Arylsulfonamidobenzylic compounds

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula:

• wherein
• R1 is a member selected from the group consisting of
• wherein
• R11 is a member selected from the group consisting of halogen, nitro, cyano, R12, OR12, SR12, NHR12, N(R12)2, (C4–C8)cycloalkyl, (C5–C8)cycloalkenyl, COR12, CO2R12, CONHR12, CON(R12)2, aryl, aryl(C1–C4)alkyl, heteroaryl and heteroaryl(C1–C4)alkyl;
• wherein each R12 is (C1–C8)alkyl, (C3—C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl or two R12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR13, NHSO2R14 and NHC(O)R13, and any aryl or heteroaryl portions of R11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R14, OR13, SR13, N(R13)2, NHSO2R14, NHC(O)R13, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R13 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl and each R14 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl;
• or optionally, R11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S;
• each R18 is independently selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl, aryl and heteroaryl;
• X is a member selected from the group consisting of H, NH2, NHR15, NHSO2R15, OH and OR15, wherein R15 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl or halo(C1–C8)alkyl, or is combined with R11 as described above;
• Y is fluoro(C1–C4)alkyl, or is combined with R11 as described above;
• R2 is a member selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C3–C8)cycloalkyl and (C4–C8)cycloalkyl-alkyl, wherein any alkyl portions of R2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R2 is combined with R4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S;
• R3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R16, OR16, SR16, COR16, CO2R16, NHR16, N(R16)2, CONHR16, CON(R16)2, NHSO2R16, NHC(O)R16, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R16 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• the subscript n is an integer of from 0 to 3;
• and
• each R4 is independently selected from the group consisting of halogen, cyano, nitro, R17, OR17, SR17, COR17, CO2R17, N(R17)2 and CON(R17)2, wherein each R17 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• and pharmaceutically acceptable salts thereof.

A method of modulating LXR function in a cell, said method comprising contacting said cell with an LXR-modulating amount of a compound of the formula:

• wherein
• R1 is a member selected from the group consisting of
• wherein
• R11 is a member selected from the group consisting of halogen, nitro, cyano, R12, OR12, SR12, NHR12, N(R12)2, (C4–C8)cycloalkyl, (C5–C8)cycloalkenyl, COR12, CO2R12, CONHR12, CON(R12)2, aryl, aryl(C1–C4)alkyl, heteroaryl and heteroaryl(C1–C4)alkyl;
• wherein each R12 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl or two R12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR13, NHSO2R14 and NHC(O)R13, and any aryl or heteroaryl portions of R11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R14, OR13, SR13, N(R13)2, NHSO2R14, NHC(O)R13, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R13 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl and each R14 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl;
• or optionally, R11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S;
• each R18 is independently selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl, aryl and heteroaryl;
• X is a member selected from the group consisting of H, NH2, NHR15, NHSO2R15, OH and OR15, wherein R15 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl or halo(C1–C8)alkyl, or is combined with R11 as described above;
• Y is fluoro(C1–C4)alkyl, or is combined with R11 as described above;
• R2 is a member selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C3–C8)cycloalkyl and (C4–C8)cycloalkyl-alkyl, wherein any alkyl portions of R2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R2 is combined with R4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S;
• R3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R16, OR16, SR16, COR16, CO2R16, NHR16, N(R16)2, CONHR16, CON(R16)2, NHSO2R16, NHC(O)R16, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R16 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• the subscript n is an integer of from 0 to 3;
• and
• each R4 is independently selected from the group consisting of halogen, cyano, nitro, R17, OR17, SR17, COR17, CO2R17, N(R17)2 and CON(R17)2, wherein each R17 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• and pharmaceutically acceptable salts thereof.

