Modulators of LXR

• US 7,998,986 B2
• Filed: 12/20/2002
• Issued: 08/16/2011
• Est. Priority Date: 12/21/2001
• Status: Active Grant

• Current Assignee: Exelixis Incorporated
• Original Assignee: Exelixis Patent Company LLC (Exelixis Incorporated)
• Inventors: Johnson, Alan T., Bayne, Christopher D., Griffith, Ronald C., Lu, Shao-Po, Mohan, Raju
• Primary Examiner(s): McKane; Joseph K.
• Assistant Examiner(s): Coppins; Janet L
• Application Number:
  US10/327,813
• Publication Number:
  US 20030181420A1
• Time in Patent Office: 3,161 Days
• Field of Search: 546/300, 546/301, 546/302, 514/345
• US Class Current: 514/345
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of nuclear receptors, including liver X receptor (LXR) and orphan nuclear receptors. In certain embodiments, the compounds are N-substituted pyridones.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is substituted or unsubstituted aryl.

3. The compound of claim 1, wherein R¹ is substituted or unsubstituted heteroaryl.

4. The compound of claim 1, wherein R¹ is substituted or unsubstituted heterocyclyl.

5. The compound of claim 1, wherein R¹ is substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentenyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indanyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothiophenyl or substituted or unsubstituted indolyl, where the substituents are each independently selected from one or more Q¹.

6. The compound of claim 1, wherein R¹ is substituted or unsubstituted phenyl.

7. The compound of claim 1, wherein R¹ is substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothiophenyl or substituted or unsubstituted indolyl, where the substituents are each independently selected from one or more Q¹.

8. The compound of claim 1, wherein R¹ is substituted or unsubstituted thienyl.

9. The compound of claim 8, wherein R¹ is thienyl.

10. The compound of claim 1, wherein R¹ is substituted with one to five substituents each independently selected from Q¹, where Q¹ is halo, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, azide, nitro, hydroxy, amino, hydroxyalkyl, hydroxyalkylaryloxy, hydroxyaryl, hydroxyalkylaryl, hydroxycarbonyl, haloalkyl, alkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylaralkyl, alkylarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylaryloxy, aryloxycarbonyl, heterocyclylcarbonylalkylaryl, aralkoxycarbonyl, alkoxy, aryloxy, heteroaryloxy, aralkoxy, alkylaryloxy, alkylaryloxyalkyl, alkyldiaryloxy, aryloxyalkoxy, aralkoxyaryloxy, alkylarylcycloalkyloxy, alkylheteroaryloxy, cycloalkyloxy, heterocyclylalkoxy, heterocyclyloxy, haloaryloxy, alkylcarbonylaryloxy, arylamino, alkylarylamino, aralkylamino, alkylcarbonylamino, alkylaminocarbonyl, haloalkylcarbonylamino, or arylthio;

and each Q¹ is unsubstituted or further substituted with Q², which is alkyl, aryl, alkoxy, hydroxycarbonyl, alkoxycarbonyl, pseudohalidecyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, azide, halo, aryloxy, aralkoxy, haloalkyl, alkylthio, alkylamino, dialkylamino or hydroxy.

11. The compound of claim 1, wherein R¹ is substituted with Q¹, which is selected from alkoxycarbonylaryloxy, aryloxy, alkylaryloxy, alkylaryloxyalkyl, alkyldiaryloxy, aryloxyalkoxy, aralkoxyaryloxy, alkylarylcycloallyloxy, alkylheteroaryloxy, cycloalkyloxy, heterocyclylalkoxy, heterocyclyloxy, heteroaryloxy, haloaryloxy, alkoxycarbonylheterocycloxy, alkylcarbonylaryloxy, dialkylaminoaryloxy, alkoxyaryloxy, cyanoaryloxy, aryloxyaryloxy, dialkylaryloxy, haloalkylaryloxy, alkylthioaryloxy, alkylarylamino, hydroxyaryloxy, arylamino, alkylamino, aralkylamino and arylthio.

