Prodrug Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use

Abstract

The present invention relates to prodrug compounds and their use in the treatment of Cystic Fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

What is claimed: 
     
         1 . A compound which is (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (dimethylamino)acetate, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound which is (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl 3-(dimethylamino)propanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A compound which is (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate. 
     
     
         5 . (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A pharmaceutical composition comprising the compound of  claim 3 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 
     
     
         7 . The pharmaceutical composition of  claim 6  further comprising one or more additional therapeutic agents. 
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the additional therapeutic agents are selected from CFTR modulators and CFTR amplifiers. 
     
     
         9 . The pharmaceutical composition of  claim 8  wherein the additional therapeutic agents are CFTR modulators. 
     
     
         10 . A method for treating cystic fibrosis in a subject comprising the compound of  claim 3  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         11 . The method of  claim 10  further comprising one or more additional therapeutic agents. 
     
     
         12 . The method of  claim 11  wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. 
     
     
         13 . The method of  claim 12  the wherein the additional therapeutic agents are CFTR modulators. 
     
     
         14 . The method of  claim 11 , wherein the additional therapeutic agents are a potentiator, and one or more corrector. 
     
     
         15 . The method of  claim 14 , wherein the corrector is 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method for treating cystic fibrosis in a subject comprising (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate or a pharmaceutically acceptable salt thereof, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4- dihydro-2H-chromen-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and one or more corrector, to a subject in need thereof. 
     
     
         17 . A process for preparing (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate comprising adding trifluoroacetic acid to a mixture of (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-yl}-1,3,4-oxadiazol-2-yl)methyl(2S)-2-[(tert- butoxycarbonyl)amino]-3-methylbutanoate and dichloromethane. 
     
     
         18 . A method of manufacturing (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (2S)-2-amino-3-methylbutanoate comprising adding trifluoroacetic acid to a mixture of (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-yl}-1,3,4-oxadiazol-2-yl)methyl(2S)-2-[(tert- butoxycarbonyl)amino]-3-methylbutanoate and dichloromethane.