COMPOUNDS AND METHODS FOR MODULATING G PROTEIN-COUPLED RECEPTORS
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with or mediated by G protein-coupled receptors, in particular G protein-coupled receptor 120.
1 . A compound of Formula (I):
wherein:
n is selected from 0, 1, 2, 3 and 4;
A is selected from:
A is:
R 8 is selected from H, C 1-4 alkyl and phenyl optionally substituted with 1 to 3 radicals independently selected from halo, C 1-4 alkyl, halo-substitued-C 1-4 alkyl, C 1-4 alkoxy and halo-substituted-C 1-4 alkoxy;
R 1 is selected from —COOH, —SO 3 H and tetrazolyl;
R 2 is selected from halo, C 1-4 alkyl, halo-substitued-C 1-4 alkyl, C 1-4 alkoxy and halo-substituted-C 1-4 alkoxy;
R 3 , R 4 , R 5 , R 6 or R 7 are independently selected from H, cyano, hydroxyl, nitro, halo, C 1-4 alkyl, halo-substitued-C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkoxy, X 2 OR 11 , —X 2 NR 12 R 13 , —X 2 R 11 , —X 2 OX 3 R 11 and —X 2 OX 3 OR 11 ; wherein X 2 is selected from a bond and C 1-4 alkylene; X 3 is C 1-4 alkylene; R 11 is selected from C 1-6 alkyl, heteroaryl and aryl, each optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxyl, nitro, amino, C 1-4 alkyl, halo-substitued-C 1-4 alkyl, C 1-4 alkoxy and halo-substituted-C 1-4 alkoxy; R 12 and R 13 are independently selected from H and C 1-6 alkyl; or
R 3 and R 4 or R 5 and R 6 are each independently C 1-4 alkyl and taken together with the carbon atoms to which they are attached can form a phenyl ring; wherein said phenyl of the combination of R 3 and R 4 or R 5 and R 6 is optionally substituted with 1 to 3 radicals independently selected from cyano, amino, hydroxyl, nitro, halo, C 1-4 alkyl, halo-substitued-C 1-4 alkyl, C 1-4 alkoxy and halo-substituted-C 1-4 alkoxy;
or the pharmaceutically acceptable salts thereof.
2 . (canceled)
3 . The compound of claim 1 , wherein R 8 is H or C 1-4 alkyl.
4 . The compound of claim 3 , wherein each R 2 is independently a halo.
5 . The compound of claim 4 , wherein each R 2 is independently selected from fluoro and bromo.
6 . (canceled)
7 . The compound of claim 1 , wherein the compound of Formula (I) has a structure of Formula (Ic) or Formula (Id):
8 . The compound of claim 1 selected from:
3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid,
3-(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)benzoic acid,
3-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-methoxybenzoic acid,
3-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-fluorobenzoic acid,
3-(1-(2-fluoro-4-methylphenyl)-1H-1,2,3-triazol-4-yl)benzoic acid,
5-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-2-fluorobenzoic acid and
3-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-4-fluorobenzoic acid.
9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of claim 1 , and a pharmaceutically acceptable carrier.
10 . (canceled)
11 . (canceled)
12 . (canceled)
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . A method for treating a disease or disorder where modulation of GPR120 is implicated, comprising administering to a system or subject in need of such treatment an effective amount of a compound of Formula (I) of claim 1 , or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby treating the disease or disorder, wherein the disease or disorder is selected from diabetes, obesity, diabetes mellitus, dyslipidemia, hyperlipidemia, anorexia, hyperphagia, endocrine abnormalities and triglyceride storage disease.
17 . The method of claim 16 , wherein the system or subject is a cell or tissue system; or a human or animal subject.
18 . (canceled)
19 . The method of claim 16 , wherein the disease or disorder is an autoimmune disease, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, or psoriasis.
20 . (canceled)
21 . The method of claim 16 , wherein the compound is an agonist of GPR120.
22 . (canceled)