Farnesoid x receptor agonists and uses thereof

Abstract

Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.

1 - 57 . (canceled) 
     
     
         58 . A compound that has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein,
 X 1  is CH or N; 
 R 1  is H, D, halogen, —CN, —OH, —SH, —N(R 15 ) 2 , —NR 15 S(═O) 2 (C 1 -C 4 alkyl), —S(C 1 -C 4 alkyl), —S(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), —S(═O) 2 N(R 15 ) 2 , —OC(O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —C(═O)N(R 15 ) 2 , —NR 15 C(═O)(C 1 -C 4 alkyl), —NR 15 C(═O)O(C 1 -C 4 alkyl), —OC(═O)N(R 15 ) 2 , —NR 15 C(═O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, or substituted or unsubstituted monocyclic C 2 -C 5 heterocycloalkyl; 
 X 2  is CR 2  or N; 
 R 2  is H, D, halogen, —CN, —OH, —SH, —N(R 15 ) 2 , —NR 15 S(═O) 2 (C 1 -C 4 alkyl), —S(C 1 -C 4 alkyl), —S(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), —S(═O) 2 N(R 15 ) 2 , —OC(O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —C(═O)N(R 15 ) 2 , —NR 15 C(═O)(C 1 -C 4 alkyl), —NR 15 C(═O)O(C 1 -C 4 alkyl), —OC(═O)N(R 15 ) 2 , —NR 15 C(═O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 heteroalkyl, or substituted or unsubstituted monocyclic C 2 -C 5 heterocycloalkyl; 
 or R 1  and R 2  are taken together with the intervening atoms to form a substituted or unsubstituted fused 5-membered ring or substituted or unsubstituted fused 6-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring; 
 X 3  is CR 3  or N; 
 R 3  is H, D, halogen, —CN, —OH, —SH, —N(R 15 ) 2 , —NR 15 S(═O) 2 (C 1 -C 4 alkyl), —S(C 1 -C 4 alkyl), —S(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), —S(═O) 2 N(R 15 ) 2 , —OC(═O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —C(═O)N(R 15 ) 2 , —NR 15 C(═O)(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, or substituted or unsubstituted monocyclic C 2 -C 5 heterocycloalkyl; 
 each X 4  is independently CH or N; 
 R 4  is H; 
 R 5  is H; 
 or R 4  and R 5  are taken together to form a bridge that is —CH 2 — or —CH 2 CH 2 —; 
 each R 6  is independently H, D, F, —OH, or —CH 3 ;
 m is 0, 1, or 2; 
 
 R 7  is H, D, halogen, —CN, —OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 heteroalkyl; 
 L is absent, —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, —OCH 2 —, —CH 2 NR 15 —, —NR 15 CH 2 —, —CH═CH—, —C≡C—, —C(═O)NR 15 —, —NR 15 C(═O)—, —OC(═O)NR 15 —, —NR 15 C(═O)O—, —NR 15 C(═O)NR 15 —, —NR 15 S(═O) 2 —, —NR 15 —, cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene; 
 R 8  is H, D, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), —C(═O)N(R 15 ) 2 , —S(═O) 2 (C 1 -C 4 alkyl), —S(═O) 2 N(R 15 ) 2 , substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; 
 R 9  is H, D, F or —CH 3 ; 
 R 10  is —OH; 
 each R 12  is independently H, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl; 
 R 14  is C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl; 
 R 15  is H or substituted or unsubstituted C 1 -C 6 alkyl; 
 each R 16  is independently H, D, halogen, —CN, —OH, —N(R 15 ) 2 , —NR 15 S(═O) 2 (C 1 -C 4 alkyl), —S(C 1 -C 4 alkyl), —S(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), —C(═O)(C 1 -C 4 alkyl), —OC(═O)(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —NR 15 C(═O)(C 1 -C 4 alkyl), —C(═O)N(R 15 ) 2 , —NR 15 C(═O)O(C 1 -C 4 alkyl), —OC(═O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; 
 n is 0, 1, or 2. 
 
     
     
         59 . The compound of  claim 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L is absent or —C≡C—;   R 4  is H;   R 5  is H;   or R 4  and R 5  are taken together to form a bridge that is —CH 2 CH 2 —.   
     
     
         60 . The compound of  claim 59 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of  claim 60 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHS(═O) 2 CH 3 , —OC(═O)CH 3 , —CO 2 H, —CO 2 CH 3 , —NHC(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , or —CH 2 N(CH 3 ) 2 ; and 
         R 2  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHS(═O) 2 CH 3 , —OC(═O)CH 3 , —CO 2 H, —CO 2 CH 3 , —NHC(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , or —CH 2 N(CH 3 ) 2 . 
       
