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

1. A method for treating a condition selected from the group consisting of diabetes, cardiovascular diseases, Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity

comprising administering to a patient in need of such treatment an effective amount of 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 or 5- or 6-membered heterocyclyl;

n is 0, 1 or 2; and

m is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

7. The method of claim 1 wherein m is 1.

8. The method of claim 1 wherein m is 2.

9. The method of claim 1 wherein n is 1.

10. The method 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.

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

12. The method 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.

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

14. The method of claim 1 wherein R 4 is independently selected from F, CI, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl, and dichlorofluoromethoxy.

15. The method 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.

16. A method for treating a condition selected from the group consisting of diabetes, cardiovascular diseases, Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity comprising comprising administering to a patient in need of such treatment an effective amount of a compound selected from the group consisting of:

{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-[2-(2,4-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;

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-[1,3]dioxan-2-ylmethylsulfanyl]-phenoxy}-acetic acid;

{4-[2,2-Dimethyl-4-(4-trifluoromethyl-phenoxymethyl)-[1,3]dioxolan-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid;

[2-Methyl-4-(2-phenoxymethyl-allylsulfanyl)-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-Hydroxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-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;

{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-enylsulfanl]-phenyl}-acetic acid

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 wherein the compound of formula (I) 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)-allylsulfanyl]-phenoxy}-acetic acid; or a pharmaceutically acceptable salt thereof.

18. A method for treating a condition selected from the group consisting of diabetes, cardiovascular diseases, Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity comprising administering an effective amount of a compound of Formula (II):

wherein

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

Y is S or 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 or 5- or 6-membered heterocyclyl;

n is 0, 1 or 2; and

m is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof; to a patient with said condition in need of treatment.

19. The method of claim 18 wherein R 4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl, and dichlorofluoromethoxy.

20. The method of claim 18 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.

21. The method of claim 18 wherein the compound of formula (II) is [2-methyl-4-[[2-[[[4-(trifluoromethyl)phenyl]thio]methyl]-2-propenyl]thio]phenoxy]-acetic acid.