12. The compound of claim 1, wherein R¹ is substituted with Q¹, which is selected from methyl, ethyl, trifluoromethyl, nitro, hydroxy, n-butyloxy, 3-(2-piperidinyl)ethoxy, methylcarbonylamino, ethylaminocarbonylamino, chloro, bromo, benzylamino, methylphenoxymethyl, trifluoromethylcarbonylamino, methoxycarbonyl, phenoxy, cyano, n-butoxy, benzoxy, 1-piperidinyl, methoxy, hydroxycarbonyl, tert-butoxycarbonylpiperazinylcarbonyl, hydroxymethyl, 1-piperidinylcarbonyl, phenyl, methylphenyl, dimethylamino, methylcarbonylamino, methoxyphenoxy, methylphenoxy, piperidinylmethyl, biphenoxy, benzoxycarbonyl, piperazinylcarbonyl, benzyl, phenylthio, chlorophenoxy, methylbenzyl, hydroxymethylphenoxy, ethoxycarbonylphenoxy, tert-butylmethylphenoxy, tert-butylbiphenoxy, ethylphenoxy, isopropylphenoxy, tert-butylphenoxy, N,N-dimethylphenoxy, N,N-phenylmethylamino, 3-methylphenyl-1-amino, trifluoromethylphenoxy, ethylphenoxy, methylcarbonylphenoxy, tetrahydropyranyloxy, tetrahydronaphthoxy, hydroxycarbonylphenoxy, benzoxyphenoxy, cyclohexyloxy, indanyloxy, methoxycarbonylphenoxy, isopropylphenoxy, tert-butylphenoxy, N,N-dimethylaminophenoxy, methoxyphenoxy, methoxycarbonylphenoxy, cyanophenoxy, fluorophenoxy, benzoxyphenoxy, trifluoromethylphenoxy, bromophenoxy, 3,5-di(trifluoromethyl)phenoxy, methylthiophenoxy, indolyl, tert-butoxycarbonyl-piperidinyloxy, hydroxyphenoxy, pyrimidinoxy and pyrazinoxy.

29. The compound of claim 1, wherein R¹ is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyrrolyl, where the substituents are selected from one or more Q¹.

