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.

What is claimed is: 
     
         1 . A compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently selected from H, D, F, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl; 
 or R 1  and R 2  are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
 or R 1  and R 2  are taken together with the carbon atom to which they are attached to form a carbonyl (C═O); 
 R 3  is selected from substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R 3  is substituted then R 3  is substituted with one or more R 12  groups;
 each R 12  is independently selected from D, halogen, —CN, —NO 2 , —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —NR 10 S(═O) 2 R 11 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 1 -C 10 fluoroalkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted C 1 -C 10 heteroalkyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and -L 5 -L 6 -R 13 ; 
 L 5  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 10 —, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)NH—, —NHC(═O)NH—, —NHC(═O)O—, —(CH 2 ) r —, or —(OCH 2 CH 2 ) r —, r is 1, 2, 3, or 4; 
 L 6  is absent, unsubstituted or substituted C 1 -C 10 alkylene, unsubstituted or substituted C 1 -C 10 heteroalkylene, unsubstituted or substituted C 2 -C 10 alkenylene, unsubstituted or substituted C 2 -C 10 alkynylene, unsubstituted or substituted C 3 -C 10 cycloalkylene, unsubstituted or substituted C 2 -C 10 heterocycloalkylene, unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene; 
 R 13  is H, halogen, —N(R 10 ) 2 , unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 1 -C 10 alkenyl, unsubstituted or substituted C 1 -C 10 alkynyl, unsubstituted or substituted C 1 -C 10 cycloalkyl, unsubstituted or substituted C 1 -C 10 heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; 
 
 ring A is a monocyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
 each R A  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, and substituted or unsubstituted C 1 -C 6 heteroalkyl; 
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —C(═O)NR 10 —, —NR 10 C(═O)—, —OC(═O)NR 10 —, —NR 10 C(═O)O—, —NR 10 C(═O)NR 10 —, —NR 10 S(═O) 2 —, or —NR 10 —; 
 L 2  is absent or substituted or unsubstituted C 1 -C 4 alkylene; 
 
 ring C is monocyclic carbocycle, bicyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
 each R C  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —NO 2 , —N(R 10 ) 2 , —S(═O) 2 R 11 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted monocyclic heteroaryl; 
 ring B is a monocyclic carbocycle, bicyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
 each R B  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —N(R 10 ) 2 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═C)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl; 
 L 3  is —X 2 -L 4 - or -L 4 -X 2 —;
 X 2  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —C(═O)NR 10 —, —NR 10 C(═O)—, —OC(═O)NR 10 —, —NR 10 C(═O)O—, —NR 10 C(═O)NR 10 —, —NR 10 S(═O) 2 —, or —NR 10 —; 
 L 4  is absent or substituted or unsubstituted C 1 -C 4 alkylene; 
 
 ring D is phenyl, bicyclic carbocycle, monocyclic N-containing heterocycloalkyl, monocyclic heteroaryl, or bicyclic heterocycle; 
 each R D  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —N(R 10 ) 2 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -Ciocycloalkyl, and substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
 each R 10  is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl; 
 or two R 10  on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycle; 
 each R 11  is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl; 
 m is 0, 1, or 2; 
 n is 0, 1, or 2; 
 p is 0, 1, 2, 3, or 4; 
 q is 0, 1, 2, 3, or 4. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from H and D;   ring B is a monocyclic carbocycle or monocyclic heterocycle wherein the groups   
       
         
           
           
               
               
           
         
       
       are in a 1,3-relationship on ring B. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R l  and R 2  are each independently selected from H and D;   ring B is a monocyclic carbocycle or monocyclic heterocycle wherein the groups   
       
         
           
           
               
               
           
         
       
       are in a 1,4-relationship on ring B. 
     
     
         4 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring B is phenyl.   
     
     
         5 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring B is monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.   
     
     
         6 . The compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring D is phenyl.   
     
     
         8 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring D is monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.   
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring D is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidine-2,5-dionyl, piperidinyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl.   
     
     
         12 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 3  is —X 2 -L 4 - or -L 4 -X 2 —;   X 2  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, or —NR 10 —;   L 4  is absent or —CH 2 —.   
     
     
         13 . The compound of any one of  claims 1 - 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 3  is absent, —O—, —S—, —S—CH 2 —, —CH 2 —S—, —CH 2 —, —CH═CH—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, —NR 10 —, —NR 10 —CH 2 —, or —CH 2 —NR 10 —.   
     
