Retinoid x receptor modulators

A compound selected from the group consisting of:

• 3-[5-(2-hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid,
• 2-fluoro-3-[5-(2-methoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid;
• 2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester;
• 3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid;
• 3-[7-(2ethoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid;
• 3-[7-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid;
• 3-{7-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid;
• ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylbenzene)-benzo[b]thiophene;
• 3-{7-[2-(2,2-difluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid;
• (E)-2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid;
• (E)-3-{7-[5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]-benzo[b]furan-2-yl}-but-2-enoic acid;
• 3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid;
• 2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene;
• 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid,
• (E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid;
• (E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid;
• (E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid;
• (E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-2-enoic acid;
• (E) 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid;
• (E) 3-[4-(2-propyloxy-3,5-di-iso-propylphenyl)benzo[b]thien-2-yl]prop-2-enoic acid;
• 3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]thien-2-yl}-but-2-enoic acid;
• 3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]furan-2-yl}-but-2-enoic acid;
• 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3-fluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2-difluoroethoxy)-3-(adamant-1-yl)-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3,3-difluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl} but-2-enoic acid;
• (E) 3-{4-[2-(2,2-difluoroethoxy)-3-propyl-5-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3,3-difluoropropoxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-[4-(2-(2,2,2-trifluoroethoxy)-3-phenyl-5-methylphenyl]-benzo[b]thienyl}but-2-enoic acid;
• (E) 3-{4-[2-(2-methylpropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2,2-trifluoroethoxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-[4-(5-(2,2,2-trifluoroethoxy)-6-tert-butylindan-4-yl)-benzo[b]thien-2-yl]but-2-enoic acid;
• (E) 3-[4-(3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-2-enoic acid;
• (E) 3-{4-[3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)phenyl]-5-fluorobenzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3-methylbutoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3,3,3-difluoropropoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2-methylpropoxy)-3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-2-enoic acid;
• (E) 3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3-fluoropropoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3-methylbutoxy)-3,5-di(1,1-methylpropyl)phenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(3,3-difluoropropoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo[b]thiophene]but-2-enoic acid;
• (E) 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(dimethylphenylmethyl)phenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• (E) 3-{4-[2-(2,2-difluoroethoxy)-3-tert-butyl-5-phenylphenyl]-benzo[b]thien-2-yl]but-2-enoic acid;
• (E) 3-{5-[2-(2,2-difluoroethoxy)-3-phenyl-5-tert-butylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid;
• 3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-5-yl]-but-2-enoic acid;
• 3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1-methyl-1H-indol-5-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-1H-indol-5-yl]-but-2-enoic acid;
• 3-[3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2enoic acid;
• 3-[4-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-2-yl]-but-2-enoic acid;
• 3-[1-(2-butoxy-3,5-di-iso-propyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic acid;
• 3-[4-(2-butoxy-3,5-di-iso-propyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic acid;
• 3-{3-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}-but-2-enoic acid;
• 3-[3-(2-hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid;
• 3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-1H-indazol-5-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but-2-enoic acid;
• 3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acrylic acid;
• 3-[3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic acid;
• 3-{3-[3,5-di-tert-butyl-2-(2,2-difluro-ethoxy)-phenyl]-1H-indol-5-yl}-but-2-enoic acid;
• 3-{3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-yl}-but-2-enoic acid, and
• pharmaceutically acceptable salts, solvates and hydrates thereof

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and at least one compound represented by the following structural formula:

• 211
• and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an ammo group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 212
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X 4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for modulating retinoid X receptor activity in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 217
• and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 218
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for modulating RXRα:PPARα heterodimer activity in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 222
• and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 223
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for modulating RXRα:PPARγ heterodimer activity in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 227
• or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 228
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for increasing HDL cholesterol levels and reducing triglyceride levels in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 232
• or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 233
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for modulating lipid metabolism in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 237
• or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups maybe optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 allyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 238
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method for lowering blood glucose levels without altering serum triglyceride levels in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 242
• or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 243
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method treating or preventing a disease or condition selected from the group consisting of syndrome X, non-insulin dependent diabetes mellitus, cancer, photoaging, acne, psoriasis, obesity, cardiovascular disease, atherosclerosis, uterine leiomyomata, inflamatory disease, neurodegenerative diseases, wounds and baldness in a mammal comprising administering to said mammal a pharmaceutically effective amount of at least one compound represented by the following structural formula:

• 247
• or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 248
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A compound for use in therapy for a disorder modulated by a retinoid X receptor, a RXRα:PPARα heterodimer, or RXRα:PPARγ heterodimer, wherein the compound is represented by the following structural formula:

• 252
• and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 253
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

Use of a compound for the manufacture of a medicament for the treatment of a condition modulated by a retinoid X receptor, a RXRα:PPARα heterodimer, or RXRα:PPARγ heterodimer, wherein the compound is represented by the following structural formula:

• 254
• and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy, or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 allyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• R16 is OR17, OCH(R17)OC(O)R18, —NR19R20, or an aminoalkyl;
• R17, R19 and R20 are each, independently, H or a C1-C6 alkyl;
• R18 is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 255
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy.