30. The compound of claim 1, wherein R¹ is cyclohexyl, 1-cyclopentenyl, indanyl, phenyl, 1-naphthyl, 2-naphthyl, 3-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 3-ethylphenyl, 3-trifluoromethylphenyl, 3-nitrophenyl, 3-hydroxyphenyl, 3-n-butoxyphenyl, 3-benzyloxyphenyl, 3-(2-piperidinyl)ethoxyphenyl, 3-methylcarbonylaminophenyl, 3-ethylaminocarbonylaminophenyl, 2-methylphenyl, 2-methoxyphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-benzylaminophenyl, 3-(3-methyl)phenoxymethylphenyl, benzyl, 3-trifluoromethylcarbonylaminophenyl, 3,5-dimethylphenyl, 2-chloro-3-methylphenyl, phenylethyl, 4-butoxyphenyl, 4-methoxycarbonylphenyl, 4-phenoxyphenyl, 4-cyanophenyl, 4-benzoxyphenyl, 4-(1-piperidinyl)phenyl, 4-hydroxycarbonylphenyl, 4-(4-tert-butoxycarbonylpiperazin-1-ylcarbonyl)phenyl, 4-hydroxymethylphenyl, 4-(1-piperidinylcarbonyl)phenyl, 4-dimethylaminophenyl, 4-methylcarbonylaminophenyl, 4-nitrophenyl, 6-(1,2,3,4-tetrahydro)naphthyl, 4-(4-methoxyphenoxy)phenyl, 4-(2-methylphenoxy)phenyl, 4-(3-methylphenoxy)phenyl, 4-(4-methylphenoxy)phenyl, 4-(3-methoxyphenoxy)phenyl, 4-(1-piperidinylmethyl)phenyl, 4-(4-biphenoxy)phenyl, 3-(1-benzoxycarbonyl)-piperidinyl, 4-(1-piperazinylcarbonyl)phenyl, 5-(2-methyl-2,3-dihydro)benzofuryl, 4-benzylphenyl, 4-phenylthiophenyl, 4-(4-chlorophenoxy)-2-chlorophenyl, 4-(3-biphenoxy)phenyl, 4-(1-benzoxycarbonyl)-piperidinyl, 4-piperidinyl, 4-(1-(3-methylbenzyl))-piperidinyl, 4-(3-methyl-4-hydroxyphen-1-oxy)phenyl, 4-(2-methyl-4-hydroxyphenoxy)phenyl, 4-(4-ethoxycarbonylphenoxy)phenyl, 4-(2-methyl-4-tert-butylphenoxy)phenyl, 4-(2-phenyl-4-tert-butylphenoxy)phenyl, 4-(3-ethylphenoxy)phenyl, 4-(3-isopropylphenoxy)phenyl, 4-(3-tert-butylphenoxy)phenyl, 4-(3,5-dimethylphenoxy)phenyl, 4-phenoxy-2-methylphenyl, 4-(2-methylphenoxy)-2-methylphenyl, 4-(2-methylphenoxy)-3-methylphenyl, 4-N-methyl-N-phenylaminophenyl, 4-(3-trifluoromethylphenoxy)phenyl, 4-(4-ethylphenoxy)phenyl, 4-(4-isopropylphenoxy)phenyl, 4-(4-tert-butylphenoxy)phenyl, 4-(3-methylcarbonylphenoxy)phenyl, 4-(3,4-dimethylphenoxy)phenyl, 4-(2-tetrahydropyranyloxy)phenyl, 4-(2-tetrahydropyranyloxy)-3-methylphenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(4-methylphenoxy)-3-methylphenyl, 4-(2-ethylphenoxy)phenyl, 4-(2-isopropylphenoxy)phenyl, 4-(5,6,7,8-tetrahydronaphthyloxy)phenyl, 4-(3-hydroxycarbonylphenoxy)phenyl, 2-methyl-4-hydroxyphenyl, 4-phenoxy-2-hydroxyphenyl, 3-phenoxyphenyl 4-(2,3,4-trimethylphenoxy)phenyl, 4-(4-benzyloxyphenoxy)phenyl, 4-(3-(methyl-3-indanyloxy)phenyl, 4-(2-methyl-5-benzothiazoloxy)phenyl, 4-cyclohexyloxyphenyl, 4-(3-methoxycarbonylphenoxy)phenyl, 4-(3-isopropylphenoxy)-3-methylphenyl, 4-tert-butyl-phenoxy-3-methylphenyl, 4-N,N-dimethylaminophenoxy-3-methylphenyl, 4-methoxy-phenoxy-3-methylphenyl, 3-methoxy-phenoxy-3-methylphenyl, 4-(3-methoxycarbonyl-phenoxy)-3-methylphenyl, 4-(3-cyanophenoxy)-3-methylphenyl, 4-(4-fluorophenoxy)-3-methylphenyl, 4-(4-benzoxy-phenoxy)-3-methylphenyl, 4-(3-benzoxy-phenoxy)-3-methylphenyl, dimethylphenoxy)-3-methylphenyl, 4-(2-chlorophenoxy)-3-methylphenyl, 4-(3-chlorophenoxy)-3-methylphenyl, 4-(2-trifluoromethylphenoxy)-3-methylphenyl, 4-(3-trifluoromethylphenoxy)-2-methylphenyl, 4-(3-bromophenoxy)-phenyl, 4-(4-bromophenoxy)-phenyl, 4-(3-benzyloxy-phenoxy)-phenyl, 4-(3-cyanophenoxy)-phenyl, 4-(4-cyanophenoxy)phenyl, 4-(2,4-dimethylphenoxy)-phenyl, 4-(3,5-trifluoromethylphenoxy)phenyl, 4-(4-methylthio-phenoxy)-phenyl, 4-(4-N,N-dimethylamino-phenoxy)-phenyl, 5-indolyloxyphenyl, 4-(1-tert-butoxycarbonyl-piperidin-4-oxy)-phenyl, 4-(4-hydroxyphenoxy)-phenyl, 4-(2-pyrimidinoxy)-phenyl, 4-(2-pyrazinoxy)-phenyl, 2-thienyl, 2-(5-chloro)thienyl, 2-(5-bromo)thienyl, 2-(5-phenyl)thienyl, 3-benzothiophenyl, 3-methyl-2-benzothiophenyl, 2-(5-(3-methylphenyl))-thienyl, 3-pyridinyl, 2-pyrazinyl, 4-(1-phenyl-5-methyl)pyrazolyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, 3-(1-benzyloxycarbonyl)-piperidinyl, 4-(1-benzyloxyarbonyl)-piperidinyl, 4-piperidinyl, 4-(1-(3-methylbenzyl)-piperidinyl, 2-furyl, 2-(5-methyl)-furyl, 3-(2,5-dimethyl)-furyl, benzofuryl, 3-(2,4-dimethyl)uryl, 2-thiazolyl, or 5-(2,4-dimethyl)-1,3-thiazolyl.

31. The compound of claim 1, wherein R¹ is phenyl, 1-naphthyl, 2-naphthyl, 3-methylphenyl, 2-chlorophenyl, 3-ethylphenyl, 3-trifluoromethylphenyl, 3-nitrophenyl, 3-hydroxyphenyl, 3-n-butoxyphenyl, 3-benzyloxyphenyl, 3-(2-piperidinyl)ethoxyphenyl, 3-methylcarbonylaminophenyl, 3-ethylaminocarbonylaminophenyl, 2-methylphenyl, 2-methoxyphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl or 4-chlorophenyl.