     
         14 . The compound of any one of  claims 1 - 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 3  is absent, —O—, —S—, —CH═CH—, or —NR 10 —.   
     
     
         15 . The compound of any one of  claims 1 - 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is monocyclic carbocycle that is phenyl or a C 3 -C 8 cycloalkyl.   
     
     
         16 . The compound of any one of  claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is phenyl.   
     
     
         17 . The compound of any one of  claims 1 - 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of any one of  claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is monocyclic C 3 -C 8 cycloalkyl that is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.   
     
     
         19 . The compound of  claim 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is   
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of any one of  claims 1 - 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 1 -C 5 heteroarylene containing 1-4 N atoms, and 0 or 1 O or S atom or a monocyclic heterocycle that is a monocyclic C 1 -C 5 heteroarylene containing 0-4 N atoms, and 1 O or S atom.   
     
     
         21 . The compound of  claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 6-membered heteroarylene selected from pyridinylene, pyrimidinylene, pyrazinylene, or pyridazinylene.   
     
     
         22 . The compound of  claim 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 5-membered heteroarylene selected from furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene.   
     
     
         24 . The compound of  claim 20  or  claim 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The compound of any one of  claims 1 - 24 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;   X 1  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, or —NR 10 —;   L 2  is absent or —CH 2 —.   
     
     
         26 . The compound of any one of  claims 1 - 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is absent, —O—, —S—, —S—CH 2 —, —CH 2 —S—, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, —NR 10 —, —NR 10 —CH 2 —, or —CH 2 —NR 10 —.   
     
     
         27 . The compound of any one of  claims 1 - 26 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is absent.   
     
     
         28 . The compound of any one of  claims 1 - 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         29 . The compound of  claim 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of any one of  claims 1 - 14 , wherein the compound of Formula (I) has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         ring A is a monocyclic heterocycle containing 1-4 N atoms or a bicyclic heterocycle containing 1-4 N atoms. 
       
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 5-membered C 1 -C 4 heteroarylene containing 1-4 N atoms.   
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
       is a monocyclic 5-membered C 1 -C 4 heteroarylene containing 1-4 N atoms that has the structure 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         34 . The compound of  claim 33 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 30  or  claim 33 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of any one of  claims 30 - 35 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —S(═O)—, —S(═O) 2 —, —CH 2 —, —C(═O)—, —OC(═O)—, —NR 10 C(═O)—, or —NR 10 S(═O) 2 —; 
 L 2  is absent or substituted or unsubstituted C 1 -C 4 alkylene. 
   
     
     
         37 . The compound of  claim 36 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —S(═O) 2 —, —CH 2 —, or —C(═O)—; 
 L 2  is absent or —CH 2 —. 
   
     
     
         38 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is monocyclic carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.   
     
     
         39 . The compound of any one of  claims 1 - 38 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is phenyl.   
     
     
         40 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is monocyclic heterocycle, or bicyclic heterocycle.   
     
     
         41 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolylene, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.   
     
     
         42 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a bicyclic heteroaryl selected from quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, azabenzotriazolyl, benzoxazolyl, azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl, and purinyl.   
     
     
         45 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is monocyclic heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, and 1,2,3,6-tetrahydropyridinyl.   
     
     
         47 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a monocyclic C2-Csheterocycloalkyl containing at least 1 N atom in the ring.   
     
     
         48 . The compound of  claim 47 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a monocyclic C2-Csheterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         49 . The compound of  claim 47 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The compound of any one of  claims 1 - 49 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted aryl, wherein if R 3  is substituted then R 3  is substituted with one or more R 12  groups.   
     
     
         51 . The compound of any one of  claims 1 - 50 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl,   
       
         
           
           
               
               
           
         
       
       and adamantyl. 
     
     
         52 . The compound of any one of  claims 1 - 51 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from iso-propyl, iso-butyl, tert-butyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted phenyl.   
     