A method of treating obesity, diabetes, hypercholesterolemia, atherosclerosis or hyperlipoproteinemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

• wherein
• R1 is a member selected from the group consisting of
• wherein
• R11 is a member selected from the group consisting of halogen, nitro, cyano, R12, OR12, SR12, NHR12, N(R12)2, (C4–C8)cycloalkyl, (C5–C8)cycloalkenyl, COR12, CO2R12, CONHR12, CON(R12)2, aryl, aryl(C1–C4)alkyl, heteroaryl and heteroaryl(C1–C4)alkyl;
• wherein each R12 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl or two R12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR13, NHSO2R14 and NHC(O)R13, and any aryl or heteroaryl portions of R11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R14, OR13, SR13, N(R13)2, NHSO2R14, NHC(O)R13, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R13 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl and each R14 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl;
• or optionally, R11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S;
• each R18 is independently selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl, aryl and heteroaryl;
• X is a member selected from the group consisting of H, NH2, NHR15, NHSO2R15, OH and OR15, wherein R15 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl or halo(C1–C8)alkyl, or is combined with R11 described above;
• Y is fluoro(C1–C4)alkyl, or is combined with R11 as described above;
• R2 is a member selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C3–C8)cycloalkyl and (C4–C8)cycloalkyl-alkyl, wherein any alkyl portions of R2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R2 is combined with R4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S;
• R3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R16, OR16, SR16, COR16, CO2R16, NHR16, N(R16)2, CONHR16, CON(R16)2, NHSO2R16, NHC(O)R16, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R16 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• the subscript n is an integer of from 0 to 3;
• and
• each R4 is independently selected from the group consisting of halogen, cyano, nitro, R17, OR17, SR17, COR17, CO2R17, N(R17)2 and CON(R17)2, wherein each R17 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• or a pharmaceutically acceptable salt thereof.

A method of treating an LXR-mediated condition in a subject, said method comprising administering to said subject an LXR-modulating amount of a compound of the formula:

• wherein
• R1 is a member selected from the group consisting of
• wherein
• R11 is a member selected from the group consisting of halogen, nitro, cyano, R12, OR12, SR12, NHR12, N(R12)2, (C4–C8)cycloalkyl, (C5–C8)cycloalkenyl, COR12, CO2R12, CONHR12, CON(R12)2, aryl, aryl(C1–C4)alkyl, heteroaryl and heteroaryl(C1–C4)alkyl;
• wherein each R12 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl or two R12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR13, NHSO2R14 and NHC(O)R13, and any aryl or heteroaryl portions of R11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R14, OR13, SR13, N(R13)2, NHSO2R14, NHC(O)R13, phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R13 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl and each R14 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl;
• or optionally, R11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S;
• each R18 is independently selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, halo(C1–C8)alkyl, aryl and heteroaryl;
• X is a member selected from the group consisting of H, NH2, NHR15, NHSO2R15, OH and OR15, wherein R15 is (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl or halo(C1–C8)alkyl, or is combined with R11 as described above;
• Y is fluoro(C1–C4)alkyl, or is combined with R11 as described above;
• R2 is a member selected from the group consisting of H, (C1–C8)alkyl, (C2–C8)heteroalkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C3–C8)cycloalkyl and (C4–C8)cycloalkyl-alkyl, wherein any alkyl portions of R2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R2 is combined with R4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S;
• R3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R16, OR16, SR16, COR16, CO2R16, NHR16, N(R16)2, CONHR16, CON(R16)2, NHSO2R16, NHC(O)R16 phenyl, phenyl(C1–C8)alkyl, and phenyl(C2–C8)heteroalkyl;
• wherein each R16 is independently selected from (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• the subscript n is an integer of from 0 to 3;
• and
• each R4 is independently selected from the group consisting of halogen, cyano, nitro, R17, OR17, SR17, COR17, CO2R17, N(R17)2 and CON(R17)2, wherein each R17 is independently selected from H, (C1–C8)alkyl, (C3–C8)alkenyl, (C3–C8)alkynyl, (C2–C8)heteroalkyl and halo(C1–C8)alkyl, or two R17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring;
• or a pharmaceutically acceptable salt thereof.