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

Abstract

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR modulators to treat or inhibit the progression of, for example, dyslipidemia.

1 . A compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     Wherein
 m is 1, 2 or 3; 
 n is 0 or 1; 
 X is S or O; 
 Y is S, CH 2  or O; 
 R 1  and R 2  are independently selected from H, C 1-4  alkyl C 1-3  alkoxy, halo, and —NR a R b , wherein each of R a  and R b  is independently selected from H and C 1-4  alkyl; 
 each of R 3  and R 4  is independently selected from H, halo, cyano, C 1-4  alkyl C 1-3  alkoxy, and NR c R d , wherein each of R c  and R d  is independently selected from H and C 1-4  alkyl; and wherein at least one of R 3  and R 4  is not H; and 
 each of R 5  and R 6  is independently selected from H, C 1-5  alkyl C 1-5  alkoxy, C 3-5  cycloalkyl, (C 3-5  cycloalkyl)C 1-3  alkyl and NR e R f , wherein each of R e  and R f  is independently selected from H and C 1-4  alkyl; or R 5  and R 6  together to form spiro C 3-6  cycloalkyl, or spiro 5- or 6-membered heterocyclyl having between 1 and 3 heteroatoms selected from O, S, and N; and 
 each of R 7  and R 8  is independently selected from H, C 1-5  alkyl and C 3-5  cycloalkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       2 . A compound of  claim 1 , wherein m is 1 or 2. 
   
   
       3 . A compound of  claim 1 , wherein m is 1. 
   
   
       4 . A compound of  claim 1 , wherein n is 1. 
   
   
       5 . A compound of  claim 1 , wherein X is O. 
   
   
       6 . A compound of  claim 1 , wherein Y is S or O. 
   
   
       7 . A compound of  claim 1 , wherein Y is S. 
   
   
       8 . A compound of  claim 1 , wherein Y is O. 
   
   
       9 . A compound of  claim 1 , wherein R 1  is selected from H, C 1-2  alkyl C 1-2  alkoxy and halo. 
   
   
       10 . A compound of  claim 1 , wherein R 1  is selected from halo, methyl, and methoxy, and if methyl or methoxy, R 1  may be substituted or unsubstituted. 
   
   
       11 - 26 . (canceled) 
   
   
       27 . A compound of  claim 1 , selected from: 
     2-Methyl-2-{2-methyl-4-[3-(4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethoxy]-phenoxy}-propionic acid, 
     2-Methyl-2-{2-methyl-4-[3-(4-trifluoromethoxy-phenyl)-[1,2,4]thiadiazol-5-ylmethoxy]-phenoxy}-propionic acid, 
     2-Methyl-2-[2-methyl-4-(3-p-tolyl-[1,2,4]thiadiazol-5-ylmethylsulfanyl)-phenoxy]-propionic acid, 
     2-{4-[3-(4-tert-Butyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(4-Chloro-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionicacid, 
     2-{4-[3-(3-Chloro-4-trifluoromethoxy-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(3,4-Dichloro-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(2,4-Dichloro-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(3,4-Dimethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(3-Chloro-4-methyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[3-(3-Fluoro-4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     1-{2-Methyl-4-[3-(4-trifluoromethoxy-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-phenoxy}-cyclopentanecarboxylic acid, 
     1-{4-[3-(3,4-Dichloro-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-cyclopentanecarboxylic acid, 
     2-Methyl-2-{2-methyl-4-[5-(4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-3-ylmethylsulfanyl]-phenoxy}-propionic acid, 
     2-{4-[5-(4-Chloro-phenyl)-[1,2,4]thiadiazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-{4-[5-(4-Isopropyl-phenyl)-[1,2,4]thiadiazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-Methyl-2-{2-methyl-4-[5-(4-trifluoromethoxy-phenyl)-[1,2,4]thiadiazol-3-ylmethylsulfanyl]-phenoxy}-propionic acid, 
     2-{4-[5-(4-tert-Butyl-phenyl)-[1,2,4]thiadiazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid, 
     2-Methyl-2-{2-methyl-4-[3-(4-trifluoromethoxy-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-phenoxy}-propionic acid, 
     {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid, 
     2-Methyl-2-{2-methyl-4-[3-(4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-phenoxy}-propionic acid, and 
     2-Methyl-2-{4-[3-(4-trifluoromethyl-phenyl)-[1,2,4]thiadiazol-5-ylmethylsulfanyl]-phenoxy}-propionic acid. 
   
   
       28 - 40 . (canceled) 
   
   
       41 . A method for treating or inhibiting the progression of a PPAR-delta mediated condition or a PPAR-alpha mediated condition, or both, said method comprising administering to a patient in need of treatment a pharmaceutically effective amount of a composition of  claim 27 . 
   
   
       42 . A method of  claim 41 , wherein the PPAR-delta mediated condition is selected from hyperlipidemia, atherosclerosis, cardiovascular disease, hypercholesteremia, type II diabetes, insulin resistance, impaired glucose tolerance, dyslipidemia, low-HDL-C, hypertriglyceridemia, and a PPAR-alpha mediated condition is selected from Syndrome X (or Metabolic Syndrome), dyslipidemia, high blood pressure, obesity, and impaired fasting glucose, insulin resistance, type II diabetes, atherosclerosis, hypercholesteremia, hypertriglyceridemia, and low-HDL-C. 
   
   
       43 - 45 . (canceled)