     
         53 . The compound of  claim 1 , wherein the compound is:
 N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(5-methoxypyridin-3-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3′-methoxy-[1,1′-biphenyl]-3-yl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-methoxypyridin-4-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-((2-oxopyrrolidin-1-yl)methyl)phenyl)cyclohexanecarboxamide;   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-(oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide;   N-([1,1′-Biphenyl]-3-yl)-N-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamide;   N-([1,1′-Biphenyl]-3-yl)-N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-phenoxyphenyl)cyclohexanecarboxamide;   Methyl 3-(3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)phenyl)cyclobutanecarboxylate;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-(oxazol-2-yl)ethyl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(pyridin-3-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(5-methylpyridin-3-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(6-methoxypyridin-2-yl)phenyl)cyclohexanecarboxamide;   Methyl 5-(3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)phenyl)nicotinate;   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-(pyridin-2-yl)vinyl)phenyl)cyclohexanecarboxamide;   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-(pyridin-4-yl)vinyl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-methoxythiazol-4-yl)phenyl)cyclohexanecarboxamide   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(5-methoxythiophen-2-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(4-methoxypyridin-2-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(5-ethylpyridin-3-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-methoxypyrimidin-4-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(6-methoxypyrimidin-4-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(6-methoxypyrazin-2-yl)phenyl)cyclohexanecarboxamide;   3-(N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-N-(5-methoxypyridin-3-yl)benzamide;   3-(N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-N-phenylbenzamide;   Methyl 3-(3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)benzamido)benzoate;   3-(N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-N-(pyridin-4-yl)benzamide;   3-(N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-N-(pyridin-2-yl)benzamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(3-methoxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-methyl-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-(methoxymethyl)azetidin-1-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxypyrrolidin-1-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-(methoxymethyl)pyrrolidin-1-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(4-methoxypiperidin-1-yl)phenyl)cyclohexanecarboxamide;   trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxypiperidin-1-yl)phenyl)cyclohexanecarboxamide;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         54 . A compound that has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  are each independently selected from H, D, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         or R 1  and R 2  are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
         or R 1  and R 2  are taken together with the carbon atom to which they are attached to form a carbonyl (C═O); 
         R 3  is selected from substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if R 3  is substituted then R 3  is substituted with one or more R 12  groups;
 each R 12  is independently selected from D, halogen, —CN, —NO 2 , —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —NR 10 S(═O) 2 R 11 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 1 -C 10 fluoroalkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted C 1 -C 10 heteroalkyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and -L 5 -L 6 -R 13 ; 
 L 5  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 10 —, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)NH—, —NHC(═O)NH—, —NHC(═O)O—, —(CH 2 ) r —, or —(OCH 2 CH 2 ) r —, r is 1, 2, 3, or 4; 
 L 6  is absent, unsubstituted or substituted C 1 -C 10 alkylene, unsubstituted or substituted C 1 -C 10 heteroalkylene, unsubstituted or substituted C 2 -C 10 alkenylene, unsubstituted or substituted C 2 -C 10 alkynylene, unsubstituted or substituted C 3 -C 10 cycloalkylene, unsubstituted or substituted C 2 -C 10 heterocycloalkylene, unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene; 
 R 13  is H, halogen, —N(R 10 ) 2 , unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted C 1 -C 10 cycloalkyl, unsubstituted or substituted C 1 -C 10 heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; 
 
         ring A is a monocyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
         each R A  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl; 
         L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —C(═O)NR 10 —, —NR 10 C(═O)—, —OC(═O)NR 10 —, —NR 10 C(═O)O—, —NR 10 C(═O)NR 10 —, —NR 10 S(═O) 2 —, or —NR 10 —; 
 L 2  is absent or substituted or unsubstituted C 1 -C 4 alkylene; 
 
         ring C is monocyclic carbocycle, bicyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
         each R C  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —NO 2 , —N(R 10 ) 2 , —S(═O) 2 R 11 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         ring B is a monocyclic carbocycle, bicyclic carbocycle, monocyclic heterocycle, or bicyclic heterocycle; 
         each R B  is independently selected from H, D, halogen, —CN, —OH, —OR 10 , —SR 10 , —S(═O)R 11 , —S(═O) 2 R 11 , —N(R 10 ) 2 , —NHS(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —OC(═O)R 11 , —CO 2 R 10 , —OCO 2 R 11 , —C(═C)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, and substituted or unsubstituted C 1 -C 6 heteroalkyl; 
         R 4  is C 2 -C 10 alkenyl; or 
         R 4  is —N(R 9 ) 2 , -(substituted or unsubstituted C 1 -C 6 alkylene)-N(R 9 ) 2 , —NR 9 —C(R 7 )(R 8 )—CO 2 R 10 , —NR 9 -(substituted or unsubstituted C 1 -C 6 alkylene)-N(R 9 ) 2 —, or -L 3 -Y;
 L 3  is —C(R 5 )(R 6 )—, or —C(R 5 )(R 6 )—C(R 7 )(R 8 )—; 
 R 5  and R 7  are each independently selected from H, D, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl; 
 or R 5  and R 7  are taken together with the intervening atoms to form a double bond; 
 or R 5  and R 7  are taken together with the intervening atoms to form an epoxide or an substituted or unsubstituted C 3 -C 6 cycloalkyl; 
 R 6  and R 8  are each independently selected from H, D, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; 
 Y is —CH 2 N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , 
 
