Substituted triazoles as modulators of PPAR and methods of their preparation

• US 20060014809A1
• Filed: 05/24/2005
• Published: 01/19/2006
• Est. Priority Date: 05/25/2004
• Status: Active Grant

• Current Assignee: CymaBay Therapeutics Inc.
• Original Assignee: Metabolix Incorporated
• Inventors: Zhu, Yan, Cheng, Peng, Zhao, Zuchun, Ma, Jingyuan, Rakhmanova, Vera A., Gregoire, Francine M.
• Granted Patent: US 7,323,480 B2
• Time in Patent Office: Days
• US Class Current: 514/359
• 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 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 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 409/10 linked by a carbon chain containing aromatic rings

Abstract

The present invention is directed to certain novel triazole compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. The present invention is also directed to methods of making and using such compounds and pharmaceutical compositions containing such compounds to treat or control a number of diseases mediated by PPAR such as glucose metabolism, lipid metabolism and insulin secretion, specifically Type 2 diabetes, hyperinsulemia, hyperlipidemia, hyperuricemia, hypercholesteremia, atherosclerosis, one or more risk factors for cardiovascular disease, Syndrome X, hypertriglyceridemia, hyperglycemia, obesity, and eating disorders.

Claims

1. A compound having the formula:

2. A compound of claim 1, wherein Ar¹ is benzodioxole or phenyl optionally substituted with from one to three R⁷ substituents independently selected from the group consisting of halogen, halo(C₁-C₈)alkyl, heterocyclyl, heterocyclyl(C₁-C₄)alkyl, and —

OR².

3. A compound of claim 1, wherein Ar¹ is

4. A compound of claim 3, wherein Ar¹ is

5. A compound of claim 1, wherein R¹ is selected from the group consisting of (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, aryl and heterocyclyl(C₁-C₄)alkyl.

6. A compound of claim 5, wherein R¹ is selected from the group consisting of CH₃, CH(CH₃)₂, CF₃, CF₃CH₂, phenyl and

7. A compound of claim 6, wherein R¹⁰ is Cl, Oi-Pr or OCH₃.

8. A compound of claim 5, wherein R¹ is CH₃.

9. A compound of claim 1, wherein Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H;

each R⁴ and R⁵ is a member independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached; and

r2 is 0.

10. A compound of claim 9, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y³ is NH, O, or S.

11. A compound of claim 9, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

12. A compound of claim 1, wherein at least one of m1, m2, or m3 is 0.

13. A compound of claim 1, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, —

CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, —

C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, C(CH₃)₂CH₂O, (CH₂)₃S and (C═

O)NH.

14. A compound of claim 9, wherein Y⁴ is CR⁴R⁵ or 0, Y⁵ is CR⁴R⁵ and m6 is 0.

15. A compound of claim 1, wherein K is a member selected from the group consisting of:

CH₂, CH(CH₃), C(CH₃)₂, —

CH═

CH₂^E, CH═

CH₂^Z, CH≡

CH, OCH₂, —

OCH(CH₃) and OC(CH₃)₂, wherein E represents the entgegen isomer and Z represents the zusammen isomer.

16. A compound of claim 1, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

17. A compound of claim 16, wherein R⁴ and R⁵ are H.

18. A compound of claim 1, wherein Z is CO₂R⁶.

19. A compound of claim 18, wherein R⁶ is H.

20. A compound of claim 1, wherein Ar² is selected from the group consisting of:

(i) pyridine, optionally substituted with from one to three R⁸ substituents;

(ii) pyrazine, optionally substituted with from one to two R⁸ substituents;

(iii) pyrimidine, optionally substituted with from one to two R⁸ substituents;

(iv) pyridazine, optionally substituted with from one to two R⁸ substituents; and

(v) triazine, optionally substituted with one R⁸ substituent

wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈) alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R², —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

21. A compound of claim 20, wherein Ar² is selected from the group consisting of:

(i) pyridine, optionally substituted with from one to three R⁸ substituents;

(ii) pyrazine, optionally substituted with from one to two R⁸ substituents;

(iii) pyrimidine, optionally substituted with from one to two R⁸ substituents;

(iv) pyridazine, optionally substituted with from one to two R⁸ substituents; and

(v) triazine, optionally substituted with from one to two R⁸ substituents

wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR, —

CO₂R², —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

22. A compound of claim 20, wherein Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H; and

each R⁴ and R⁵ are members independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached.

23. A compound of claim 22, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y is NH, O, or S.

24. A compound of claim 22, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

25. A compound of claim 20, wherein at least one of m1, m2, or m3 is 0.

26. A compound of claim 20, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, —

CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, —

C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, —

C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, —

C(CH₃)₂CH₂O, (CH₂)₃S and (C═

O)NH.

27. A compound of claim 22, wherein Y⁴ is CR⁴R⁵ or 0, Y⁵ is CR⁴R⁵ and m6 is 0.

28. A compound of claim 20, wherein L is a member selected from the group consisting of:

CH₂, CH(CH₃), C(CH₃)₂, —

CH═

CH₂^E, CH═

CH₂^Z, CH≡

CH, OCH₂, —

OCH(CH₃) and OC(CH₃)₂, wherein E represents the entgegen isomer and Z represents the zusammen isomer.