32. The compound of claim 1, wherein R¹ is 3-(3-methyl)phenoxymethylphenyl, 4-phenoxyphenyl, 4-benzoxyphenyl, 4-(4-methoxyphenoxy)phenyl, 4-(2-methylphenoxy)phenyl, 4-(3-methylphenoxy)phenyl, 4-(4-methylphenoxy)phenyl, 4-(3-methoxyphenoxy)phenyl, 4-(4-biphenoxy)phenyl, 4-(4-chlorophenoxy)-2-chlorophenyl, 4-(3-biphenoxy)phenyl, 4-(3-methyl-4-hydroxyphenoxy)phenyl, 4-(2-methyl-4-hydroxyphenoxy)phenyl, 4-(4-ethoxycarbonylphenoxy)phenyl, 4-(2-methyl-4-tert-butylphenoxy)phenyl, 4-(2-phenyl-4-tert-butylphenoxy)phenyl, 4-(3-ethylphenoxy)phenyl, 4-(3-isopropylphenoxy)phenyl, 4-(3-tert-butylphenoxy)phenyl, 4-(3,5-dimethylphenoxy)phenyl, 4-phenoxy-2-methylphenyl, 4-(4-methylphenoxy)-2-methylphenyl, 4-(2-methylphenoxy)-3-methylphenyl, 4-(3-trifluoromethylphenoxy)phenyl, 4-(4-ethylphenoxy)phenyl, 4-(4-isopropylphenoxy)phenyl, 4-(4-tert-butylphenoxy)phenyl, 4-(3-methylcarbonylphenoxy)phenyl, 4-(3,4-dimethylphenoxy)phenyl, 4-(4-methylphenoxy)-3-methylphenyl, 4-(2-ethylphenoxy)phenyl, 4-(2-isopropylphenoxy)phenyl, 4-(5,6,7,8-tetrahydronaphthyloxy)phenyl, 4-(3-hydroxycarbonylphenoxy)phenyl, 2-methyl-4-hydroxyphenyl, 4-phenoxy-2-hydroxyphenyl, 3-phenoxyphenyl, 4-(2,3,4-trimethylphenoxy)phenyl, 4-(4-benzyloxyphenoxy)phenyl, 4-(3-methoxycarbonylphenoxy)phenyl, 4-(3-isopropylphenoxy)-3-methylphenyl, 4-tert-butyl-phenoxy-3-methylphenyl, 4-N,N-dimethylaminophenoxy-3-methylphenyl, 4-methoxy-phenoxy-3-methylphenyl, 3-methoxy-phenoxy-3-methylphenyl, 4-(3-methoxycarbonyl-phenoxy)-3-methylphenyl, 4-(3-cyanophenoxy)-3-methylphenyl, 4-(4-fluorophenoxy)-3-methylphenyl, 4-(4-benzoxy-phenoxy)-3-methylphenyl, 4-(3-benzoxy-phenoxy)-3-methylphenyl, 4-(2,5-dimethylphenoxy)-3-methylphenyl, 4-(2-chlorophenoxy)-3-methylphenyl, 4-(3-chlorophenoxy)-3-methylphenyl, 4-(2-trifluoromethylphenoxy)-3-methylphenyl, 4-(3-trifluoromethylphenoxy)-2-methylphenyl, 4-(3-bromophenoxy)-phenyl, 4-(4-bromophenoxy)-phenyl, 4-(3-benzyloxy-phenoxy)-phenyl, 4-(3-cyanophenoxy)-phenyl, 4-(4-cyanophenoxy)phenyl, 4-(2,4-dimethylphenoxy)-phenyl, 4-(3,5-trifluoromethylphenoxy)phenyl, 4-(4-methylthio-phenoxy)-phenyl or 4-(4-N,N-dimethylamino-phenoxy)-phenyl.

33. The compound of claim 1, wherein R¹ is 4-N-methyl-N-phenylaminophenyl, or 4-phenylthiophenyl.

34. The compound of claim 1, wherein R¹ is 2-thienyl, 2-(5-chloro)thienyl, 2-(5-bromo)thienyl, 2-(5-phenyl)thienyl, 3-benzothiophenyl, 3-methyl-2-benzothiophenyl or 2-(5-(3-methylphenyl p-thienyl.

35. The compound of claim 34, wherein R¹ is 2-thienyl.

36. The compound of claim 1, wherein R¹ is 3-pyridinyl, 2-pyrazinyl, 4-(1-phenyl-5-methyl)pyrazolyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, 3-(1-benzyloxycarbonyl)-piperidinyl, 4-(1-benzyloxycarbonyl)-piperidinyl, 4-piperidinyl or 4-(1-(3-methylbenzyl)-piperidinyl.

37. The compound of claim 1, wherein R¹ is 2-furyl, 2-(5-methyl)-furyl, 3-(2,5-dimethyl)-furyl, benzofuryl or 3-(2,4-dimethyl)-furyl.