       
       
         
           
           
               
               
           
         
         
           
             each R 9  is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycle, —S(═O) 2 R 11 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 11 , —CO 2 R 10 , or —C(═O)N(R 10 ) 2 ; 
             or two R 9  on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycle; 
           
         
         each R 10  is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl; 
         or two R 10  on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycle; 
         each R 11  is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl; 
         m is 0, 1, or 2; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4. 
       
     
     
         55 . The compound of  claim 54 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from H and D;   ring B is a monocyclic carbocycle or monocyclic heterocycle wherein the groups   
       
         
           
           
               
               
           
         
       
       and R 4  are in a 1,3-relationship on ring B. 
     
     
         56 . The compound of  claim 54 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from H and D;   ring B is a monocyclic carbocycle or monocyclic heterocycle wherein the groups   
       
         
           
           
               
               
           
         
       
       and R 4  are in a 1,4-relationship on ring B. 
     
     
         57 . The compound of any one of  claims 54 - 56 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring B is phenyl.   
     
     
         58 . The compound of any one of  claims 54 - 56 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring B is monocyclic heteroaryl.   
     
     
         59 . The compound of any one of  claims 54 - 56 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring B is monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.   
     
     
         60 . The compound of  claim 54  or  claim 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of any one of  claims 54 - 60 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic carbocycle.   
     
     
         62 . The compound of any one of  claims 54 - 61 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is monocyclic carbocycle that is phenyl or a C 3 -C 8 cycloalkyl.   
     
     
         63 . The compound of any one of  claims 54 - 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The compound of any one of  claims 54 - 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is C 3 -C 8 cycloalkyl that is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.   
     
     
         65 . The compound of  claim 64 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is   
       
         
           
           
               
               
           
         
       
     
     
         66 . The compound of any one of  claims 54 - 60 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle.   
     
     
         67 . The compound of  claim 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 1 -C 5 heteroarylene containing 1-4 N atoms, and 0 or 1 O or S atom, or a monocyclic heterocycle that is a monocyclic C 1 -C 5 heteroarylene containing 0-4 N atoms, and 1 O or S atom.   
     
     
         68 . The compound of  claim 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 6-membered heteroarylene selected from pyridinylene, pyrimidinylene, pyrazinylene, and pyridazinylene.   
     
     
         69 . The compound of  claim 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         70 . The compound of  claim 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 5-membered heteroarylene selected from furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene.   
     
     
         71 . The compound of  claim 66  or  claim 70 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         72 . The compound of any one of  claims 54 - 71 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;   X 1  is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NR 10 —, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, or —NR 10 —;   L 2  is absent or —CH 2 —.   
     
     
         73 . The compound of any one of  claims 54 - 72 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L l  is absent, —O—, —S—, —S—CH 2 —, —CH 2 —S—, —CH 2 —, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR 10 —, —NR 10 C(═O)—, —NR 10 S(═O) 2 —, —NR 10 —CH 2 —, or —CH 2 —NR 10 —.   
     
     
         74 . The compound of any one of  claims 54 - 73 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is absent.   
     
     
         75 . The compound of  claim 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring.   
     
     
         76 . The compound of  claim 75 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         77 . The compound of  claim 76 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         78 . The compound of any one of  claims 54 - 60 , wherein the compound of Formula (IV) has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         ring A is a monocyclic heterocycle containing 1-4 N atoms or a bicyclic heterocycle containing 1-4 N atoms. 
       
     
     
         79 . The compound of  claim 78 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic 5-membered C 1 -C 4 heteroarylene containing 1-4 N atoms.   
     