29. A compound of claim 20, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

30. A compound of claim 29, wherein R⁴ and R⁵ are H.

31. A compound of claim 20, wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, heterocyclyl, heterocyclyl(C₁-C₄)alkyl, and halo(C₁-C₈)alkyl.

32. A compound of claim 20, wherein Ar² has the formula:

33. A compound of claim 20, wherein Ar² has the formula:

34. A compound of claim 1, wherein Ar² is benzene optionally substituted with from one to three R⁸ substituents each independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R², —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

35. A compound of claim 34, wherein Ar² is benzene optionally substituted with from one to two R⁸ substituents each independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR, —

CO₂R², —

NR₂, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

36. A compound of claim 34, wherein Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H; and

each R⁴ and R⁵ are members independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached.

37. A compound of claim 36, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y³ is NH, O, or S.

38. A compound of claim 36, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

39. A compound of claim 34, wherein at least one of m1, m2, or m3 is 0.

40. A compound of claim 34, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, —

CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, —

C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, C(CH₃)₂CH₂O, (CH₂)₃S. and (C═

O)NH.

41. A compound of claim 36, wherein Y⁴ is CR⁴R⁵ or O, Y⁵ is CR⁴R⁵ and m6 is 0.

42. A compound of claim 34, wherein K is a member selected from the group consisting of:

CH₂, CH(CH₃), C(CH₃)₂, —

CH═

CH₂^E, CH═

CH₂^Z, CH≡

CH, OCH₂, —

OCH(CH₃) and OC(CH₃)₂, wherein E represents the entgegen isomer and Z represents the zusamen isomer.

43. A compound of claim 34, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

44. A compound e of claim 43, wherein R⁴ and R⁵ are H.

45. A compound of claim 34, wherein each R⁸ substituent is independently selected from the group consisting of H, halogen, (C₁-C₈)alkyl, and halo(C₁-C₈)alkyl.

46. A compound of claim 34, wherein Ar² has the formula:

47. A compound of claim 46, wherein the compound is

50. A composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients and a compound of claim 1.

51. A method of modulating a peroxisome proliferator activated receptor, comprising the step of contacting the receptor with at least one compound of claim 1.

52. A method of treating Type 2 diabetes in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

53. A method for modulating insulin resistance in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

54. A method of treating hyperinsulemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

55. A method of treating hyperlipidemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

56. A method of treating hyperuricemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

57. A method of treating hypercholesteremia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

58. A method of treating atherosclerosis in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

59. A method of treating one or more risk factors for cardiovascular disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

60. A method of treating Syndrome X in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

61. A method of treating hypertriglyceridemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

62. A method of treating hyperglycemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

63. A method of decreasing fibrinogen levels in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

64. A method of decreasing LDLc in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

65. A method of shifting LDL particle size from small dense to normal dense LDL in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

66. A method of treating obesity in a subject, said method comprising administering to said subject a therapeutically effective, amount of a compound of claim 1.

67. A method of treating eating disorders in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

68. A method of suppressing appetite in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

69. A method of modulating leptin levels in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

48. A compound selected from the group consisting of:

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acrylic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-trifluoromethoxy-phenoxy}-acetic acid;

3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

2,2-Dimethyl-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acetic acid;

5-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxymethyl}-1H-tetrazole;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclopropanecarboxylic acid;

3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acrylic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenylsulfanyl}-acetic acid;

{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Methoxy-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2,6-Dimethyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acetic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acetic acid;

(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

{4-[5-Isopropyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{2-Methyl-4-[5-propyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[5-phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[5-(2,2,2-trifluoro-ethyl)-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[5-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-amino}-phenoxy)-acetic acid;

{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(4-Bromo-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]2-methyl-phenoxy}-acetic acid;

{4-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(4-[2-(3,4-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(4-Methoxy-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethoxy-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

[4-(2-Benzo[1,3]dioxol-5-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid;

{2-Methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{4-[2-(3-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(3-Bromo-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclobutanecarboxylic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclopentanecarboxylic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclohexanecarboxylic acid;

{2-Ethyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{2-Isopropyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

{4-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazole-4-carbonyl]-amino}-phenoxy)-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenylsulfanyl}-acetic acid;

{4-[2-(4-Fluoro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}acetic acid;

{4-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(3,4-Difluoro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-3-propyl-phenyl}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-propynoic acid;

2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

2-{4-[5-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

{2-Ethyl-4-[5-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid;

2-{4-[5-[4-(4-Isopropoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

2-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid;

{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

2-{5-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid; and

{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-thiophen-2-yl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid.

49. A compound selected from the group consisting of:

2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]phenoxy}-propionic acid;

2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-phenoxy)-acetic acid;

(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid and 2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic acid;

2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid;

2-{2-Chloro-4-[2-(4-chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-2-methyl-propionic acid;

2-{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-2-methyl-propionic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-acetic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-propionic acid;

2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid;

[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-phenoxy)-acetic acid; and

2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid.