Compounds and methods for modulating fxr

Abstract

The present invention relates to compounds of Formula (I), a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesiod X receptors (FXR).

1 . A method for treating a condition mediated by FXR in a subject suffering therefrom, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I-A), (I-D), (I-E) or (I-H): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein R 1  is phenyl substituted with 1-3 R 1a ; 
         R 3  is X—CO 2 R 4 ; 
         X is a bond; 
         R 4  is hydrogen or C 1-6  alkyl; 
         R 1a  and R 6  are independently halogen, C 1-6  alkyl, haloC 1-6  alkyl, C 1-6  alkoxy, haloC 1-6  alkoxy; and 
         m is 0-1. 
       
     
     
         2 . The method of  claim 1 , wherein R 6  is methyl, methoxy, fluoro or trifluoromethoxy. 
     
     
         3 . The method of  claim 1 , wherein said condition is cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis of pregnancy, parenteral nutrition-associated cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familiar cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile duct injury, gallstones, liver cirrhosis, alcohol-induced cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis, liver fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic nephropathy, colitis, newborn jaundice, kernicterus, veno-occlusive disease, portal hypertension, metabolic syndrome, hypercholesterolemia, intestinal bacterial overgrowth, or erectile dysfunction. 
     
     
         4 . The method of  claim 3 , wherein said condition is primary biliary cirrhosis (PBC). 
     
     
         5 . The method of  claim 1 , wherein said compound is administered in combination with a second therapeutic agent.