38. The compound of claim 1, wherein R¹ is 2-thiazolyl or 5-(2,4-dimethyl)thiazolyl.

39. The compound of claim 1, wherein R¹ is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyrrolyl, where the substituents are selected from one or more Q¹.

40. The compound of claim 1, wherein R¹ is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted thienyl, where the substituents are selected from one or more Q¹.

41. The compound of claim 1, wherein R¹ is substituted with Q¹, which is selected from alkyl, alkoxy, halo, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, azide, haloalkyl, nitro, hydroxy, alkoxy, aralkoxy, heterocyclylalkoxy, alkylcarbonylamino and alkylaminocarbonylamino.

42. The compound of claim 1, wherein R¹ is substituted with Q¹, which is selected from methyl, methoxy, chloro, ethyl, trifluoromethyl, nitro, hydroxy, n-butoxy, 3-(2-piperidinyl)ethoxy, methylcarbonylamino or ethylaminocarbonylamino.

43. The compound of claim 1, wherein R² is alkyl or hydrogen, wherein the alkyl selected from the group consisting of propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isopentyl, neopentyl, tert-pentyl, and isohexyl.

44. The compound of claim 1, wherein R² is hydrogen.

45. The compound of claim 1, wherein R³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted alkylaminocarbonyl, where the substitutents are each independently selected from one or more Q¹.

46. The compound of claim 1, wherein R³ is substituted or unsubstituted alkoxycarbonyl, where the substitutents are each independently selected from one or more Q¹.

47. The compound of claim 1, wherein R³ is haloalkyl.

48. The compound of claim 1, wherein R³ is substituted with Q¹, which are selected from halo, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, azide, alkyl, alkoxy, alkoxycarbonyl and aryloxycarbonyl.

49. The compound of claim 1, wherein R³ is substituted with one or more Q¹, which are selected from halo.

50. The compound of claim 1, wherein R³ is substituted with one or more Q¹, which are selected from fluoro, chloro, phenyl, methyl, methoxy and methylamino.

51. The compound of claim 1, wherein R³ is perfluoroalkyl.

52. The compound of claim 1, wherein R³ is methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, chlorodifluoromethyl, 1-(1-methoxy-1-fluoro)ethyl, methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, dimethoxymethyl, or methoxycarbonylmethyl.

53. The compound of claim 1, wherein R³ is trifluoromethyl or pentafluoroethyl.

54. The compound of claim 1, wherein R³ is trifluoromethyl.

55. The compound of claim 1, wherein R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, azide, C(J)R³⁰, CH₂NR³¹R³² or NO₂, where the substituents are each independently selected from one or more Q¹.

56. The compound of claim 1, wherein R⁴ is substituted or unsubstituted methyl, substituted or unsubstituted acetyl or cyano, where the substituents are each independently selected from one or more Q¹.

57. The compound of claim 1, wherein R⁴ is substituted or unsubstituted methyl, where the substituents are each independently selected from one or more Q¹.

58. The compound of claim 1, wherein R⁴ is substituted or unsubstituted acetyl, where the substitutent is trialkylsilyl.

59. The compound of claim 1, wherein R⁴ is substituted with Q¹, which is selected from trialkylsilyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkoxycarbonylamino, dialkylamino, alkylamino and amino.

60. The compound of claim 1, wherein R⁴ is alkylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aralkoxycarbonylaminoalkyl or aryloxycarbonylaminoalkyl.

61. The compound of claim 1, wherein R⁴ is hydrogen, cyano, nitro, hydroxycarbonyl, trimethylsilylacetyl, acetyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, isopropylcarbonylaminomethyl, n-octylcarbonylaminomethyl, phenylcarbonylaminomethyl, benzylcarbonylaminomethyl, phenylethylcarbonylaminomethyl, ethoxycabonylaminomethyl dimethylaminomethyl or aminomethyl.

62. The compound of claim 1, wherein R⁴ is cyano.

63. The compound of claim 1, wherein R³ and R⁴, together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic ring, with the proviso that the heterocyclic ring has one oxo substitutent.

64. The compound of claim 1, wherein R³ and R⁴ together with the atoms to which they are attached form 2-oxo-tetrahydropyridine or 2-oxo-pyrrole.

65. The compound of claim 1, wherein R⁵ is substituted or unsubstituted C₂-C₆-alkyl, substituted or unsubstituted aralkyl, substituted aryl, unsubstituted N, O, or S-containing heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, —

N═

CR⁶R⁷ or —

NR⁹R¹⁰, wherein substituted or unsubstituted heteroaralkyl is selected from the group consisting of substituted or unsubstituted 3-pyridylmethyl, substituted or unsubstituted 4-pyridylmethyl, substituted or unsubstituted thiazolylmethyl, and substituted or unsubstituted oxazolylmethyl, and wherein the R⁵ substituents are selected from alkyl, haloalkyl, halohydroxyalkyl, alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, aryl, halo, alkylthio, aryloxy, haloalkoxy, aralkyl, heteroaryl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, alkylcarbonyl, arylcarbonyl, alkylalkelenedioxy and dialkylalkelenedioxy.