     
         80 . The compound of  claim 78 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
       is a monocyclic 5-membered C 1 -C 4 heteroarylene containing 1-4 N atoms that has the structure 
       
         
           
           
               
               
           
         
       
     
     
         81 . The compound of  claim 78 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring A is a monocyclic heterocycle that is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         82 . The compound of  claim 81 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         83 . The compound of  claim 78  or  claim 81 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         84 . The compound of any one of  claims 78 - 83 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —S(═O)—, —S(═O) 2 —, —CH 2 —, —C(═O)—, —OC(═O)—, —NR 10 C(═O)—, or —NR 10 S(═O) 2 —; 
 L 2  is absent or substituted or unsubstituted C 1 -C 4 alkylene. 
   
     
     
         85 . The compound of  claim 84 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 1  is —X 1 -L 2 - or -L 2 -X 1 —;
 X 1  is absent, —S(═O) 2 —, —CH 2 —, or —C(═O)—; 
 L 2  is absent or —CH 2 —. 
   
     
     
         86 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is monocyclic carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.   
     
     
         87 . The compound of any one of  claims 54 - 86 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is phenyl.   
     
     
         88 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolylene, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.   
     
     
         89 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         90 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         91 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a bicyclic heteroaryl selected from quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, azabenzotriazolyl, benzoxazolyl, azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl, and purinyl.   
     
     
         92 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         93 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is monocyclic heterocycle selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, and 1,2,3,6-tetrahydropyridinyl.   
     
     
         94 . The compound of any one of  claims 54 - 85 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 ring C is a monocyclic C 2 -C 8 heterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and azepanyl.   
     
     
         95 . The compound of  claim 94 , or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       
         
           
           
               
               
           
         
       
     
     
         96 . The compound of any one of  claims 54 - 95 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted aryl, wherein if R 3  is substituted then R 3  is substituted with one or more R 12  groups.   
     
     
         97 . The compound of any one of  claims 54 - 96 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted phenyl, wherein if R 3  is substituted then R 3  is substituted with one or more R 12  groups.   
     
     
         98 . The compound of any one of  claims 54 - 96 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 3  is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl,   
       
         
           
           
               
               
           
         
       
       and adamantyl. 
     
     
         99 . The compound of any one of  claims 54 - 98 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is   
       
         
           
           
               
               
           
         
       
     
     
         100 . The compound of any one of  claims 54 - 98 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is   
       
         
           
           
               
               
           
         
       
     
     
         101 . The compound of  claim 100 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is   
       
         
           
           
               
               
           
         
       
     
     
         102 . The compound of any one of  claims 54 - 98 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is -L 3 -Y;
 L 3  is —CH 2 —; 
 Y is 
   
       
         
           
           
               
               
           
         
       
     
     
         103 . A compound of  claim 54 , wherein the compound is:
 N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-((2-methoxyethyl)amino)-phenyl)cyclohexanecarboxamide;   N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-((2-(dimethylamino)-ethyl)amino)phenyl)cyclohexanecarboxamide;   N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(isobutylamino)-phenyl)cyclohexanecarboxamide;   N-(3-Bromophenyl)-N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl) cyclohexanecarboxamide;   Methyl 2-((3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)phenyl)amino)acetate;   Methyl 2-((3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)phenyl)(methyl)amino)acetate;   Methyl 3-(N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-cyclohexanecarboxamido)benzylcarbamate;   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)cyclohexanecarboxamide;   (E)-N -(3-(3-(Dimethylamino)-3-oxoprop-1-en-1-yl)phenyl)-N-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)cyclohexanecarboxamide;   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(prop-1-en-1-yl)phenyl)-cyclohexanecarboxamide;   (Z)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(prop-1-en-1-yl)phenyl)-cyclohexanecarboxamide;   N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-vinylphenyl)-cyclohexanecarboxamide; or   (E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(3-methylbut-1-en-1-yl)phenyl)cyclohexanecarboxamide;   or a pharmaceutically acceptable salt, or solvate thereof.   
     
     
         104 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 103 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. 
     
     
         106 . The pharmaceutical composition of  claim 104 , wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. 
     
     
         107 . A method of treating or preventing a liver disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of one or more of the compounds of any one of  claims 1 - 103 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         108 . The method of  claim 107 , wherein the liver disease or condition is an alcoholic or non-alcoholic liver disease. 
     
