Compositions and methods for the treatment of liver disorders

A pharmaceutical composition comprising at least one compound of Formula

• or a pharmaceutically acceptable salt thereof, wherein:
• G is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —Se—, —CH2—, —CF2—, —CHF—, —C(O)—, —CH(OH)—, —CH(C1-C4 alkyl)-, —CH(C1-C4 alkoxy)-, —C(═CH2)—, —NH—, and —N(C1-C4 alkyl)-;
• T is selected from the group consisting of —(CRa2)k—, —CRb═CRb—(CRa2)n—, —(CRa2)n—CRb═CRb—, —(CRa2)—CRb═CRb—(CRa2)—, —O(CRb2)(CRa2)n—, —S(CRb2)(CRa2)n—, N(Rc)(CRb2)(CRa2)n—, N(Rb)C(O)(CRa2)n, —C(O)(CRa2)m—, —(CRa2)mC(O)—, —(CRa2)C(O)(CRa2)n, —(CRa2)nC(O)(CRa2)—, and —C(O)NH(CRb2)(CRa2)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 Ra is independently selected from the group consisting of hydrogen, optionally substituted —C1-C4 alkyl, halogen, —OH, optionally substituted —O—C1-C4 alkyl, —OCF3, optionally substituted —S—C1-C4 alkyl, —NRbRc, optionally substituted —C2-C4 alkenyl, and optionally substituted —C2-C4 alkynyl;
• with the proviso that when one Ra is attached to C through an O, S, or N atom, then the other Ra attached to the same C is a hydrogen, or attached via a carbon atom;
• each Rb is independently selected from the group consisting of hydrogen and optionally substituted —C1-C4 alkyl;
• each Rc is independently selected from the group consisting of hydrogen and optionally substituted —C1-C4 alkyl, optionally substituted —C(O)—C1-C4 alkyl, and —C(O)H;
• R1, and R2 are each independently selected from the group consisting of halogen, optionally substituted —C1-C4 alkyl, optionally substituted —S—C1-C3 alkyl, optionally substituted —C2-C4 alkenyl, optionally substituted —C2-C4 alkynyl, —CF3, —OCF3, optionally substituted-O—C1-C3 alkyl, and cyano;
• R6, R7, R8, and R9 are each independently selected from the group consisting of are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C C1-C4 alkyl, optionally substituted —S—C1-C3 alkyl, optionally substituted —C2-C4 alkenyl, optionally substituted —C2-C4 alkynyl, —CF3, —OCF3, optionally substituted-O—C1-C3 alkyl, and cyano;
• or R6 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 —NRi—, —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 —(CRa2)— or —C(O)— bonded to a ring carbon or a ring nitrogen;
• Ri is selected from the group consisting of hydrogen, —C(O)C1-C4 alkyl, —C1-C4 alkyl, and —C1-C4-aryl;
• R3 and R4 are independently selected from the group consisting of hydrogen, halogen, —CF3, —OCF3, cyano, optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, —SRd, —S(═O)Re, —S(═O)2Re, —S(═O)2NRfRg, —C(O)ORh, —C(O)Re, —N(Rb)C(O)NRfRg, —N(Rb)S(═O)2Re, —N(Rb)S(═O)2NRfRg, and —NRfRg;
• each Rd is selected from the group consisting of optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)n aryl, optionally substituted —(CRb2)n cycloalkyl, optionally substituted —(CRb2)n heterocycloalkyl, and —C(O)NRfRg;
• each Re is selected from the group consisting of optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRa2)n aryl, optionally substituted —(CRa2)n cycloalkyl, and optionally substituted —(CRa2)n heterocycloalkyl;
• Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)n aryl, optionally substituted —(CRb2)n cycloalkyl, and optionally substituted —(CRb2)n heterocycloalkyl, or Rf and Rg may together form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group consisting of O, NRC, and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C1-C4 alkyl, —ORb, oxo, cyano, —CF3, optionally substituted phenyl, and —C(O)ORh;
• each Rh is selected from the group consisting of optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)n aryl, optionally substituted —(CRb2)n cycloalkyl, and optionally substituted —(CRb2)n heterocycloalkyl;
• R5 is selected from the group consisting of —OH, optionally substituted —OC1-C6 alkyl, OC(O)Re, —OC(O)ORh, —F, —NHC(O)Re, —NHS(═O)Re, —NHS(═O)2Re, —NHC(═S)NH(Rh), and —NHC(O)NH(Rh);
• X is P(O)YR11Y′R11;
• Y and Y′ are each independently selected from the group consisting of —O—, and —NRv—;
• when Y and Y′ are —O—, R11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(Rz)2OC(O)NRz2, —NRz—C(O)—Ry, —C(Rz)2—OC(O)Ry, —C(Rz)2—O—C(O)ORy, —C(Rz)2OC(O)SRy, -alkyl-S—C(O)Ry, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
• when Y and Y′ are —NRv—, then R11 attached to —NRv— is independently selected from the group consisting of —H, —[C(Rz)2]q—COORy, —C(Rx)2COORY, —[C(Rz)2]q—C(O)SRy, and -cycloalkylene-COORy;
• when Y is —O— and Y′ is NRv, then R11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(Rz)2OC(O)NRz2, —NRz—C(O)—Ry, —C(Rz)2—OC(O)Ry, —C(Rz)2—O—C(O)ORy, —C(Rz)2OC(O)SRy, -alkyl-S—C(O)Ry, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
• and R11 attached to —NRv— is independently selected from the group consisting of H, —[C(Rz)2]q—COORy, —C(Rx)2COORy, —[C(Rz)2]q—C(O)SRy, and -cycloalkylene-COORy;
• or when Y and Y′ are independently selected from —O— and NRv, then together R11 and R11 are -alkyl-S—S-alkyl- to form a cyclic group, or together R11 and R11 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 —CHRzOH, —CHRzOC(O)Ry, —CHRzOC(S)Ry, —CHRzOC(S)ORy, —CHRzOC(O)SRy, —CHRzOCO2Ry, —ORz, —SRz, —CHRzN3, —CH2-aryl, —CH(aryl)OH, —CH(CH═CRz2)OH, —CH(C≡CRz)OH, —Rz, —NRz2, —OCORy, —OCO2Ry, —SCORy, —SCO2Ry, —NHCORz, —NHCO2Ry, —CH2NH-aryl, —(CH2)q-ORz, and —(CH2)q-SRz;
• q is an integer 2 or 3;
• each Rz is selected from the group consisting of Ry and —H;
• each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
• each Rx is independently selected from the group consisting of —H, and alkyl, or together Rx and Rx form a cyclic alkyl group;
• and
• each Rv is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• or one or more compounds selected from
• or one or more compounds having a structure of Formula (A):
• wherein
• R3′ is H or CH2Ra′, in which Ra′ is hydroxyl, O-linked amino acid, —OP(O)(OH)2 or OC(O)Rb′, Rb′ being lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or —(CH2)n′-heteroaryl and n′ being 0 or 1;
• R4′ is H, and R5′ is CH2COOH, C(O)CO2H, or an ester or amide thereof, or R4′ and R5′ together are —N═C(Rc′)—C—(O)—NH—C(O)—;
• in which Rc′ is H or cyano;
• or pharmaceutically acceptable salts thereof;
• or
• and one or more pharmaceutically acceptable excipients;
• in combination with a second pharmaceutical agent.