Arylsulfonamidobenzylic compounds
View Patent ↗Arylsulfonamidobenzyl alcohols, amines and sulfonamides are provided which are useful in treating lipid disorders, metabolic diseases and cell-proliferative diseases.
1. A compound having the formula:
wherein
R 1 is a member selected from the group consisting of
wherein
R 11 is a member selected from the group consisting of halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl and heteroaryl(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 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 , 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; or optionally, R 11 is combined with either 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 R 18 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, aryl and heteroaryl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH or OR 15 , 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, or is combined with R 11 as described above;
Y is fluoro(C 1 –C 4 )alkyl, or is combined with R 11 as described above;
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 is combined with R 4 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;
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;
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , wherein X is OH.
3. A compound of claim 1 , wherein X is OH and R 1 has the formula:
wherein R 11 is a member selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, indolyl, benzimidazolyl, benzothienyl and benzothiazolyl, each of said R 11 groups being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
4. A compound of claim 3 , 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, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
5. A compound of claim 4 , 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.
6. A compound of claim 5 , 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.
7. A compound of claim 6 , 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.
8. A compound of claim 3 , wherein R 11 is pyridyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
9. A compound of claim 8 , 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.
10. A compound of claim 9 , 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.
11. A compound of claim 10 , 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.
12. A compound of claim 3 , wherein R 11 is pyridazinyl or pyrrolyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
13. A compound of claim 1 , wherein X is OH and R 1 has the formula:
wherein R 11 is a member selected from the group consisting of phenyl, pyridyl, pyrrolyl and pyridazinyl, each of said R 11 groups being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
14. A compound of claim 13 , wherein R 11 is phenyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
15. A compound of claim 14 , 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.
16. A compound of claim 15 , 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.
17. A compound of claim 16 , 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.
18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula:
wherein
R 1 is a member selected from the group consisting of
wherein
R 11 is a member selected from the group consisting of halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl and heteroaryl(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 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 , 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; or optionally, R 11 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 R 18 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, aryl and heteroaryl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR 15 , 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, or is combined with R 11 as described above;
Y is fluoro(C 1 –C 4 )alkyl, or is combined with R 11 as described above;
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 is combined with R 4 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;
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;
and pharmaceutically acceptable salts thereof.
19. A pharmaceutical composition of claim 18 , wherein said compound is a compound of any of claims 3 – 17 .
20. 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
R 1 is a member selected from the group consisting of
wherein
R 11 is a member selected from the group consisting of halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl and heteroaryl(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 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 , 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; or optionally, R 11 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 R 18 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, aryl and heteroaryl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR 15 , 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, or is combined with R 11 as described above;
Y is fluoro(C 1 –C 4 )alkyl, or is combined with R 11 as described above;
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 is combined with R 4 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;
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;
and pharmaceutically acceptable salts thereof.
21. 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
R 1 is a member selected from the group consisting of
wherein
R 11 is a member selected from the group consisting of halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl and heteroaryl(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 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 , 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; or optionally, R 11 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 R 18 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, aryl and heteroaryl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR 15 , 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, or is combined with R 11 described above;
Y is fluoro(C 1 –C 4 )alkyl, or is combined with R 11 as described above;
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 is combined with R 4 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;
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;
or a pharmaceutically acceptable salt thereof.
22. 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
R 1 is a member selected from the group consisting of
wherein
R 11 is a member selected from the group consisting of halogen, nitro, cyano, R 12 , OR 12 , SR 12 , NHR 12 , N(R 12 ) 2 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, COR 12 , CO 2 R 12 , CONHR 12 , CON(R 12 ) 2 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl and heteroaryl(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 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 , 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; or optionally, R 11 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 R 18 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, aryl and heteroaryl;
X is a member selected from the group consisting of H, NH 2 , NHR 15 , NHSO 2 R 15 , OH and OR 15 , 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, or is combined with R 11 as described above;
Y is fluoro(C 1 –C 4 )alkyl, or is combined with R 11 as described above;
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 is combined with R 4 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;
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;
or a pharmaceutically acceptable salt thereof.
23. A method in accordance with claim 22 , wherein said condition is selected from the group consisting of obesity, diabetes, hypercholesterolemia, atherosclerosis and hyperlipoproteinemia.
24. A method in accordance with claim 23 , wherein said compound is administered in combination with an anti-hypercholesterolemic agent.
25. A method in accordance with claim 22 , wherein said compound is an LXR agonist.