Compositions and methods for the treatment of liver disorders

1 . A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein

R 1 is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 5-10 membered heterocyclyl, each of which is optionally substituted with 1-3 R 1A ;

R 2 is halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 5-10 membered heterocyclyl each of which is optionally substituted with 1-3 R 2A ;

G is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 5-10 membered heterocyclyl, each of which is optionally substituted with 1-3 R G ;

R 3 is —P(═O)(X)(Y) or 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R 3A independently selected from halogen, —OR 5 , C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, or C 3-10 cycloalkyl;

each R 1A is independently selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 5-10 membered heterocyclyl;

each R 2A is independently selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 5-10 membered heterocyclyl;

each R G is independently selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkoxy;

X and Y are each independently —OR 4 , NR 5 R 6 , C 1-6 alkyl, or haloC 1-6 alkyl;

each R 4 is independently hydrogen, C 1-6 alkyl, or haloC 1-6 alkyl;

each R 5 is independently hydrogen or C 1-6 alkyl; and

each R 6 is independently hydrogen or C 1-6 alkyl.

2 . The compound of claim 1 , wherein R 1 is (trifluoromethoxy)phenyl.

3 . The compound of claim 1 , wherein R 2 is cyclopropyl.

4 . The compound of claim 1 , wherein G is selected from the group consisting of: phenyl, pyridine, imidazole, pyrrole, triazole, thiazole, furanyl, pyrazine, pyrimidine, indole, quinoline, isoquinoline, benzothiazole, benzimidazole, benzoxazole, and naphthyl, each of which is optionally substituted with 1-3 R G .

5 . The compound of claim 1 , having the Formula (IIaa):

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 , wherein R G is halogen.

7 . The compound of claim 1 , wherein R 3 is —P(═O)(X)(Y).

8 . The compound of claim 7 , wherein X is —OR 4 .

9 . The compound of claim 8 , wherein R 4 is hydrogen or C 1-6 alkyl.

10 . The compound of claim 7 , wherein Y is —OR 4 .

11 . The compound of claim 10 , wherein R 4 is hydrogen or C 1-6 alkyl.

12 . The compound of claim 7 , wherein Y is C 1-6 alkyl.

13 . The compound of claim 1 , wherein R 3 is

14 . The compound of claim 13 , wherein R 1A is C 1-6 alkoxy or hydroxy.

15 . The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

16 . A method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject, comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

17 . A method of preventing, treating, or ameliorating one or disease or disorders in a subject, comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

18 . The method of claim 17 , further comprising administering to the subject at least one TR-β agonist or a pharmaceutically acceptable salt thereof, in combination with the compound of claim 1 , or the pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein the TR-β agonist is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

G is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 —, —Se—, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4 alkyl)-, —CH(C 1 -C 4 alkoxy)-, —C(═CH 2 )—, —NH—, and —N(C 1 -C 4 alkyl)-;

T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR a 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, —(CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n —, N(R c )(CR b 2 )(CR a 2 ) n —, N(R b )C(O)(CR a 2 ) n , —C(O)(CR a 2 ) n —, —(CR a 2 ) m C(O)—, —(CR a 2 )C(O)(CR a 2 ) n , —(CR a 2 ) n C(O)(CR a 2 )—, and —C(O)NH(CR b 2 )(CR a 2 ) p —;

k is an integer from 1-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;

each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;

each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;

R 1 , and R 2 are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —OCF 3 , optionally substituted —O—C 1 -C 3 alkyl, and cyano;

R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —OCF 3 , optionally substituted-O—C 1 -C 3 alkyl, and cyano; or R 6 and T are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms including 0 to 2 heteroatoms independently selected from —NR i —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;

and X is attached to this ring by a direct bond to a ring carbon, or by —(CR a 2 )— or —C(O)— bonded to a ring carbon or a ring nitrogen;

R i is selected from the group consisting of hydrogen, —C(O)C 1 -C 4 alkyl, —C 1 -C 4 alkyl, and —C 1 -C 4 -aryl;

R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, —CF 3 , —OCF 3 , cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)NR f R g , —N(R e )S(═O) 2 R e , —N(R e )S(═O) 2 NR f R g , and —NR f R g ;

each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR a 2 ) n heterocycloalkyl, and —C(O)NR f R g ;

each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;

R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , optionally substituted phenyl, and —C(O)OR h ;

each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;

R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, OC(O)R e , —OC(O)OR h , —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h );

X is P(O)YR 11 Y′R 11 ;

Y and Y′ are each independently selected from the group consisting of —O—, and —NR v —; when Y and Y′ are —O—, R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z )—(O)OR y , —C(R z )OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;

when Y and Y′ are —NR v —, then R 11 attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR Y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ;

when Y is —O— and Y′ is NR v , then R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11 attached to —NR v — is independently selected from the group consisting of H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ;

or when Y and Y′ are independently selected from —O— and NR v , then together R 11 and R 11 are -alkyl-S—S-alkyl- to form a cyclic group, or together R 11 and R 11 are the group:

wherein:

V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl;

or together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;

or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;

or together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;

or together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 -aryl, —CH(aryl)OH, —CH(CH═CR z 2 )OH, —CH(C≡CR z )OH, —R z , —N z 2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NH-aryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ;

q is an integer 2 or 3;

each R z is selected from the group consisting of R y and —H;

each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R x is independently selected from the group consisting of —H, and alkyl, or together R x and R x form a cyclic alkyl group; and

each R 1 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

20 . The method of claim 18 , wherein the TR-β agonist is a compound having the structure of Formula (A):

wherein

R 3 ′ is H or CH 2 R a′ , in which R a′ is hydroxyl, O-linked amino acid, —OP(O)(OH) 2 or OC(O)R b′ , R b′ being lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or —(CH 2 ) n′ -heteroaryl and n′ being 0 or 1;

R 4 ′ is H, and R 5 ′ is CH 2 COOH, C(O)CO 2 H, or an ester or amide thereof, or R 4′ and R 5′ together are —N═C(R c′ )—C—(O)—NH—C(O)—; in which R c′ is H or cyano;

or pharmaceutically acceptable salts thereof.