CF 3 ; and
R 3 is CH 2 F, CHF 2 or CF 3 ;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein the compound is represented by Formula III:
wherein:
X is CH or N;
R 2 is independently H, Cl, F, CH 3 or CHF 2 ; and
R 3 is CH 2 F, CHF 2 or CF 3 ;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , wherein R 1 is chloro or fluoro.
5. A compound according to claim 1 , wherein R 1 is fluoro.
6. A compound according to claim 2 , wherein n is 1.
7. A compound according to claim 6 , wherein R 2 is chloro or fluoro.
8. A compound according to claim 6 , wherein R 2 is chloro.
9. A compound according to claim 8 , wherein X is N.
10. A compound according to claim 8 , wherein X is CH.
11. A compound according to claim 9 , wherein R 3 is CF 3 .
12. A compound according to claim 11 , wherein the compound is in the form of a free acid.
13. A compound selected from:
3-fluoro-4-(1-(2-methyl-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)benzoic acid;
4-(1-(2-chloro-6-(1-(difluoromethyl)cyclopropyl) benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-3-fluoro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;
4-(1-(2-(difluoromethyl)-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;
4-(1-(2-chloro-6-(1-(difluoromethyl)cyclopropyl)-3-fluorobenzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluorobenzoic acid;
3-fluoro-4-(1-(3-fluoro-2-methyl-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)benzoic acid; and
4-(1-(2-chloro-6-(1-(trifluoromethyl)cyclopropyl)benzoyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-3-fluorobenzoic acid;
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
15. A pharmaceutical composition comprising a compound of claim 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
16. A method of treating a disorder selected from the group consisting of an autoimmune disorder and an inflammatory disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 to treat the disorder.
17. The method of claim 16 , wherein the disorder is an autoimmune disorder.
18. The method of claim 17 , wherein the autoimmune disorder is rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, or epidermal hyperplasia.
19. The method of claim 16 , wherein the disorder is an inflammatory disorder.
20. A method of inhibiting the activity of a RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to inhibit the activity of said RORγ.
21. The method of claim 18 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. A compound having the following formula:
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 22 and one or more pharmaceutically acceptable carriers.