66. The compound of claim 1, wherein R⁵ is substituted or unsubstituted aralkyl, wherein the substituents are selected from alkyl, haloalkyl, halohydroxyalkyl, alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, aryl, halo, alkylthio, aryloxy, haloalkoxy, aralkyl, heteroaryl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, alkylcarbonyl, arylcarbonyl, alkylalkelenedioxy and dialkylalkelenedioxy.

67. The compound of claim 1, wherein R⁵ is substituted or unsubstituted heteroaralkyl, wherein substituted or unsubstituted heteroaralkyl is selected from the group consisting of substituted or unsubstituted 3-pyridylmethyl, substituted or unsubstituted 4-pyridylmethyl, substituted or unsubstituted thiazolylmethyl, and substituted or unsubstituted oxazolylmethyl, and wherein the R⁵ substituents are selected from alkyl, haloalkyl, halohydroxyalkyl, alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, aryl, halo, alkylthio, aryloxy, haloalkoxy, aralkyl, heteroaryl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, alkylcarbonyl, arylcarbonyl, alkylalkelenedioxy and dialkylalkelenedioxy.

68. The compound of claim 1, wherein R⁵ is unsubstituted heterocyclylalkyl.

69. The compound of claim 1, wherein R⁵ is substituted or unsubstituted N-heterocyclyl, wherein the substituents are selected from alkyl, haloalkyl, halohydroxyalkyl, alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, aryl, halo, alkoxycarbonyl, alkylthio, aryloxy, haloalkoxy, aralkyl, heteroaryl, hydroxy, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, alkylcarbonyl, arylcarbonyl, alkylalkelenedioxy and dialkylalkelenedioxy.

70. The compound of claim 1, wherein R⁵ is —

N═

CR⁶R⁷.

71. The compound of claim 1, wherein R⁵ is substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, substituted or unsubstituted 1-phenethyl, substituted or unsubstituted 3-phenylpropyl, substituted or unsubstituted 1,2,3,4-tetrahydro-1-naphthyl, substituted or unsubstituted 3-pyridylmethyl, substituted or unsubstituted 4-pyridylmethyl, substituted or unsubstituted 2-pyrazinyl, substituted or unsubstituted thiazolylmethyl, substituted or unsubstituted oxazolylmethyl.

72. The compound of claim 1, wherein R⁵ is substituted or unsubstituted piperidinyl, substituted or unsubstituted 3-pyridylmethyl, substituted or unsubstituted 4-pyridylmethyl, substituted or unsubstituted 2-pyrazinyl, substituted or unsubstituted thiazolylmethyl, or substituted or unsubstituted oxazolylmethyl.

73. The compound of claim 1, wherein R⁵ is substituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, substituted or unsubstituted 1-phenethyl, substituted or unsubstituted 3-phenylpropyl, or —

N═

CR⁶R⁷.

74. The compound of claim 1, wherein R⁵ is substituted or unsubstituted benzyl, or —

N═

CR⁶R⁷.

75. The compound of claim 1, R⁵ is substituted with alkyl, haloalkyl, alkoxy, aryl, halo, alkylthio, aryloxy, haloalkoxy, aralkyl, heteroaryl, alkylcarbonyl or arylcarbonyl.

76. The compound of claim 1, R⁵ is substituted with methyl, isopropyl, trifluoromethyl, methoxy, fluoro, bromo, methoxycarbonyl, chloro, methylthio, phenoxy, trifluoromethoxy, 3-pyridyl, 4-pyridyl, 2-pyridyl, ethyl, n-propyl, n-propyloxymethyl, n-pentyloxymethyl, n-octyloxymethyl, ethoxymethyl, n-butoxymethyl, n-hexyloxymethyl, n-octyloxymethyl, tert-butyl, methylcarbonyl, phenyl, benzyl, n-butyl, ethoxy, phenylcarbonyl, 2-(2-methyl)-methylenedioxy, 1-piperidinyl, (5-(2,2-dimethyl-1,3-dioxolanyl)methyl), methoxymethoxymethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, 1-piperidinylmethyl or 1,1,1,3,3,3-hexafluoro-2-hydroxypropyl.

