Farnesoid x receptor antagonists

Abstract

Provided herein are Farnesoid X receptor (FXR) antagonists having the structure of formula (I), and pharmaceutical compositions comprising the compound of formula (I) and a pharmaceutically acceptable excipient. Also provided are methods of antagonizing FXR, and methods of treating metabolic disease in a subject in need thereof, comprising administering an effective amount of the FXR antagonists of formula (I) to a subject.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is —CH 2 — or —C(O)— or —CY(OH)—; 
         Y is hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OR 9A , —NHR 9A , —COOR 9A , —CONHR 9A , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         L 1  is independently a bond, —C(O)—, —C(O)—O, —O—, —S—, —NR 9B —, —C(O)NR 9B —, —S(O) n —, —S(O)NR 9B —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2  is independently a bond, —C(O)—, —C(O)—O, —O—, —S—, —NR 9C —, —C(O)NR 9C —, —S(O) n —, —S(O)NR 9C —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         R 1  and R 2  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 3  is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 3A , —NR 3B R 3C , —COOR 3A , —C(C)NR 3B R 3C , —NO 2 , —SR 3D , —S(O) n3 R 3B , —S(O) n3 OR 3B , —S(O) n3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , or substituted or unsubstituted alkyl, 
         R 5  is hydrogen or substituted or unsubstituted alkyl; 
         R 6  is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 6A , —NR 6B R 6C , —COOR 6A , —CONR 6B R 6C , —NO 2 , —SR 6D , —SO n6 R 6B , —SO n6 OR 6B , —SO n6 NR 6B R 6C , —NHNR 6B R 6C , —ONR 6B R 6C , —NHC(O)NHNR 6B R 6C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; 
         R 7  is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 7A , —NR 7B R 7C , —COOR 7A , —C(O)NR 7B R 7C , —NO 2 , —SR 7D , —S(O) n7 R 7B , —S(O) n7 OR 7B , —S(O) n7 NR 7B R 7C , —NHNR 7B R 7C , —ONR 7B R 7D , —NHC(O)NHNR 7B R 7C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 8  is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 8A , —NR 8B R 8C , —COOR 8A , —C(O)NR 8B R 8C , —NO 2 , —S(O) n8 R 8B , —S(O) n8 OR 8B , —S(O) n8 NR 8B R 8C , —NHNR 8B R 8C , —ONR 8B R 8C , —NHC(O)NHNR 8B R 8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 9A , R 9B , R 9C  areindependently hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —COOH, —CONH 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 3A , R 6A , R 7A , and R 8A  are independently hydrogen or unsubstituted alkyl; 
         R 3B , R 6B , R 7B , R 8B , R 3C , R 6C , R 7C , R 8C , R 3D , R 6D , R 7D , and R 8D  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         z1 is 1, 2, 3, 4, 5 or 6; 
         z2 is 1, 2, 3, 4, 5, 6, 7 or 8; 
         n, n3, n6, n7, and n8 are independently 1 or 2; and 
         wherein if X is —C(O)— and -L 1 -R 1  is unsubstituted phenyl, then -L 2 -R 2  is not methyl, p-substituted or unsubstituted phenyl, or unsubstituted pyridine. 
       
     
     
         2 . The compound of  claim 1 , wherein R 6  is substituted or unsubstituted C 1 -C 5  alkyl. 
     
     
         3 . The compound of  claim 1 , wherein X is —C(O)—. 
     
     
         4 . The compound of  claim 1 , wherein L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. 
     
     
         5 . The compound of  claim 1 , wherein L 1  is substituted or unsubstituted C 1 -C 5  alkylene. 
     
     
         6 . The compound of  claim 1 , wherein L 2  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene 
     
     
         7 . The compound of  claim 1 , wherein L 2  is a bond or substituted or unsubstituted alkylene. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl. 
     
     
         9 . The compound of  claim 1 , having formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein R 1  is substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein R 2  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         17 .- 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein R 3  is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 3A , or substituted or unsubstituted alkyl, wherein R 3A  is hydrogen or unsubstituted C 1 -C 5  alkyl. 
     
     
         20 . The compound of  claim 1 , wherein R 3  is hydrogen, halogen, —CF 3 , —OH, or substituted or unsubstituted alkyl. 
     
     
         21 . The compound of  claim 1 , wherein R 5  is hydrogen or methyl. 
     
     
         22 . The compound of  claim 1 , wherein R 7  and R 8  are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —OCH 3 , or substituted or unsubstituted alkyl. 
     
     
         23 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is —C(R 4A )(R 4B )—, —C(O)— or —CY(OH)—; 
         Y is hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OR 9A , —NHR 9A , —COOR 9A , —CONHR 9A , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         L 1  is independently a bond, —C(O)—, —C(O)O—, —O—, —S—, —NR 9B —, —C(O)NR 9B —, —S(O) n —, —S(O)NR 9B —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2  is independently a bond, —C(O)—, —C(O)—O, —O—, —S—, —NR 9C —, —C(O)NR 9C —, —S(O) n —, —S(O)NR 9C —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         R 1 , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7 , and R 8  are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 11A , —NR 11B R 11C , —COOR 11A , —C(O)NR 11B R 11C , —NO 2 , —SR 11D , —S(O) n11 R 11B , —S(O) n11 OR 11B , —S(O) n11 NR 11B R 11C , —NHNR 11B R 11C , —ONR 11B R 11C , —NHC(O)NHNR 11B R 11C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 9A , R 9B , R 9C  areindependently hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —COOH, —CONH 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         n11 is 1 or 2; 
         z1 is 1, 2, 3, 4, 5, or 6; 
         z2 is 1, 2, 3, 4, 5, 6, 7, or 8; and 
         R 11A , R 11B , R 11C , and R 11D  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
       
     
     
         25 . A method of antagonizing Farnesoid X Receptor (FXR) protein, said method comprising contacting a FXR protein with a compound of any one of  claims 1  to  23  or the pharmaceutical composition of  claim 24 . 
     
     
         26 . A method of treating metabolic disease, said method comprising administering to a subject in need thereof a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is —C(R 4A )(R 4B )—, —C(O)— or —CY(OH)—; 
         Y is hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OR 9A , —NHR 9A , —COOR 9A , —CONHR 9A , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         L 1  is independently a bond, —C(O)—, —C(O)O—, —O—, —S—, —NR 9B —, —C(O)NR 9B —, —S(O) n —, —S(O)NR 9B —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2  is independently a bond, —C(O)—, —C(O)—O, —O—, —S—, —NR 9C —, —C(O)NR 9C —, —S(O) n —, —S(O)NR 9C —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
         R 1 , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7 , and R 8  are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 11A , —NR 11B R 11C , —COOR 11A , —C(O)NR 11B R 11C , —NO 2 , —SR 11D , —S(O) n11 R 11B , —S(O) n11 OR 11B , —S(O) n11 NR 11B R 11C , —NHNR 11B R 11C , —ONR 11B R 11C , —NHC(O)NHNR 11B R 11C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 9A , R 9B , R 9C  areindependently hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —COOH, —CONH 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         n11 is 1 or 2; 
         z1 is 1, 2, 3, 4, 5, or 6; 
         z2 is 1, 2, 3, 4, 5, 6, 7, or 8; and 
         R 11A , R 11B , R 11C , and R 11D  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, thereby treating said metabolic disease. 
       
     
     
         27 .- 50 . (canceled)