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 .- 18 . (canceled) 
     
     
         19 . A compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         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; 
 R 8  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 9  and R 10  together with the carbon atoms to which they are attached, form a phenyl ring substituted with (R 11 ) n ; or R 9  and R 10  together with the carbon atoms to which they are attached, form a nitrogen containing 6-membered heteroaryl ring substituted with (R 11 ) n ; or R 9  and R 10  together with the carbon atoms to which they are attached, form a 5-membered heteroaryl ring substituted with (R 39 ) p  and (R 12 ) q ; 
 each R 11  is independently selected from the group consisting of 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 , —C(═O)N(R 13 )R 14 ; 
 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 , —C(═O)N(R 13 )R 14 ; 
 n is 0, 1, 2, or 3; 
 p is 0, 1 or 2; 
 q is 0 or 1; 
 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. 
       
     
     
         20 . The compound of  claim 19  having the structure of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof: 
       
         
           
           
               
               
           
         
       
     
     
         21 .- 24 . (canceled) 
     
     
         25 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0 or 1. 
     
     
         26 .- 34 . (canceled) 
     
     
         35 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 3  is —C(═O)R 20 . 
     
     
         36 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 20  is —R 34 R 35 . 
     
     
         37 .- 39 . (canceled) 
     
     
         40 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 20  is —R 31 . 
     
     
         41 . The compound of  claim 40 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 31  is R 36a . 
     
     
         42 . The compound of  claim 40 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 31  is R 36c . 
     
     
         43 .- 44 . (canceled) 
     
     
         45 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 6  and R 7  are hydrogen. 
     
     
         46 . (canceled) 
     
     
         47 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4  and R 5  are methyl. 
     
     
         48 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2  is —C(O)OR 25 . 
     
     
         49 . (canceled) 
     
     
         50 . The compound of  claim 48 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 25  is selected from the group consisting of methyl, ethyl, and isopropyl. 
     
     
         51 .- 52 . (canceled) 
     
     
         53 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2  is —C(O)N(R 25 )R 26 . 
     
     
         54 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1  is hydrogen. 
     
     
         55 . (canceled) 
     
     
         56 . The compound of  claim 19 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1  is methyl. 
     
     
         57 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 19 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         58 . 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 compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 19 . 
     
     
         59 . The method of  claim 58 , 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 . (canceled) 
     
     
         61 . A method of modulating FXR activity comprising contacting FXR, or portion thereof, with a compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 19 . 
     
     
         62 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.