4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs

1. A compound of Formula (I):

wherein

X is selected from a covalent bond, S, or O;

Y is S or O;

- - - W - - - represents a group selected from ═—CH—, —CH═, —CH 2 —, —CH 2 —CH 2 —, ═CH—CH 2 , —CH 2 —CH═, ═CH—CH═, and —CH═CH—;

Z is selected from O, CH, and CH 2 , provided when Y is O, Z is O;

R 1 and R 2 are independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, halo, and NR a R b wherein R a and R b are independently H or C 1-3 alkyl;

R 3 and R 4 are independently selected from H, halo, cyano, hydroxy, acetyl, C 1-5 alkyl, C 1-4 alkoxy, and NR c R d wherein R c and R d are independently H or C 1-3 alkyl, provided that R 3 and R 4 are not both H;

R 5 is selected from halo, phenyl, phenoxy, (phenyl)C 1-5 alkoxy, (phenyl)C 1-5 alkyl, C 2-5 heteroaryloxy, C 2-5 heteroarylC 1-5 alkoxy, C 2-5 heterocyclyloxy, C 1-9 alkyl, C 1-8 alkoxy, C 2-9 alkenyl, C 2-9 alkenyloxy, C 2-9 alkynyl, C 2-9 alkynyloxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 3-7 cycloalkyl-C 1-7 alkyl, C 3-7 cycloalkyl-C 1-7 alkoxy, C 3-7 cycloalkyloxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-5 alkoxy-C 1-5 alkoxy, or C 3-7 cycloalkyloxy-C 1-7 alkoxy;

R 6 is H when - - - W - - - represents a group selected from —CH═, —CH 2 , —CH 2 —CH 2 , —CH 2 —CH═, and —CH═CH—,

or R 6 is absent when - - - W - - - represents a group selected from ═CH—, ═CH—CH 2 , and ═CH—CH═; and

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein X is S or O.

3. The compound of claim 1 wherein X is a covalent bond.

4. The compound of claim 2 wherein X is O.

5. The compound of claim 1 wherein Y is O.

6. The compound of claim 1 wherein Y is S.

7. The compound of claim 1 wherein Z is O.

8. The compound of claim 1 wherein Z is CH or CH 2 .

9. The compound of claim 1 wherein - - - W - - - represents —CH 2 — or —CH 2 —CH 2 .

10. The compound of claim 9 wherein - - - W - - - represents —CH 2 —.

11. The compound of claim 1 wherein - - - W - - - represents ═CH—, —CH═, ═CH—CH 2 —, —CH 2 —CH═, ═CH—CH═, or —CH═CH—.

12. The compound of claim 1 wherein R 3 and R 4 are independently selected from H, halo, cyano, C 1-4 alkyl, and C 1-3 alkoxy.

13. The compound of claim 1 wherein R 1 and R 2 are independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, F, Cl, and Br.

14. The compound of claim 13 wherein R 1 and R 2 are independently selected from H, methyl, methoxy, F and Cl.

15. The compound of claim 1 wherein R 3 and R 4 are independently selected from H, halo, cyano, hydroxy, C 2-4 acyl, C 1-4 alkyl, and C 1-3 alkoxy.

16. The compound of claim 12 wherein R 3 is independently selected from H, F, Cl, methyl, and methoxy.

17. The compound of claim 12 wherein R 4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy.

18. The compound of claim 1 wherein R 3 is selected from methyl, methoxy, H, Cl, Br, I, CH, —CH(CF 3 ) 2 , CF 3 , —OCF 3 , —N(CH 3 ) 2 , —O—CH 2 COOH, and —COCH 3 , and R 4 is selected from H, Cl, and methyl.

19. The compound of claim 1 wherein R 5 is selected from C 1-7 alkyl, C 1-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, C 2-7 alkynyl, C 2-7 alkynyloxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-5 alkoxy-C 1-5 alkoxy, and C 3-7 cycloalkyloxy-C 1-7 alkoxy.

20. The compound of claim 1 wherein R 5 is selected from phenoxy, (phenyl)C 1-5 alkoxy, (phenyl)C 1-5 alkyl, C 2-5 heteroaryloxy, C 2-5 heteroarylC 1-5 alkoxy, C 2-5 heterocyclyloxy, C 3-7 cycloalkyl-C 1-7 alkyl, C 3-7 cycloalkyl-C 1-7 alkoxy, and C 3-7 cycloalkyloxy-C 1-6 alkyl.

21. The compound of claim 1 wherein R 6 is H.

22. The compound of claim 1 wherein R 3 is selected from H, F, Cl, methyl, and methoxy, and R 4 is selected from F, Cl, methyl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and methoxy.

23. The compound of claim 1 wherein R 1 is selected from H, CF 3 , methyl, Cl, and methoxy, and R 2 is selected from H, Cl, and methyl.

24. The compound of claim 23 wherein X is a covalent bond.

25. The compound of claim 23 wherein X is covalent bond, Y is S and Z is O.

26. The compound of claim 1 wherein X is O and Y is O.

27. The compound of claim 1 wherein X is O and Y is S.

28. The compound of claim 1 wherein Y is O and Z is O.

29. The compound of claim 1 wherein Y is S and Z is O.

30. The compound of claim 1 wherein R 6 is H and R 5 is selected from C 1-7 alkyl, C 1-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, C 1-6 alkoxy-C 1-6 alkyl, and C 1-5 alkoxy-C 1-5 alkoxy.