     
         109 . The method of  claim 107 , wherein the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD). 
     
     
         110 . The method of  claim 107 , wherein the alcoholic liver disease or condition is fatty liver (steatosis), cirrhosis, or alcoholic hepatitis. 
     
     
         111 . The method of  claim 108 , wherein the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD). 
     
     
         112 . The method of  claim 108 , wherein the non-alcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis. 
     
     
         113 . A method of treating or preventing a metabolic disorder in a subject, comprising:
 administering to a gastrointestinal tract of the subject a therapeutically effective amount of one or more of the compounds of any one of  claims 1 - 103 , or a pharmaceutically acceptable salt or solvate thereof, thereby activating farnesoid X receptors (FXR) in the intestines, and treating or preventing a metabolic disorder in the subject.   
     
     
         114 . The method of  claim 113 , wherein the method reduces or prevents diet-induced weight gain. 
     
     
         115 . The method of one of  claims 113 - 114 , wherein the method increases a metabolic rate in the subject. 
     
     
         116 . The method of  claim 115 , wherein the increasing the metabolic rate comprises enhancing oxidative phosphorylation in the subject. 
     
     
         117 . The method of one of  claims 113 - 116 , further comprising improving glucose and/or lipid homeostasis in the subject. 
     
     
         118 . The method of one of  claims 113 - 117 , wherein the metabolic disorder is selected from obesity, diabetes, insulin resistance, dyslipidemia or any combination thereof. 
     
     
         119 . The method of one of  claims 113 - 117 , wherein the metabolic disorder is non-insulin dependent diabetes mellitus. 
     
     
         120 . The method of one of  claims 113 - 119 , wherein the method protects against diet-induced weight gain, reduces inflammation, enhances thermogenesis, enhances insulin sensitivity in the liver, reduces hepatic steatosis, promotes activation of brown adipose tissue (BAT), decreases blood glucose, increases weight loss, or any combination thereof. 
     
     
         121 . The method of  claim 120 , wherein the method enhances insulin sensitivity in the liver and promotes brown adipose tissue (BAT) activation. 
     
     
         122 . The method of one of  claims 113 - 121 , further comprising administering to the subject an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a glucagon-like peptide (GLP) agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, nicotinamide ribonucleoside, an analog of nicotinamide ribonucleoside, or combinations thereof. 
     
     
         123 . A method of treating or preventing inflammation in an intestinal region of a subject, comprising:
 administering to a gastrointestinal tract of the subject a therapeutically effective amount of one or more of the compounds of any one of  claims 1 - 103 , or a pharmaceutically acceptable salt or solvate thereof, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.   
     
     
         124 . The method of  claim 123 , wherein the inflammation is associated with condition selected from 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, intestinal celiac disease, post-surgical inflammation, gastric carcinogenesis or any combination thereof. 
     
     
         125 . The method of one of  claims 124 , further comprising administering a therapeutically effective amount of an antibiotic therapy to the subject, wherein the method treats or prevents inflammation associated with pseudomembranous colitis in the subject. 
     
     
         126 . The method of one of  claims 123 - 125 , further comprising administering to the subject a therapeutically effective amount of an oral corticosteroid, other anti-inflammatory or immunomodulatory therapy, nicotinamide ribonucleoside, an analog of nicotinamide ribonucleoside, or combinations thereof. 
     
     
         127 . A method of treating or preventing a cell proliferation disease in a subject, comprising administering to a gastrointestinal tract of the subject a therapeutically effective amount of one or more of the compounds of any one of  claims 1 - 103 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         128 . The method of  claim 127 , wherein the cell proliferation disease is an adenocarcinoma. 
     
     
         129 . The method of  claim 127 , wherein the adenocarcinoma is a colon cancer. 
     
     
         130 . The method of  claim 129 , wherein the treating the adenocarcinoma reduces the size of the adenocarcinoma, the volume of the adenocarcinoma, the number of adenocarcinomas, cachexia due to the adenocarcinoma, delays progression of the adenocarcinoma, increases survival of the subject, or combinations thereof. 
     
     
         131 . The method of any of  claims 127 - 130 , wherein the method further comprises administering to the subject an additional therapeutic compound selected from the group consisting of a chemotherapeutic, a biologic, a radiotherapeutic, or combinations thereof.