Arylsulfonamidobenzylic compounds
Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment or prevention of lipid disorders, metabolic disorders and cell-proliferative diseases. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in cholesterol metabolism. The subject compounds are particularly useful in the treatment of obesity, diabetes, hypercholesterolemia, atherosclerosis and hypolipoproteinemia.
1 . A compound having the formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is a member selected from the group consisting of hydrogen, halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 5 -C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , C═N—NR 12 , aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, (C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl and hetero(C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl; wherein each R 12 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, aryl or two R 12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R 11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR 13 , NHSO 2 R 14 and NHC(O)R 13 , and any aryl or heteroaryl portions of R 11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C(O)R 13 , SO 2 R 13 , SO 2 N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 -C 8 )alkyl and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl and each R 14 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR′, wherein R 15 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl or halo(C 1 -C 8 )alkyl and R′ is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, aryl(C 1 -C 4 )alkyl, heterocyclo(C 5 -C 8 )alkyl, (C 1 -C 4 )alkylsulfonyl, arylsulfonyl, (C 1 -C 4 )alkylcarbonyl or (C 1 -C 4 )alkylsilyl;
Y is fluoro(C 1 -C 4 )alkyl;
R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally, R 2 and R 4 are combined to form a five- to seven-membered fused ring containing the nitrogen atom to which R 2 is attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 3 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, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 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 R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
2 . A compound of claim 1 , wherein X is OH.
3 . A compound of claim 2 , wherein R 11 is phenyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, phenyl(C 1 -C 6 )alkyl and phenyl(C 2 -C 6 )heteroalkyl.
4 . A compound of claim 3 , wherein R 2 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino.
5 . A compound of claim 4 , wherein R 3 is a member selected from the group consisting of phenyl, pyridyl, thienyl and thiazolyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
6 . A compound of claim 5 , wherein the subscript n is an integer of from 0 to 2, and each R 4 is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl and halo(C 1 -C 8 )alkyl.
7 . A compound of claim 6 , wherein R 2 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino.
8 . A compound of claim 7 , wherein R 3 is a member selected from the group consisting of phenyl, pyridyl, thienyl and thiazolyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 6 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
9 . A compound of claim 8 , wherein the subscript n is an integer of from 0 to 2, and each R 4 is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl and halo(C 1 -C 8 )alkyl.
10 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is a member selected from the group consisting of hydrogen, halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 5 -C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , C═N—NR 12 , aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, (C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl and hetero(C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl; wherein each R 12 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, aryl or two R 12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R 11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR 13 , NHSO 2 R 14 and NHC(O)R 13 , and any aryl or heteroaryl portions of R 11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C(O)R 13 , SO 2 R 13 , SO 2 N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 -C 8 )alkyl and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl and each R 14 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR′, wherein R 15 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl or halo(C 1 -C 8 )alkyl and R′ is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, aryl(C 1 -C 4 )alkyl, heterocyclo(C 5 -C 8 )alkyl, (C 1 -C 4 )alkylsulfonyl, arylsulfonyl, (C 1 -C 4 )alkylcarbonyl or (C 1 -C 4 )alkylsilyl;
Y is fluoro(C 1 -C 4 )alkyl;
R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally, R 2 and R 4 are combined to form a five- to seven-membered fused ring containing the nitrogen atom to which R 2 is attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 3 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, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 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 R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
11 . A pharmaceutical composition of claim 10 , wherein said compound is a compound of any of claims 2 - 9 .
12 . 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:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is a member selected from the group consisting of hydrogen, halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 5 -C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 2 , CON(R 12 ) 2 , C═N—NR 12 , aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, (C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl and hetero(C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl; wherein each R 12 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, aryl or two R 12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R 11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR 13 , NHSO 2 R 14 and NHC(O)R 13 , and any aryl or heteroaryl portions of R 11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C(O)R 13 , SO 2 R 13 , SO 2 N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 -C 8 )alkyl and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl and each R 14 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR′, wherein R 15 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl or halo(C 1 -C 8 )alkyl and R′ is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, aryl(C 1 -C 4 )alkyl, heterocyclo(C 5 -C 8 )alkyl, (C 1 -C 4 )alkylsulfonyl, arylsulfonyl, (C 1 -C 4 )alkylcarbonyl or (C 1 -C 4 )alkylsilyl;
Y is fluoro(C 1 -C 4 )alkyl;
R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally, R 2 and R 4 are combined to form a five- to seven-membered fused ring containing the nitrogen atom to which R 2 is attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 3 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, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 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 R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
13 . A method of treating obesity, diabetes, hypercholesterolemia, atherosclerosis or hypolipoproteinemia, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is a member selected from the group consisting of hydrogen, halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 5 -C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , C═N—NR 12 , aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, (C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl and hetero(C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl; wherein each R 12 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, aryl or two R 12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R 11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR 13 , NHSO 2 R 14 and NHC(O)R 13 , and any aryl or heteroaryl portions of R 11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C(O)R 13 , SO 2 R 13 , SO 2 N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 -C 8 )alkyl and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl and each R 14 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR′, wherein R 15 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl or halo(C 1 -C 8 )alkyl and R′ is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, aryl(C 1 -C 4 )alkyl, heterocyclo(C 5 -C 8 )alkyl, (C 1 -C 4 )alkylsulfonyl, arylsulfonyl, (C 1 -C 4 )alkylcarbonyl or (C 1 -C 4 )alkylsilyl;
Y is fluoro(C 1 -C 4 )alkyl;
R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally, R 2 and R 4 are combined to form a five- to seven-membered fused ring containing the nitrogen atom to which R 2 is attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 3 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, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 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 R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
14 . 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:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is a member selected from the group consisting of hydrogen, halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 5 -C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , C═N—NR 12 , aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, (C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl and hetero(C 4 -C 8 )cycloalkyl(C 1 -C 4 )alkyl; wherein each R 12 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, aryl or two R 12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R 11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR 13 , NHSO 2 R 14 and NHC(O)R 13 , and any aryl or heteroaryl portions of R 11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C(O)R 13 , SO 2 R 13 , SO 2 N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 -C 8 )alkyl and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl and each R 14 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR′, wherein R 15 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl or halo(C 1 -C 8 )alkyl and R′ is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl, halo(C 1 -C 8 )alkyl, aryl(C 1 -C 4 )alkyl, heterocyclo(C 5 -C 8 )alkyl, (C 1 -C 4 )alkylsulfonyl, arylsulfonyl, (C 1 -C 4 )alkylcarbonyl or (C 1 -C 4 )alkylsilyl;
Y is fluoro(C 1 -C 4 )alkyl;
R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl and (C 4 -C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally, R 2 and R 4 are combined to form a five- to seven-membered fused ring containing the nitrogen atom to which R 2 is attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 3 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, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 -C 8 )alkyl, and phenyl(C 2 -C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 16 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 R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 2 -C 8 )heteroalkyl and halo(C 1 -C 8 )alkyl, or two R 17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.
15 . A method in accordance with claim 14 , wherein said condition is selected from the group consisting of obesity, diabetes, hypercholesterolemia, atherosclerosis and hyperlipoproteinemia.
16 . A method in accordance with claim 15 , wherein said compound is administered in combination with an anti-hypercholesterolemic agent.
17 . A method in accordance with claim 14 , wherein said compound is an LXR agonist.
18 . A method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis and hyperlipoproteinemia, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1 .
19 . A method of treating a condition selected from the group consisting of diabetes and obesity, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1.