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 - 30 . (canceled) 
     
     
         31 . A method of treating a disease, disorder or condition in a mammal that would benefit from farnesoid X receptor (FXR) modulation comprising administering to the mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, having a structure according to Formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         —X—Y—Z— is selected from 
       
       
         
           
           
               
               
           
         
         R 1  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 C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 2  is selected from the group consisting of —CN, —C(═O)OR 25 , —C(═O)N(R 25 )R 26 , 
       
       
         
           
           
               
               
           
         
       
       or R 1  and R 2  together with the carbon atoms to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring or an optionally substituted heteroaryl ring;
 R 3  is —C(═O)R 20  or —S(═O) 2 R 20 ; 
 R 4  and R 5  are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4  and R 5  together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 -C 7 heterocycloalkyl ring; 
 R 6  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, and —C(═O)N(R 27 )R 28 ; 
 R 7  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; 
 each R 12  is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; 
 each R 13  and R 14  are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 13  and R 14  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
 each R 39  is independently selected from the group consisting of hydrogen, halogen, —CN, amino, alkylamino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, heteroaryl, —C(═O)OR 12 , and —C(═O)N(R 13 )R 14 ; 
 R 20  is selected from the group consisting of —R 34 R 35  or —R 31 ; 
 R 34  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 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 35  is —(C 1 -C 6 alkyl)-R 30 , —O(C 2 -C 6 alkyl)-R 30 , or —N(R 12 )(C 2 -C 6 alkyl)-R 30 ; 
 R 30  is R 36a , R 36b , or R 36c ; 
 R 31  is R 36a  or R 36c ; 
 R 36a  is 
 
       
         
           
           
               
               
           
         
         R 36b  is 
       
       
         
           
           
               
               
           
         
         R 36c  is 
       
       
         
           
           
               
               
           
         
         R 17a  is C 1 -C 6 alkyl; 
         R 17b  is C 1 -C 6 alkyl optionally substituted with phenyl, —C(═O)OH or —S(═O) 2 OH; 
         R 18  is hydrogen, —OH, —(C 0 -C 6 alkyl)-C(═O)OH, or C 1 -C 6 alkyl; 
         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); and 
         R 27  and R 28  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); or R 27  and R 28  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring. 
       
     
     
         32 .- 33 . (canceled) 
     
     
         34 . The method of  claim 31 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, has a structure according to Formula (IVc): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 34 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is —C(═O)R 20 . 
     
     
         36 . The method of  claim 35 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 20  is —R 34 R 35 . 
     
     
         37 . The method of  claim 36 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 34  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, and optionally substituted aryl. 
     
     
         38 . The method of  claim 37 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 34  is optionally substituted aryl and R 35  is —O(C 2 -C 6 alkyl)-R 30 . 
     
     
         39 . The method of  claim 38 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 30  is R 36b  or R 36c . 
     
     
         40 . The method of  claim 39 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 36b  is 
       
         
           
           
               
               
           
         
       
     
     
         41 .- 42 . (canceled) 
     
     
         43 . The method of  claim 34 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 39  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl. 
     
     
         44 . The method of  claim 34 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 , R 6 , R 7 , and R 12  are each hydrogen. 
     
     
         45 .- 46 . (canceled) 
     
     
         47 . The method of  claim 34 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4  and R 5  are methyl. 
     
     
         48 . The method of  claim 34 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2  is —C(O)OR 25 . 
     
     
         49 . The method of  claim 48 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 25  is optionally substituted C 1 -C 6 alkyl. 
     
     
         50 .- 51 . (canceled) 
     
     
         52 . The method of  claim 48 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 25  is isopropyl. 
     
     
         53 .- 58 . (canceled) 
     
     
         59 . The method of claim  30 , wherein the disease, disorder or condition in a mammal is selected from nonalcoholic steatohepatitis (NASH), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis and obesity. 
     
     
         60 . The method of  claim 59 , wherein the disease, disorder or condition is nonalcoholic steatohepatitis (NASH). 
     
     
         61 . (canceled)