77. The compound of claim 1, R⁵ is substituted with methyl, trifluoromethyl, methoxy, fluoro, bromo, chloro, methylthio, phenoxy, trifluoromethoxy, 3-pyridyl, 4-pyridyl, 2-pyridyl, ethyl, tert-butyl, methylcarbonyl, phenyl, benzyl, n-butyl, ethoxy or phenylcarbonyl.

78. The compound of claim 1, wherein R⁵ is 2,4-dimethylbenzyl, 4-isopropylbenzyl, 4-tert-butylbenzyl, 2,4,5-trifluorobenzyl, 1-naphthylmethyl, 4-(2-methyl-[1,3]dioxolan-2-yl)benzyl, 4-methylbenzyl, 4-ethylbenzyl, 1-piperidinyl, 4-methylcarbonylbenzyl, (5-(2,2-dimethyl-1,3-dioxolanyl)methyl), 1,2-dihydroxypropanyl, benzyl, 4-(2-methyl)-thiazolylmethyl, 4-(2-phenyl)thiazolylmethyl, 3-methoxymethoxymethylbenzyl, 3-hydroxymethylbenzyl, 4-hydroxymethylbenzyl, 4-hydroxyethylbenzyl, 4-methoxymethylbenzyl, 4-(1-piperidinylmethyl)benzyl, 3-biphenylyl, 4-biphenylyl, 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenyl, 4-(2-ethyl)thiazolylmethyl, 4-(2-isopropyl)thiazolylmethyl, 4-(2-propyl)thiazolylmethyl, 4-(2-benzyl)thiazolylmethyl, 4-(2-methyl)oxazolylmethyl, 4-(2-ethyl)oxazolylmethyl, 4-(2-propyl)oxazolylmethyl, 4-(2-phenyl)oxazolylmethyl, 4-(2-benzyl)oxazolylmethyl, 4-(2-cyclohexyl)oxazolylmethyl, 4-n-propyloxymethylbenzyl, 2-(5-methyl)pyrazinylmethyl, 4-n-pentyloxymethylbenzyl, 4-n-octyloxymethylbenzyl, 3-ethoxymethylbenzyl, 3-n-butoxymethylbenzyl, 3-n-hexyloxymethylbenzyl, 3-n-octyloxymethylbenzyl, 2-methylbenzyl, 4-methylbenzyl, 3-methylbenzyl, phenylethyl, 4-(2,5-dimethyl)thiazolylmethyl, 4-(2-isopropyl-5-methyl)thiazolylmethyl, 4-(2-ethyl-5-methyl)thiazolylmethyl, 4-(2-methyl-5-ethyl)thiazolylmethyl, 4-(2,5-diethyl)thiazolylmethyl, phenyl, 2-phenylethyl, 3-phenylpropyl, benzyl, 3-methylbenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-phenylbenzyl, 1-phenylethyl, 1,2,3,4-tetrahydro-1-naphthyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 4-bromobenzyl, 4-methoxycarbonylbenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-methylthiobenzyl, 4-phenoxybenzyl, 4-trifluoromethoxybenzyl, 3-pyridylmethyl or 4-pyridylmethyl.

79. The compound of claim 1, wherein R⁵ is 4-(2-methyl-[1,3]dioxolan-2-yl)benzyl, 1-piperidinyl, (5-(2,2-dimethyl-1,3-dioxolanyl)methyl), 4-(2-methyl)-thiazolylmethyl, 4-(2-phenyl)thiazolylmethyl, 4-(1-piperidinylmethyl)benzyl, 4-(2-ethyl)thiazolylmethyl, 4-(2-isopropyl)thiazolylmethyl, 4-(2-propyl)thiazolylmethyl, 4-(2-benzyl)thiazolylmethyl, 4-(2-methyl)oxazolylmethyl, 4-(2-ethyl)oxazolylmethyl, 4-(2-propyl)oxazolylmethyl, 4-(2-phenyl)oxazolylmethyl, 4-(2-benzyl)oxazolylmethyl, 4-(2-cyclohexyl)oxazolylmethyl, 2-(5-methyl)pyrazinylmethyl, 4-(2,5-dimethyl)thiazolylmethyl, 4-(2-isopropyl-5-methyl)thiazolylmethyl, 4-(2-ethyl-5-methyl)thiazolylmethyl, 4-(2-methyl-5-ethyl)thiazolylmethyl, 4-(2,5-diethyl)thiazolylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

80. The compound of claim 1, wherein R⁵ is 2-phenylethyl, 3-phenylpropyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-phenylbenzyl, 1-phenylethyl, 2,4-dimethylbenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 4-bromobenzyl, 4-methoxycarbonylbenzyl, 2-chlorobenzyl, 4-chorobenzyl, 4-methylthiobenzyl, 4-phenoxybenzyl or 4-trifluoromethoxybenzyl.

