Compounds that modulate PPAR activity and methods for their preparation

1. A compound of formula (I):

and pharmaceutically acceptably salts thereof; wherein:

X 0 is S; X 1 is absent, O, S, —CH 2 —, —CH 2 —CH 2 —, or —CH═CH;

Ar 1 and Ar 2 are each independently unsubstituted or substituted phenyl or pyridinyl;

 is absent, R 1 and R 2 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitrogen, cyano, —OH, —SH or —CF 3 ;

R 3 an R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ,

provided that at least one of R 1 -R 4 is H, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;

m is 0 to 5;

q is 0 to 1; and

r is 0 to 1.

2. The compound of claim 1 , wherein

X 1 is absent or 0;

Ar 1 aud Ar 2 are each independently unsubstituted or substituted phenyl or pyridinyl;

R 1 is hydrogen;

R 2 is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;

R 3 is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or CF 3 ;

R 4 is hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen,

m is 0 to 5;

q is 1; and

r is 0 to 1.

3. The compound of claim 1 , wherein

X 1 is absent;

Ar 1 is phenyl;

Ar 2 is substituted phenyl or pyridinyl;

R 1 is hydrogen;

R 2 is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , —OH or —SH;

R 3 is lower alkyl or haloalkyl;

R 4 is hydrogen;

m is 0 to 5;

q is 1; and

r is 0.

4. The compound of claim 1 , wherein

X 1 is absent or 0;

Ar 1 is phenyl;

Ar 2 is substituted phenyl;

R 1 is hydrogen;

R 2 is lower alkoxy,

R 3 is lower alkyl;

R 4 is hydrogen;

q is 1; and

r is 0 to 1.

5. The compound of claim 1 , wherein

X 1 is absent or 0;

Ar 1 is phenyl;

Ar 2 is substituted phenyl;

R 1 is hydrogen;

R 2 is methoxy;

R 3 is methyl;

R 4 is hydrogen;

q is 1; and

r is 0 to 1.

6. The compound of claim 1 , wherein q is 1.

7. The compound of claim 1 , wherein Ar 1 is substituted or unsubstituted phenyl.

8. The compound of claim 1 , wherein Ar 2 is 4-trifluoromethylphenyl.

9. The compound of claim 1 , wherein:

R 1 , R 2 , R 3 , and R 4 are selected from hydrogen, alkyl, or alkoxy.

10. The compound of claim 1 , wherein:

R 2 and R 3 are hydrogen; and

R 1 and R 4 are alkyl or alkoxy.

11. The compound of claim 1 , wherein:

R 1 is alkyl;

R 2 and R 3 are hydrogen; and

R 4 is alkoxy.

12. The compound of claim 1 , wherein:

R 1 is methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl;

R 2 and R 3 are hydrogen; and

R 4 is methyoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, or isobutoxy.

13. A compound selected from:

[4-Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]acetic acid;

[4-(2′,4′-Dichloro-biphenyl-4′-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;

{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;

{(5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-acetic acid;

{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-acetic acid;

[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-acetic acid;

[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-acetic acid;

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

{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy]-acetic acid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;

and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof admixed with a carrier, diluent, or excipient.

15. A method of treating or controlling dyslipidemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

16. A method of treating or controlling hypercholesteremia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

17. A method of treating or controlling atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

18. A method of treating or controlling hypertriglyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

19. A method of making a compound of claim 1 of a pharmaceutically acceptable salt thereof, comprising, reacting:

wherein:

X 1 is OH or SH;

X 1 is absent, O or S;

Ar 1 and Ar 2 are each independently a unsubstituted or substituted phenyl or pyridinyl;

 is absent;

R 1 and R 2 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) p CF 3 , halogen, nitro, cyano, —OH, SH or —CF 3 ;

R 3 and R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) p CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;

R 11 is a lower alkyl;

X is a halogen;

m is 0 to 5;

q is 0 to 1; and

r is 0 to 1.

20. A process for preparing the compound of formula I-4 which is:

or a pharmaceutically acceptable salt thereof comprising:

(a) conversion of phenol 1A to the thiocyante 1B;

(b) alkylation of phenol moiety of thiocyanate 1B to acetoxyester 1C;

(c) reduction of the thiocyanate moiety in 1C to form thiol 1D;

(d) alkylation of thiol 1D with chloride 3C to form 4a;

(e) saponification of the ester moiety in 4a to form I-4;

wherein

R 1 is hydrogen;

R 2 is methoxy;

R 3 is hydrogen or methyl;

R 4 is hydrogen;

X 1 is absent or O; and

r is 0 or 1.

21. A compound having a formula I-4

or a pharmaceutically acceptable salt thereof, wherein

R 1 is hydrogen;

R 2 is methoxy;

R 3 hydrogen or methyl;

R 4 is hydrogen;

X 1 is absent or 0; and

r is 0 or 1.

22. A compound selected from the group consisting of:

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]acetic acid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;

{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid;

{(5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-acetic acid;

(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy}-acetic acid;

[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;

{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid; and pharmaceutically acceptable salts thereof.

23. The compound:

{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid; and pharmaceutically acceptable salts thereof.

24. The compound:

{(5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-acetic acid; and pharmaceutically acceptable salts thereof.