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

1. 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 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 method of claim 1 , wherein the PPAR-delta mediated condition is selected from the group consisting of diabetes, cardiovascular diseases, Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.

3. The method of claim 1 wherein X is S or O.

4. The method of claim 1 wherein X is a covalent bond.

5. The method of claim 1 wherein X is O.

6. The method of claim 1 wherein Y is O.

7. The method of claim 1 wherein Y is S.

8. The method of claim 1 wherein Z is O.

9. The method of claim 1 wherein Z is CH or CH 2 .

10. The method of claim 1 wherein - - - - - W - - - - - represents —CH 2 — or —CH 2 —CH 2 —.

11. The method of claim 1 wherein - - - - - W - - - - - represents —CH 2 —.

12. The method of claim 1 wherein the compound of Formula (I) is selected from the group consisting of

acetic acid, [4-[[2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-,

acetic acid, [4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-, and

acetic acid, [4-[[(2S)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-.

13. The method of claim 1 wherein the compound of Formula (I) is acetic acid, [4-[[2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-.

14. The method of claim 1 wherein the compound of Formula (I) is acetic acid, [4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-.

15. The method of claim 1 wherein the compound of Formula (I) is acetic acid, [4-[[(2S)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-.

16. The method of claim 1 wherein the compound of Formula (I) is selected from the group consisting of

{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.

17. The method of claim 1 wherein the compound of Formula (I) is selected from the group consisting of

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

{4-[5-Cyano-2-(4-trifluoromethyl-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; and

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

18. The method of claim 1 wherein the compound of Formula (I) is selected from the group consisting of

{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-dihydro-2H-pyran-2-ylmethylsulfanyl]-phenoxy}-acetic acid; and

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

19. The method of claim 1 wherein the compound of Formula (I) is selected from the group consisting of

(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.