A method of preparing an RXR modulator represented by the following structural formula:

• 256
• and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy, or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• Rx is a C1-C6 alkyl;
• ring A is a heteroaryl group represented by the following structural formula:
• 257
• wherein:
• X1 and X2 are each, independently, O, S, N, NH, or CH;
• X3 is N or C;
• X4 is CH or N;
• p is 0 or 1, provided that when X1 is O or S, then X2 is CH or N and p is 0;
• and
• ring A is optionally substituted with one or more substituents selected from a halo, a C1-C6 alkyl, or a C1-C6 alkoxy, comprising the steps of:
• a) reacting in the presence of tetrakis(triphenylphosphine) palladium(0) and a base with a heteroaromatic compound represented by the following structural formula:
• 258
• wherein:
• Z is a halo or a triflate,
• with a substituted phenylboronic acid represented by the following structural formula:
• 259
• to form a (substituted phenyl)-heteroaromatic compound represented by the following structural formula:
• 260
• b) forming an enol anion of a trialkyl phosphonoacetate by treating with a base the trialkyl phosphonoacetate, wherein the trialkyl phosphonoacetate is represented by the following structural formula:
• 261
• wherein R21 and R22 are each, independently, a C1-C6 alkyl;
• and
• c) reacting the trialkyl phosphonoacetate anion with the (substituted phenyl)-heteroaromatic compound, thereby forming said RXR modulator.

A method of preparing a benzo[b]furanyl RXR modulator represented by the following structural formula:

• 263
• wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups maybe optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy, or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• and
• Rx is a C1-C6 alkyl, comprising the steps of:
• a) reacting in the presence of tetrakis(triphenylphosphine) palladium(0) and a base a halosalicyaldehyde represented by the following structural formula:
• 264
• wherein:
• Z2 is a halo,
• with a substituted phenylboronic acid represented by the following structural formula:
• 265
• to form a (substituted phenyl)-salicyaldehyde represented by the following structural formula:
• 266
• b) reacting the (substituted phenyl)-salicyaldehyde with an α-halocarbonyl compound represented by the following structural formula:
• 267
• wherein:
• Z6 is a halo;
• to form a (substituted phenyl)-2-carbonylbenzo[b]furan represented by the following structural formula:
• 268
• c) forming an enol anion of a trialkyl phosphonoacetate by treating with a base the trialkyl phosphonoacetate, wherein the trialkyl phosphonoacetate is represented by the following structural formula:
• 269
• wherein R21 and R22 are each, independently, a C1-C6 alkyl;
• and
• d) reacting the trialkyl phosphonoacetate anion with the (substituted phenyl)-2-carbonylbenzo[b]furan, thereby forming said benzo[b]furanyl RXR modulator.

A method of preparing a benzo[b]thiophenyl RXR modulator represented by the following structural formula:

• 271
• wherein:
• R is H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
• R1 and R2 are each, independently, H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, a C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl, or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy, or
• R1 and R2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C1-C6 alkyl groups;
• or
• R and R1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R3 is H, a halo, a C1-C10 alkyl, a C3-C10 cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C1-C6-alkyl or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy,
• R4 is H, a halo, an aryl-C1-C6-alkyl, a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, aryl, heteroaryl, a C1-C6 alkoxy, an amino group represented by the formula NR14R15;
• or
• R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents;
• and
• R5 is H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo;
• R6 is H or halo;
• R14 and R15 are each, independently, H, a C1-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
• and
• Rx is a C1-C6 alkyl, comprising the steps of:
• a) forming a reaction mixture of a base and an alkyl thioglycolate represented by the following structural formula:
• 272
• b) adding to the reaction mixture a fluorophenyl-acetic acid represented by the following structural formula:
• 273
• thereby forming a thiophenyl-acetic acid alkyl ester represented by the following structural formula:
• 274
• c) treating the thiophenyl-acetic acid alkyl ester with an alkali metal hydroxide to form a thiophenyl-acetic acid;
• d) reacting the thiophenyl-acetic acid with thionyl chloride, thereby forming a thiophenyl-acetic acid chloride;
• e) treating the thiophenyl-acetic acid chloride with a Friedel-Crafts catalyst to form a benzo[b]thiophen-3-one, represented by the following structural formula:
• 275
• f) treating the benzo[b]thiophen-3-one with a base to form an anion of the carbonylbenzo[b]thiophen-3-one;
• g) reacting the anion of benzo[b]thiophen-3-one with N-phenyltrifluoromethanesulfonimide to form a trifluoromethanesulfonic acid benzo[b]thiophen-3-yl ester represented by the following structural formula:
• 276
• h) reacting in the presence of tetrakis(triphenylphosphine) palladium(0) and a base with the trifluoromethanesulfonic acid benzo[b]thiophen-3-yl ester with a substituted phenylboronic acid represented by the following structural formula:
• 277
• to form a (substituted phenyl)-heteroaromatic compound represented by the following structural formula:
• 278
• i) forming an enol anion of a trialkyl phosphonoacetate by treating with a base the trialkyl phosphonoacetate, wherein the trialkyl phosphonoacetate is represented by the following structural formula:
• 279
• wherein R21 and R22 are each, independently, a C1-C6 alkyl;
• and
• j) reacting the trialkyl phosphonoacetate anion with the (substituted phenyl)-heteroaromatic compound, thereby forming said benzo[b]thiophenyl RXR modulator.