Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia

Abstract

A compound having the general structure of Formula (I):

Description

Claims

1. A compound of Formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is selected from the group consisting of H, R4, (C1-C6)haloalkyl, —(C1-C6)alkylene-R4, —(C1-C6)alkylene-R5, —(C1-C6)alkylene-R6, (C1-C6)alkenyl, (C1-C6)alkynyl, and —(C1-C6)alkylene-O—(C1-C6)alkyl;R2 is selected from the group consisting of R7, (C1-C6)alkyl, (C1-C6)haloalkyl, —(C1-C6-)alkylene-R5, R4, R5, R6, R7 and —(C1-C6)alkylene-O—R8;R3 is selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, —(C1-C6-)alkylene-R5, R4, R5, R6, and R7; orR2 and R3 together with the carbon atom to which they are both attached form a (C3-C10)cycloalkyl or (C2-C10)heterocycloalkyl ring, wherein said (C3-C10)cycloalkyl or (C2-C10)heterocycloalkyl ring is unsubstituted or substituted with one or more X5 groups.R4 is unsubstituted (C3-C10)cycloalkyl or (C3-C10)cycloalkyl substituted with one or more X1 groups;R5 is unsubstituted (C6-C14)aryl and (C6-C14)aryl substituted with one or more X2 groups;R6 is selected from the group consisting of unsubstituted (C2-C10)heteroaryl and (C2-C10)heteroaryl substituted with one or more X3 groups;R7 is unsubstituted (C2-C10)heterocycloalkyl and (C2-C10)heterocycloalkyl substituted with one or more X4 groups;R8 is selected from the group consisting of H, (C1-C6)alkyl, R4, R5, R6, R7, —C(O)—(C1-C6)alkyl, —C(O)—R5 each R9 is independently selected from the group consisting of H, (C1-C6)alkyl, R4, R5, R6, and R7;R10 is selected from the group consisting of R9, —C(O)—(C1-C6)alkyl, and —C(O)—R5;Y is —O— or —N(R10)—;each X1 is independently selected from the group consisting of halogen, (C1-C6)alkyl, —O—(C1-C6)alkyl, —OH, (C1-C6)haloalkyl, (C6-C14)aryl, and (C1-C6)alkyne;each X2 is independently selected from the group consisting of halogen, (C1-C6)alkyl, —O—(C1-C6)alkyl, —OH, (C1-C6)haloalkyl, (C6-C14)aryl, and (C1-C6)alkyne;each X3 is independently selected from the group consisting of halogen, (C1-C6)alkyl, and N-oxide;each X4 is independently selected form the group consisting of (C1-C6)alkyl, R5, —C(O)—(C1-C6)alkyl, —C(O)—R5, —C(O)—O—(C1-C6)alkyl, —(C1-C6-)alkylene-R5, R4, and —S(O2)—(C1-C6)alkyl; andeach X5 is independently selected from the group consisting of (C1-C6)alkyl, a fused (C6-C14)aryl ring, —C(O)—(C1-C6)alkyl, a fused (C2-C10)heteroaryl ring, —C(O)—O—(C1-C6)alkyl, —C(O)—R5, —S(O2)—(C1-C6)alkyl, —C(O)—N(R9)2, R5, R6, —C(O)—R4, —C(O)—O—R4, —S(O2)—R4, —S(O2)—(C1-C6)alkylene-R4, —S(O2)—(C1-C6-)alkylene-R5, —N(R9)—C(O)—O—(C1-C6)alkyl, —N(R9)—C(O)—O—R4, —N(R9)—C(O)—N(R9)2 and —N(R9)2; wherein said fused (C6-C14)aryl ring of X5 is unsubstituted or independently substituted with one or more substitutent selected from —(C1-C6)alkylene-R7 or X2, and said fused (C2-C10)heteroaryl ring of X5 is unsubstituted or substituted with one or more X3 groups.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is -alkylene-R4.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is -alkylene-R5.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is -alkylene-R6.

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is alkyl; andR2 and R3 are each independently selected from the group consisting of alkyl, haloalkyl, -alkylene-R5, R4, R5, R6, and R7.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is haloalkyl; andR2 and R3 are each independently selected from the group consisting of alkyl, haloalkyl, -alkylene-R5, R4, R5, R6, and R7.

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is -alkylene-R4; andR2 and R3 are each independently selected from the group consisting of alkyl, haloalkyl, -alkylene-R5, R4, R5, R6, and R7.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is -alkylene-R5; andR2 and R3 are each independently selected from the group consisting of alkyl, haloalkyl, -alkylene-R5, R4, R5, R6, and R7.

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is -alkylene-R6; andR2 and R3 are each independently selected from the group consisting of alkyl, haloalkyl, -alkylene-R5, R4, R5, R6, and R7.

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is alkyl; andR2 and R3 together with the carbon atom to which they are both attached form a cycloalkyl ring, wherein said cycloalkyl ring is unsubstituted or substituted with one or more X1 groups.

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is alkyl; andR2 and R3 together with the carbon atom to which they are both attached form a heterocycloalkyl ring, wherein said heterocycloalkyl ring is unsubstituted or substituted with one or more X4 groups.

14. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is —CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH2CH2CH3, —CH2CH2CH(CH3)2, or —CH2CH2CH2-cyclopropyl; R2 and R3 are each independently selected from the group consisting of —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2C(CH3)3, —CH2CH2CF3, —CH2CH2—R5, cyclopropyl, piperazinyl, piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl; andR5 is phenyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, selected from the group consisting of:

16. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is —CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH2CH2CH3, or —CH2CH2CH(CH3)2; andR2 and R3 together with the carbon atom to which they are both attached form a cycloalkyl or heterocycloalkyl group selected from:

17. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, selected from the group consisting of:

18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein R1 is —CH2CH2CH2CF3, —CH2CH2—R4, —CH2CH2CH2—R4, —CH2—R5, or —CH2—R6.

19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R2 and R3 together with the carbon atom to which they are both attached form a cycloalkyl or heterocycloalkyl group selected from:

20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, selected from the group consisting of:

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: R1 is —CH2CH2CH2CF3 or —CH2CH2—R4; andR2 and R3 are each independently selected from the group consisting of —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2C(CH3)3, —CH2CH2CF3, —CH2CH2—R5, cyclopropyl, piperazinyl, piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, selected from the group consisting of:

23. A compound having the following structural formula:

24. A compound having the following structural formula:

25. A compound having the following structural formula:

26. A compound having the following structural formula:

27. A compound having the following structural formula:

28. A compound having the following structural formula:

29. A composition comprising: a compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof; andat least one pharmaceutically acceptable carrier.

30. The composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA: Cholesterol O-acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB1 antagonists/inverse agonists, ghrelin antagonists, H3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

31. The composition of claim 30, wherein said at least one additional therapeutic agent is a HMG CoA synthetase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

32. The composition of claim 31, wherein said HMG CoA synthetase inhibitor is simvastatin.

33. The composition of claim 30, wherein said at least one additional therapeutic agent is a cholesteryl ester transfer protein inhibitor.

34. The composition of claim 33, wherein said cholesteryl ester transfer protein inhibitor is torcetrapib.

35. A method of treating a disease, disorder, or condition comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof;wherein said disease, disorder, or condition is selected from the group consisting of metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease.

36. The method of claim 35, wherein said disease, disorder, or condition is dyslipidemia.

37. The method of claim 35, further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB1 antagonists/inverse agonists, ghrelin antagonists, H3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

38. The method of claim 37, wherein said at least one additional active ingredient is a HMG CoA synthetase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

39. The method of claim 38, wherein said HMG CoA synthetase inhibitor is simvastatin.

40. The compound of claim 1 having the formula:

41. The compound of claim 40, wherein R1 is alkyl.

42. The compound of claim 40, wherein R1 is -alkylene-cycloalkyl.

43. The compound of claim 40, wherein R1 is alkylene-O-alkyl.

44. The compound of claim 40, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic cycloalkyl.

45. The compound of claim 40, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form: (i) a bicyclic cycloalkyl; or (ii) a monocyclic cycloalkyl which forms a spirocycle with a second cycloalkyl group or with a heterocycloalkyl group.

46. The compound of claim 40, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic heterocycloalkyl.

47. The compound of claim 41, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic cycloalkyl.

48. The compound of claim 41, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form: (i) a bicyclic cycloalkyl; or (ii) a monocyclic cycloalkyl which forms a spirocycle with a second cycloalkyl group or with a heterocycloalkyl group.

49. The compound of claim 41, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic heterocycloalkyl.

50. The compound of claim 42, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic cycloalkyl.

51. The compound of claim 42, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form: (i) a bicyclic cycloalkyl; or (ii) a monocyclic cycloalkyl which forms a spirocycle with a second cycloalkyl group or with a heterocycloalkyl group.

52. The compound of claim 42, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic heterocycloalkyl.

53. The compound of claim 43, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic cycloalkyl.

54. The compound of claim 43, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form: (i) a bicyclic cycloalkyl; or (ii) a monocyclic cycloalkyl which forms a spirocycle with a second cycloalkyl group or with a heterocycloalkyl group.

55. The compound of claim 43, wherein R2 and R3 together with the carbon atom to which they are both attached, combine to form a monocyclic heterocycloalkyl.

56. The compound of claim 40 having the structure:

57. A composition comprising: a compound of claim 40, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof; andat least one pharmaceutically acceptable carrier.

58. The composition of claim 57, further comprising at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB1 antagonists/inverse agonists, ghrelin antagonists, H3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

59. The composition of claim 58, wherein said at least one additional therapeutic agent is a HMG CoA synthetase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

60. The composition of claim 59, wherein said HMG CoA synthetase inhibitor is simvastatin.

61. The composition of claim 58, wherein said at least one additional therapeutic agent is a cholesteryl ester transfer protein inhibitor.

62. The composition of claim 61, wherein said cholesteryl ester transfer protein inhibitor is torcetrapib.

63. A method of treating a disease, disorder, or condition comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 40, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof;wherein said disease, disorder, or condition is selected from the group consisting of metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease.

64. The method of claim 63, wherein said disease, disorder, or condition is dyslipidemia.

65. The method of claim 63, further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB1 antagonists/inverse agonists, ghrelin antagonists, H3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

66. The method of claim 65, wherein said at least one additional active ingredient is a HMG CoA synthetase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

67. The method of claim 66, wherein said HMG CoA synthetase inhibitor is simvastatin.