Farnesoid X receptor agonists and uses thereof

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;

R 3 is a substituted or unsubstituted C 3 -C 10 cycloalkyl, 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 3 -C 10 cycloalkyl, unsubstituted or substituted C 2 -C 10 heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

ring A is a monocyclic carbocycle that is phenyl or a C 3 -C 8 cycloalkyl, or monocyclic 5-membered or 6-membered heteroaryl;

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 absent;

ring C monocyclic carbocycle that is phenyl or a C 3 -C 8 cyclocalkyl, bicyclic carbocycle that is indanyl, indenyl, or naphthyl, monocyclic C 2 -C 8 heterocycloalkyl, 5-membered or 6-membered heteroaryl, or bicyclic heterocycle that is a bicyclic C 5 -C 8 heterocycloalkyl or a bicyclic C 6 -C 9 heteroaryl;

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, and substituted or unsubstituted phenyl;

ring B is a phenyl or monocyclic 5-membered or 6-membered heteroaryl

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, —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 3 is —X 2 -L 4 - or -L 4 -X 2 —;

X 2 is absent or —CH═CH—;

L 4 is absent;

ring D is phenyl, monocyclic N-containing C 2 -C 8 heterocycloalkyl, or monocyclic 5-membered or 6-membered heteroaryl

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 1 , —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 -C 10 cycloalkyl, 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; and

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; and

wherein the groups

and are in a 1,3-relationship on ring B.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is phenyl; or

ring B is monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

5. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring D is phenyl; or

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; or

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.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

L 3 is absent.

8. The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is monocyclic carbocycle that is phenyl or a C 3 -C 8 cycloalkyl that is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure:

10. The compound of claim 9 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring C is phenyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 3 is a substituted or unsubstituted cyclohexyl.

12. 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;

(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-(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)cyclohebxanecarboxamide;

(E)-N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(2-(pyridin-4-yl)vinyl)phenyl)cyclohebxanecarboxamide;

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;

N-((4′-(Dimethylamino)-[1,1′-biphenyl]-4-yl)methyl)-N-(3-(3-methoxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide;

N-((4′-(Dimethyl amino)-[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.

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.

14. A method of treating 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 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 14 , wherein the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD).

16. A method of treating 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 claim 1 , or a pharmaceutically acceptable salt or solvate thereof, thereby activating FXR receptors in the intestines, and thereby treating inflammation in the intestinal region of the subject; wherein the inflammation is associated with a 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.