     
     
         62 . The compound of  claim 61 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IV) or Formula (V), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         63 . The compound of  claim 59 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (VII) or Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The compound of  claim 63 , or a pharmaceutically acceptable salt or solvate thereof wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHS(═O) 2 CH 3 , —OC(═O)CH 3 , —CO 2 H, —CO 2 CH 3 , —NHC(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , or —CH 2 N(CH 3 ) 2 ; and 
         R 2  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHS(═O) 2 CH 3 , —OC(═O)CH 3 , —CO 2 H, —CO 2 CH 3 , —NHC(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , or —CH 2 N(CH 3 ) 2 . 
       
     
     
         65 . The compound of  claim 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , or —OCH 2 CF 3 ; and 
         R 2  is H, D, F, Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , or —OCH 2 CF 3 . 
       
     
     
         66 . The compound of  claim 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, D, F, Cl, —CN, —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , or —OCH 2 CF 3 ; and 
         R 2  is H, D, F, Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , or —OCH 2 CF 3 . 
       
     
     
         67 . The compound of  claim 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 8  is H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CD3, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CHFCH 3 , —CH 2 CH 2 F, —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl.   
     
     
         68 . The compound of  claim 67 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 each R 16  is independently H, D, F, Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —CD3, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl.   
     
     
         69 . The compound of  claim 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         70 . The compound of  claim 69 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is —OH, —SH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —OCH 3 , —SCH 3 , —CD3, —OCD 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , or —OCH 2 CF 3 ;   R 2  is H, D, F, Cl, —CH 3 , —CD3, —CH 2 F, —CHF 2 , or —CF 3 ;   R 8  is H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CD3, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CHFCH 3 , —CH 2 CH 2 F, —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and   R 10  is —OH.   
     
     
         71 . A compound that is:
 trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)phenyl)cyclohexanecarboxamide;   trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)-N-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-N-(3-(1-Ethyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)-4-hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-N-(3-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-(3-(1-isobutyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-propyl-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-(3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-(2-(Dimethylamino)ethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclobutyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   trans-N-(3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-(2-Fluoroethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-(sec-Butyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-((1H-Pyrazol-4-yl)ethynyl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)cyclohexanecarboxamide;   trans-N-(3-((1H-Pyrazol-3-yl)ethynyl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)phenyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)-4-hydroxycyclohexane carboxamide;   trans-N-((trans-4-(3-Chloro-4-methoxyphenyl)cyclohexyl)methyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-N-((trans-4-(Benzo[d][1,3]dioxol-5-yl)cyclohexyl)methyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-(tert-Butyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(5-chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide;   trans-4-Hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(6-methoxy-5-methylpyridin-3-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide;   trans-N-((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)-4-hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide;   trans-N-(3-(1-(tert-Butyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(1-ethyl-1H-pyrazol-4-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide;   trans-N-(3-(1-Cyclobutyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(5-methoxy-4-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)-4-hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide;   trans-N-((trans-4-(6-Cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)-4-hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)cyclohexanecarboxamide;   N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   cis-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylpyridin-2-yl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-hydroxycyclohexanecarboxamide;   trans-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide;   trans-4-Amino-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   trans-4-Amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide;   trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-((trans-4-(4-hydroxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide;   (1r, 4r)-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-methylcyclohexanecarboxamide   (1s, 4s)-4-Hydroxy-N-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-methylcyclohexanecarboxamide   trans-4-Hydroxy-N-(4-(1-Isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-(6-methoxy-5-methylpyridin-3-yl)cyclohexyl)methyl)cyclohexanecarboxamide   trans-N-((trans-4-(5-Chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)-4-hydroxy-N-(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide;   or a pharmaceutically acceptable salt, or solvate thereof.   
     
     
         72 . A pharmaceutical composition comprising a compound of  claim 58 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         73 . A method of treating a liver disease or condition in a mammal, comprising administering to the mammal a compound of  claim 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD). 
     
     
         74 . A method of treating fatty liver in a mammal, comprising administering to the mammal a compound of  claim 58 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         75 . A method of treating or preventing a gastrointestinal disease or condition in a mammal, comprising administering to the mammal a compound of  claim 58 , or a pharmaceutically acceptable salt or solvate thereof; wherein the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, post-surgical inflammation, gastric carcinogenesis, graft versus host disease or any combination thereof. 
     
     
         76 . The method of claim  53 , wherein the gastrointestinal disease or condition is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unsubtyped IBS (IBS-U), or bile acid diarrhea (BAD). 
     
     
         77 . The method of  claim 73 , further comprising administering at least one additional therapeutic agent.