Benzothia(di)azepine compounds and their use as bile acid modulators

A method for treating a liver disease or disorder comprising orally administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I)

• wherein
• M is selected from —CH2— and —NR7—;
• R1 and R2 are each independently C1-4 alkyl;
• R3 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyano, nitro, amino, N—(C1-4 alkyl)amino, N,N-di(C1-4 alkyl)amino, N-(aryl-C1-4 alkyl)amino, C1-6 alkylcarbonylamino, C3-6 cycloalkylcarbonylamino, N—(C1-4 alkyl)aminocarbonyl, N,N-di(C1-4 alkyl)aminocarbonyl, C1-4 alkyloxycarbonylamino, C3-6 cycloalkyloxycarbonylamino, C1-4 alkylsulfonamido and C3-6 cycloalkylsulfonamido;
• n is an integer 1, 2 or 3;
• R4 is selected from the group consisting of hydrogen, halogen, cyano, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, C3-6 cycloalkyloxy, C1-4 alkylthio, C3-6 cycloalkylthio, amino, N—(C1-4 alkyl)amino and N,N-di(C1-4 alkyl)amino;
• one of R5 and R6 is carboxy, and the other of R5 and R6 is selected from the group consisting of hydrogen, fluoro, C1-4 alkyl and C1-4 haloalkyl;
• R7 is selected from the group consisting of hydrogen and C1-4 alkyl;
• and
• R8 is selected from the group consisting of hydrogen and C1-4 alkyl;
• or a pharmaceutically acceptable salt thereof;
• and
• wherein the liver disease or disorder is selected from the group consisting of:
• inherited metabolic disorder of the liver;
• inborn errors of bile acid synthesis;
• congenital bile duct anomalies;
• biliary atresia;
• neonatal hepatitis;
• neonatal cholestasis;
• hereditary forms of cholestasis;
• cerebrotendinous xanthomatosis;
• a secondary defect of BA synthesis;
• Zellweger's syndrome;
• cystic fibrosis-associated liver disease;
• alpha1-antitrypsin deficiency;
• Alagilles syndrome (ALGS);
• Byler syndrome;
• a primary defect of bile acid (BA) synthesis;
• progressive familial intrahepatic cholestasis (PFIC);
• autoimmune hepatitis;
• primary biliary cirrhosis (PBC);
• liver fibrosis;
• non-alcoholic fatty liver disease (NAFLD);
• non-alcoholic steatohepatitis (NASH);
• portal hypertension;
• cholestasis;
• Down syndrome cholestasis;
• drug-induced cholestasis;
• intrahepatic cholestasis of pregnancy;
• intrahepatic cholestasis;
• extrahepatic cholestasis;
• parenteral nutrition associated cholestasis (PNAC);
• low phospholipid-associated cholestasis;
• lymphedema cholestasis syndrome 1 (LSC1);
• primary sclerosing cholangitis (PSC) immunoglobulin G4 associated cholangitis;
• primary biliary cholangitis;
• cholelithiasis (gall stones);
• biliary lithiasis;
• choledocholithiasis;
• gallstone pancreatitis;
• Caroli disease;
• malignancy of bile ducts;
• malignancy causing obstruction of the biliary tree;
• biliary strictures;
• AIDS cholangiopathy;
• ischemic cholangiopathy;
• pruritus due to cholestasis or jaundice;
• pancreatitis;
• chronic autoimmune liver disease leading to progressive cholestasis;
• hepatic steatosis;
• alcoholic hepatitis;
• acute fatty liver;
• fatty liver of pregnancy;
• drug-induced hepatitis;
• iron overload disorders;
• congenital bile acid synthesis defect type 1 (BAS type 1);
• drug-induced liver injury (DILI);
• hepatic fibrosis;
• congenital hepatic fibrosis;
• hepatic cirrhosis;
• Langerhans cell histiocytosis (LCH);
• neonatal ichthyosis sclerosing cholangitis (NISCH);
• erythropoietic protoporphyria (EPP);
• idiopathic adulthood ductopenia (IAD);
• idiopathic neonatal hepatitis (INH);
• non syndromic paucity of interlobular bile ducts (NS PILBD);
• North American Indian childhood cirrhosis (NAIC);
• hepatic sarcoidosis;
• amyloidosis;
• necrotizing enterocolitis;
• serum bile acid-caused toxicities;
• viral hepatitis;
• hepatocellular carcinoma (hepatoma);
• cholangiocarcinoma;
• bile acid-related gastrointestinal cancers;
• and cholestasis caused by tumours and neoplasms of the liver, of the biliary tract and of the pancreas.