Fused bicyclic compounds for the treatment of disease

Abstract

Described herein are fused bicyclic compounds, compositions, and methods for their use for the treatment of disease.

1 - 85 . (canceled) 
     
     
         86 . A compound having the Formula (II), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted —(C 1 -C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted —(C 1 -C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl), —OR 10 , —SR 10 , —N(R 11 )R 12 , —N(R 11 )S(O) 2 R 15 ; —N(R 13 )N(R 11 )R 12 , —N(R 13 )N(R 11 )S(O) 2 R 15 , —C(O)R 14 , —C(O)OR 10 , —C(S)OR 10 , —C(O)SR 10 , —C(O)N(R 11 )R 12 , —C(S)N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 15 , —C(S)N(R 11 )S(O) 2 R 15 , —C(O)N(R 13 )N(R 11 )R 12 , —C(S)N(R 13 )N(R 11 )R 12  and —C(O)N(R 13 )N(R 11 )S(O) 2 R 15 ; 
         R 2  is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 3  is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl), —C(O)R 20 , —C(O)OR 20 , —S(O) 2 R 20 , —C(O)N(R 21 )R 22 , —C(O)N(R 21 )S(O) 2 R 24 , —C(O)N(R 23 )N(R 21 )R 22 , —C(O)N(R 23 )N(R 21 )S(O) 2 R 24 , —N(R 23 )C(O)R 20 , —N(R 23 )C(O)N(R 21 )R 22 , —N(R 23 )C(O)N(R 21 )S(O) 2 R 24 , —N(R 20 )C(O)N(R 23 )N(R 21 )R 22 , —N(R 20 )C(O)N(R 23 )N(R 21 )S(O) 2 R 24 , —N(R 23 )C(O)OR 20 , —P(O)OR 20 , and —P(O)(OR 19 )OR 20 ; 
         R 4 , R 5 , R 6 , and R 7  are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; 
         R 8  is selected from the group consisting of —CN, —C(O)OR 25 , —C(O)N(R 25 )R 26 , 
       
       
         
           
           
               
               
           
         
         R 10 , R 13  and R 14  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); or optionally R 11  and R 12  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         R 15  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 19 , R 20 , and R 23  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 21  and R 22  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); or optionally R 21  and R 22  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         R 24  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted aryl optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); and 
         R 25  and R 26  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl). 
       
     
     
         87 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  and R 7  are hydrogen. 
     
     
         88 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  and R 5  are each independently optionally substituted C 1 -C 6 alkyl. 
     
     
         89 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3  is selected from the group consisting of —C(O)R 20 , —S(O) 2 R 20 , and —C(O)N(R 21 )R 22 . 
     
     
         90 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 20  is selected from the group consisting of optionally substituted aryl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 -C 9 heterocycloalkyl. 
     
     
         91 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 21  is hydrogen and R 22  is optionally substituted aryl. 
     
     
         92 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 8  is —C(O)OR 25 . 
     
     
         93 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 25  is optionally substituted C 1 -C 6 alkyl. 
     
     
         94 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2  is hydrogen. 
     
     
         95 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is hydrogen. 
     
     
         96 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl. 
     
     
         97 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is C 1 -C 6 alkyl. 
     
     
         98 . The compound of  claim 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is —CF 3 . 
     
     
         99 . A compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         100 . The compound according to  claim 99  having the structure: 
       
         
           
           
               
               
           
         
         wherein the pharmaceutically acceptable salt is formed with hydrochloric acid. 
       
     
     
         101 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 86 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         102 . A method of treating a disease, disorder or condition in a mammal that would benefit from farnesoid X receptor (FXR) agonism comprising administering to the mammal a compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 86 , wherein the disease, disorder or condition is selected from nonalcoholic steatohepatitis (NASH), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis and obesity. 
     
     
         103 . The method of  claim 102 , wherein the disease, disorder or condition in a mammal is nonalcoholic steatohepatitis (NASH). 
     
     
         104 . A method of treating a disease, disorder or condition in a mammal that would benefit from farnesoid X receptor (FXR) agonism comprising administering to the mammal a compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 99 , wherein the disease, disorder or condition is selected from nonalcoholic steatohepatitis (NASH), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis and obesity.