31. The compound of claim 30 wherein R 5 is selected from C 1-5 alkyl, C 1-4 alkoxy, C 2-5 alkenyl, C 2-5 alkenyloxy, and C 1-5 alkoxy-C 1-5 alkoxy.

32. The compound of claim 30 wherein R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, and C 1-3 alkoxy-C 1-3 alkoxy.

33. The compound of claim 30 wherein R 5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxy-methoxy, methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl, and ethoxy-ethyl.

34. The compound of claim 1 wherein

R 1 is selected from H, CF 3 , methyl, Cl, and methoxy;

R 2 is selected from H, Cl, and methyl;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl, fluoromethoxy, difluoromethyl, difluoromethoxy, and methoxy.

35. The compound of claim 1 wherein

X is O;

Y is O;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy.

36. The compound of claim 1 wherein

X is O;

Y is S;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy.

37. The compound of claim 1 wherein

X is covalent bond;

Y is S;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 , and methoxy.

38. The compound of claim 1 wherein

Y is O;

Z is O;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy.

39. The compound of claim 1 wherein

Y is S;

Z is O;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy.

40. The compound of claim 1 wherein

R 3 is selected from H, F, Cl, methyl, and methoxy;

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 , and methoxy;

R 5 is selected from C 1-7 alkyl, C 1-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, C 1-6 alkoxy-C 1-6 alkyl, and C 1-5 alkoxy-C 1-5 alkoxy; and

R 6 is H.

41. The compound of claim 1 wherein

X is O;

Y is O;

R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, and C 1-3 alkoxy-C 1-3 alkoxy; and

R 6 is H.

42. The compound of claim 1 wherein

X is O;

Y is S;

R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, and

C 1-3 alkoxy-C 1-3 alkoxy; and

R 6 is H.

43. The compound of claim 1 wherein

X is O;

Y is O;

R 1 is selected from H, CF 3 , methyl, Cl, and methoxy;

R 2 is selected from H, Cl, and methyl;

R 3 is selected from H, F, Cl, methyl, and methoxy;

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy; and

n is 1.

44. The compound of claim 1 wherein

X is O;

Y is S;

R 1 is selected from H, CF 3 , methyl, Cl, and methoxy;

R 2 is selected from H, Cl, and methyl;

R 3 is selected from H, F, Cl, methyl, and methoxy; and

R 4 is selected from F, Cl, methyl, CF 3 , OCF 3 and methoxy.

45. The compound of claim 44 , wherein n=1.

46. The compound of claim 45 wherein R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, and C 1-3 alkoxy-C 1-3 alkoxy; and R 6 is H.

47. The compound of claim 1 which is selected from

{4-[2-Ethoxy-3-(4-trifluoromethvl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; and

(S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid.

48. The compound of claim 1 which is {4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid.

49. The compound of claim 1 which is (R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid.

50. The compound of claim 1 which is (S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid.

51. A compound of claim 1 selected from

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-pentylsulfanyl]-phenoxy}-acetic acid;

{4-[4-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{3-Chloro-4-[2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenyl}-acetic acid;

{4-[2-Ethoxymethyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[4-Ethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; and

{4-[2-(5-Chloro-thiophen-2-ylmethoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid.

52. A compound of claim 1 selected from

{4-[3-Cyano-2-(4-trifl uoromethyl-phenoxymethyl )-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[5-Cyano-2-(4-trifl uoromethyl-phenoxymethyl )-pent-4-enylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{3-Chloro-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenyl}-acetic acid;

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-acetic acid;

{4-[2-Benzyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[2-(4-Butyryl-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propenylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[2-methylsulfanylmethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-phenoxy}-acetic acid;

{4-[2,4-Diethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; and

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-acetic acid.

53. A compound of claim 1 selected from

{4-[2-(4-Trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-heptylsulfanyl]-phenoxy}-acetic acid;

{4-[4-Methoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-acetic acid;

{2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-3,6-d ihydro-2H-pyran-2-ylmethylsulfanyl]-phenoxy}-acetic acid; and

{2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-phenoxy}-acetic acid.

54. A compound of claim 1 , selected from

(R)-{4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[3-(4-Chloro-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[3-(4-tert-Butyl-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid;

(R)-{4-[2-(4-Chloro-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{4-[2-(4-tert-Butyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid;

(R)-{3-Chloro-4-[2-ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-phenyl}-acetic acid;

(R)-{3-Chloro-4-[3-(4-chloro-phenoxy)-2-ethoxy-propylsulfanyl]-phenyl}-acetic acid;

(R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic acid;

(R)-{4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic acid;

(R)-{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic acid; and

(R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic acid.

55. A pharmaceutical composition comprising a compound of any of claim 1 , 27 , 30 , 31 , 32 , 34 , 36 , 37 , 39 , 40 , 42 , 44 , 45 , 46 , 47 , 51 , 52 , 53 and 54 .

56. The compound of claim 45 wherein R 6 is H and R 5 is selected from C 1-7 alkyl, C 1-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, C 1-6 alkoxy-C 1-6 alkyl, and C 1-5 -C 1-5 alkoxy.

57. The compound of claim 45 wherein R 6 is H and R 5 is selected from C 1-5 alkyl, C 1-4 alkoxy, C 2-5 alkenyl, C 2-5 alkenyloxy, and C 1-5 alkoxy-C 1-5 alkoxy.

58. The compound of claim 45 wherein R 6 is H and R 5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxymethoxy, methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl, and ethoxy-ethyl.