Fxr (nr1h4) modulating compounds

Abstract

The present disclosure relates generally to compounds that bind to FXR and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

1 - 49 . (canceled) 
     
     
         50 . A method of treating a Farnesoid X Receptor (FXR) mediated condition in a patient comprising administering to the patient a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         51 . The method of claim  1 , wherein the FXR mediated condition is selected from the group consisting of:
 a chronic intrahepatic or extrahepatic cholestatic condition;   liver fibrosis;   a chronic or obstructive inflammatory disorder of the liver;   liver cirrhosis;   liver steatosis or an associated syndrome;   a cholestatic or fibrotic effect that is associated with alcohol-induced cirrhosis or with a viral-borne form of hepatitis;   acute or chronic liver failure;   liver ischemia after major liver resection;   chemotherapy associated steatohepatitis (CASH);   Primary Biliary Cirrhosis (PBC);   Primary Sclerosing Cholangitis (PSC);   a neoplastic disease of the gastrointestinal tract or liver; and   an Inflammatory Bowel Disease (IBD);   a lipid disorder or lipoprotein disorder;   Type I Diabetes;   Type II Diabetes;   clinical complications of Type I and Type II Diabetes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifest long term Diabetes;   Non-Alcoholic Fatty Liver Disease (NAFLD);   Non-Alcoholic Steatohepatitis (NASH);   obesity;   a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabetes and abnormally high body-mass index;   acute myocardial infarction;   acute stroke; and   thrombosis that occurs as an endpoint of chronic obstructive atherosclerosis;   a non-malignant hyperproliferative disorder;   a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis;   colon adenocarcinoma;   breast cancer;   pancreas adenocarcinoma; and   Barrett's esophagus.   
     
     
         52 . A method of treating a Farnesoid X Receptor (FXR) mediated condition in a patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an Apoptosis Signal-Regulating Kinase 1 (ASK1) inhibitor and a therapeutically effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         53 . The method of  claim 52 , wherein the ASK1 inhibitor is a compound of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof. 
       
     
     
         54 . A method of treating a Farnesoid X Receptor (FXR) mediated condition in a patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an Acetyl CoA Carboxylase (ACC) inhibitor and a therapeutically effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         55 . The method of  claim 54 , wherein the ACC inhibitor is a compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof. 
       
     
     
         56 . A method of treating a Farnesoid X Receptor (FXR) mediated condition in a patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a Thyroid Hormone Receptor (THR) β agonist and a therapeutically effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         57 . The method of  claim 56 , wherein the THR β agonist is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof. 
       
     
     
         58 . The method of  claim 50 , wherein the FXR mediated condition is Primary Biliary Cirrhosis (PBC). 
     
     
         59 . The method of  claim 50 , wherein the FXR mediated condition is Primary Primary Sclerosing Cholangitis (PSC). 
     
     
         60 . The method of  claim 50 , wherein the FXR mediated condition is Primary Non Alcoholic Steatohepatitis (NASH). 
     
     
         61 . The method of  claim 50 , wherein the FXR mediated condition is Primary Inflammatory Bowel Disease. 
     
     
         62 . The method of  claim 52 , wherein the FXR mediated condition is Primary Biliary Cirrhosis (PBC). 
     
     
         63 . The method of  claim 52 , wherein the FXR mediated condition is Primary Primary Sclerosing Cholangitis (PSC). 
     
     
         64 . The method of  claim 52 , wherein the FXR mediated condition is Primary Non Alcoholic Steatohepatitis (NASH). 
     
     
         65 . The method of  claim 52 , wherein the FXR mediated condition is Primary Inflammatory Bowel Disease. 
     
     
         66 . The method of  claim 54 , wherein the FXR mediated condition is Primary Biliary Cirrhosis (PBC). 
     
     
         67 . The method of  claim 54 , wherein the FXR mediated condition is Primary Primary Sclerosing Cholangitis (PSC). 
     
     
         68 . The method of  claim 54 , wherein the FXR mediated condition is Primary Non Alcoholic Steatohepatitis (NASH). 
     
     
         69 . The method of  claim 54 , wherein the FXR mediated condition is Primary Inflammatory Bowel Disease. 
     
     
         70 . The method of  claim 56 , wherein the FXR mediated condition is Primary Biliary Cirrhosis (PBC). 
     
     
         71 . The method of  claim 56 , wherein the FXR mediated condition is Primary Primary Sclerosing Cholangitis (PSC). 
     
     
         72 . The method of  claim 56 , wherein the FXR mediated condition is Primary Non Alcoholic Steatohepatitis (NASH). 
     
     
         73 . The method of  claim 56 , wherein the FXR mediated condition is Primary Inflammatory Bowel Disease.