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 .- 73 . (canceled) 
     
     
         74 . A compound having the structure of Formula (Ie), or a pharmaceutically acceptable salt or solvate 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 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  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 an optionally substituted nitrogen containing 6-membered heteroaryl ring; 
 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; 
 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 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 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); 
 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; and, 
 n is 0, 1, or 2. 
 
     
     
         75 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIe): 
       
         
           
           
               
               
           
         
       
       wherein:
 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; and 
 n is 0, 1, or 2. 
 
     
     
         76 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof wherein n is 0. 
     
     
         77 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  and R 7  are hydrogen. 
     
     
         78 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  and R 5  are each independently optionally substituted C 1 -C 6 alkyl. 
     
     
         79 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  and R 5  are methyl. 
     
     
         80 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2  is —C(O)OR 25 . 
     
     
         81 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 25  is optionally substituted C 1 -C 6 alkyl. 
     
     
         82 . The compound of  claim 74 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 25  is methyl, ethyl, or isopropyl. 
     
     
         83 . A compound according to Formula (Ie) of  claim 74  having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         84 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 74 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         85 . 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 74 . 
     
     
         86 . 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 74 . 
     
     
         87 . The method of  claim 86 , 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. 
     
     
         88 . The method of  claim 87 , wherein the disease or disorder is nonalcoholic steatohepatitis (NASH).