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

1. A compound of Formula (I):

wherein

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

Y is S or O;

Z is O or CH 2 , provided when Y is O, then 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, C 1-5 alkyl, hydroxy, C 2-4 acyl, 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 and R 6 are independently selected from halo, phenyl, C 1-9 alkyl, C 1-8 alkoxy, C 2-9 alkenyl, C 2-9 alkenyloxy, 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, and C 3-7 cycloalkyloxy-C 1-7 alkoxy, or

R 5 and R 6 together form C 1-9 alkylidenyl or C 3-9 alkenylidenyl; or R 5 ,

R 6 and the carbon atom to which they are attached together form C 3-7 cycloalkyl;

n is 0, 1 or 2; and

m is 0, 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 2 wherein X is O.

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

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

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

7. The compound of claim 1 wherein Z is CH 2 .

8. The compound of claim 1 wherein m is 1.

9. The compound of claim 1 wherein m is 2.

10. The compound of claim 1 wherein n is 1.

11. 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.

12. The compound of claim 11 wherein R 1 and R 2 are independently selected from H, methyl, methoxy, F and Cl.

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

14. The compound of claim 1 wherein R 3 is independently selected from H, F, Cl, hydroxy, methyl, and methoxy.

15. The compound of claim 13 wherein R 4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl, and dichlorofluoromethoxy.

16. The compound of claim 1 wherein R 3 is selected from methyl, methoxy, H, Cl, Br, I, OH, —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.

17. The compound of claim 1 wherein R 5 and R 6 together form C 1-9 alkylidenyl or C 3-9 alkenylidenyl, or R 5 , R 6 and the carbon atom to which they are attached together form C 3-7 cycloalkyl.

18. The compound of claim 1 wherein R 5 and R 6 are independently selected from halo, phenyl, C 1-9 alkyl, C 1-8 alkoxy, C 2-9 alkenyl, C 2-9 alkenyloxy, 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, and C 3-7 cycloalkyloxy-C 1-7 alkoxy.

19. 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, acetyl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl, and dichlorofluoromethoxy.

20. 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.

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

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

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

24. The compound of claim 1 wherein X is a covalent bond and Y is S.

25. 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, and methoxy.

26. 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, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, and fluoromethoxy.

27. 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, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, and fluoromethoxy.

28. 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, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, and fluoromethoxy.

29. 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;

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

R 5 and R 6 together form C 1-9 alkylidenyl or C 3-9 alkenylidenyl, or R 5 , R 6 and the carbon atom to which they attach together form C 3-7 cycloalkyl.

30. The compound of claim 25 wherein

X is O;

Y is O or S; and

Z is O.

31. The compound of claim 25 wherein R 5 and R 6 together form C 1-9 alkylidenyl or C 3-9 alkenylidenyl, or R 5 , R 6 and the carbon atom to which they attach together form C 3-7 cycloalkyl.

32. The compound of claim 25 wherein R 5 and R 6 are independently selected from halo, phenyl, C 1-9 alkyl, C 1-8 alkoxy, C 2-9 alkenyl, C 2-9 alkenyloxy, 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, and C 3-7 cycloalkyloxy-C 1-7 alkoxy.

33. The compound of claim 25 wherein m is 1 and n is 1.

34. The compound of claim 25 wherein Y is S.

35. A compound which is selected from:

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

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

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

{2-Chloro-4-[2-(4-trifluoromethyl-phenoxymethyl )-allylsulfanyl]-phenoxy}-acetic acid;

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

{4-[3,3-Difluoro-2-(4-trifluoromethyl-phenoxymethyl )-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

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

{2-Methyl-4-[1-(4-trifluoromethyl-phenoxymethyl)-cyclopropylmethylsulfanyl]-phenoxy}-acetic acid;

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

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

{4-[2-(3,4-Dichloro-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{4-[3-Cyano-2-(4-trifluoromethyl-phenoxymethyl )-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

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

{2-Methyl-4-[3-naphthalen-1-yl-2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-acetic acid;

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

{4-[2-(4-Chloro-3-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

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

{4-[2-(4-Dimethylamino-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

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

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

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

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

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

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

{4-[2-(4-Isopropyl-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;

{2-Chloro-4-[2-(3,4-dichloro-phenoxymethyl)-allylsulfanyl]-phenoxy}-acetic acid;

{2-Chloro-4-[2-(4-trifluoromethoxy-phenoxymethyl)-allylsulfanyl]-phenoxy}-acetic acid;

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

{2-Chloro-4-[2,2-dimethyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-acetic acid; and

{2-Chloro-4-[1-(4-trifluoromethyl-phenoxymethyl)-cyclopropylmethylsulfanyl]-phenoxy}-acetic acid;

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

{3-Chloro-4-[2,2-dimethyl-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-phenyl}-acetic acid; and

{3-Chloro-4-[3-methyl-2-(4-trifluoromethyl-phenoxymethyl)-but-2-enylsulfanyl]-phenyl}-acetic acid

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 which is selected from the group consisting of acetic acid, [2-methyl-4-[[2-[[4-(trifluoromethyl)phenoxy]methyl]-2-propenyl]thio]phenoxy]-; (2-Methyl-4-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-allylsulfanyl}-phenoxy)-acetic acid; and

{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-allysulfanyl]-phenoxy}-acetic acid.

37. A pharmaceutical composition comprising a compound of any of claim 1 , 16 , 17 , 19 , 25 , 26 , 29 , 35 , or 36 .

38. A method for treating or inhibiting the progression of a PPAR-delta mediated condition, said method comprising administering to a patient in need of treatment a pharmaceutically effective amount of the composition of claim 37 .

39. A compound which is {2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-acetic acid or a pharmaceutically acceptable salt thereof.