81. The compound of claim 1, wherein R⁵ is —

N═

CR⁶R⁷ where R⁶ and R⁷ are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted i-propyl, substituted or unsubstituted i-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted s-butyl, or substituted or unsubstituted 3-pentyl;

where the substituents are selected from one or more Q¹, with the proviso that R⁶ and R⁷ are not both methyl.

82. The compound of claim 81, wherein R⁶ and R⁷ are unsubstituted or substituted with one or more Q¹ groups, where Q¹ is hydroxy, halo, alkyl or alkoxy.

83. The compound of claim 81, wherein R⁶ and R⁷ are unsubstituted or substituted with one or more Q¹ groups, where Q¹ is hydroxy, chloro, bromo, methyl or methoxy.

84. The compound of claim 81, wherein R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, isopropyl, n-propyl, s-butyl, 3-pentyl, isobutyl or t-butyl, with the proviso that R⁶ and R⁷ are not both methyl.

92. The compound of claim 1 that has formula X:

105. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

106. The pharmaceutical composition of claim 105 formulated for single dosage administration.

107. A method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

108. A method of treating or ameliorating a symptom of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, lipid disorders, and obesity.

109. A method of enhancing cholesterol metabolism, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

110. A method of treating, preventing or ameiliorating a symptom of hypocholesterolemia in a subject in need thereof, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

111. An in vitro method for altering liver X receptor (LXRα

or LXRβ

) activity, comprising contacting the nuclear receptor with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

117. The compound of claim 1 that has formula II:

13. A compound of formula I,

14. The compound of claim 13, wherein q and r are each independently an integer from 0 to 3.

15. The compound of claim 13, wherein q and r are each independently 0 or 1.

16. The compound of claim 13, wherein n is 1 to 3.

17. The compound of claim 13, wherein n is 1.

18. The compound of claim 13, wherein X is O.

19. The compound of claim 13, wherein X is S.

20. The compound of claim 13, wherein X is NR′

.

21. The compound of claim 20, wherein R′

is alkyl or hydrogen.

22. The compound of claim 21, wherein R′

is lower alkyl or hydrogen.

23. The compound of claim 22, wherein R′

is hydrogen.

24. The compound of claim 13, wherein Y is substituted or unsubstituted heteroaryl, where the substituents, when present are each independently selected from one or more Q¹.

25. The compound of claim 13, wherein Y is substituted or unsubstituted heterocyclyl, where the substituents, when present are each independently selected from one or more Q¹.

26. The compound of claim 13, wherein Y is substituted or unsubstituted aryl, where the substituents, when present are each independently selected from one or more Q¹.

27. The compound of claim 13, wherein Y is substituted or unsubstituted phenyl, where the substituents, when present are each independently selected from one or more Q¹.

28. The compound of claim 13, wherein Y is substituted with Q¹, which is selected from halo, hydroxy, alkyl, alkoxy, alkoxycarbonyl, haloalkyl, alkylcarbonyl, hydroxycarbonyl, hydroxyhaloalkyl, aryl, aralkoxy, alkylaryl, alkylheteroaryl and heteroaryl.

85. A compound of formula III:

86. The compound of claim 85 that has formula IV:

87. The compound of claim 85 that has formula V:

88. The compound of claim 85 that has formula VI:

89. The compound of claim 85 that has formula VII:

90. The compound of claim 85 that has formula VIII:

91. The compound of claim 85 that has formula IX:

93. The compound of claim 85 that has formula XI:

94. The compound of claim 85 that has formula XII:

95. The compound of claim 85 that has formula XIII:

96. The compound of claim 85 that has formula XIV:

97. The compound of claim 85 that has formula XV:

98. The compound of claim 85 that has formula XVI:

99. The compound of claim 85 that has formula XVII:

100. The compound of claim 85 that has formula XVII:

101. The compound of claim 85 that has formula XVIII:

102. The compound of claim 85 that has formula XIX:

103. The compound of claim 85 that has formula XX:

118. The compound of claim 85, wherein each Ar is independently substituted or unsubstituted heteroaryl.

104. A compound selected from FIG. 1.

112. A method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective amount of a compound of formula I:

113. A method of treating or ameliorating hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, lipid disorders, or obesity comprising administering to a subject in need thereof an effective amount of a compound of formula I:

114. A method of enhancing cholesterol metabolism, comprising administering an effective amount of a compound of formula I:

115. A method of treating, preventing or ameliorating hypocholesterolemia in a subject in need thereof, comprising administering an effective amount of a compound of formula I:

116. An in vitro method for altering liver X receptor (LXRα

or LXRβ

) activity, comprising contacting the nuclear receptor with a compound of formula I;

119. A compound having formula I: