Amino acid compounds and methods of use

Abstract

The invention relates to compounds of formula (I):or a salt thereof, wherein R1, R5, R7, R8, X, m, n, p and q are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are αvβ6 integrin inhibitors that are useful for treating tissue specific fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSW).

1 .- 33 . (canceled) 
     
     
         34 . A compound selected from the group consisting of:
 (S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamido)piperidin-1-yl)butanoic acid,   (S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)amino)piperidin-1-yl)butanoic acid,   (S)-2-benzamido-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (2S)-2-benzamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(2-chloro-3-fluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid   (S)-2-(2-ethylbutanamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-morpholinobenzamido)butanoic acid,   (S)-2-(3,5-difluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-(2-methoxyethoxy)benzamido)butanoic acid,   (S)-2-(2,6-dichlorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(2-chloro-3-fluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(3,5-difluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-fluoro-5-(trifluoromethyl)benzamido)butanoic acid,   (S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoic acid,   (S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(2-ethylbutanamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,   (S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoic acid,   (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-((5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-benzamido-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-4-((S)-4-acetyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperazin-1-yl)-2-benzamidobutanoic acid,   (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoic acid,   (S)-2-(2-methyl-2-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoic acid,   (S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-44(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-44(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (2S)-2-(1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,   (2S)-2-(1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,   (S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,   (S)-2-((S)-1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,   (S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,   (S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid, and   (S)-2-(2-ethylbutanamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,   or a pharmaceutically acceptable salt thereof.   
     
     
         35 . A pharmaceutical composition comprising a compound of  claim 34 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         36 . A method of treating a fibrotic disease in an individual in need thereof comprising administering a compound of  claim 34  or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 36 , wherein the fibrotic disease is selected from the group consisting of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis. 
     
     
         38 . A kit comprising a compound of  claim 34 , or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The kit of  claim 38 , further comprising instructions for the treatment of a fibrotic disease. 
     
     
         40 . The kit of  claim 39 , wherein the fibrotic disease is selected from the group consisting of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis. 
     
     
         41 . A method of inhibiting a v (36 integrin in an individual comprising administering a compound of  claim 34  or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method of inhibiting TGFP activation in a cell comprising administering to the cell a compound of  claim 34  or a pharmaceutically acceptable salt thereof.