Novel compounds, their preparation and use

Abstract

Novel compounds of the general formula (I), the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR), in particular the PPARδ suptype.

1 - 16 . (canceled) 
     
     
         17 . A method for treating conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR), the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X 1  is aryl or heteroaryl each of which is optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylcarbonyl, arylcarbonyl, C 1-6 -alkylsulfonyl, arylsulfonyl, C 1-6 -alkylsulfonyloxy, arylsulfonyloxy, C 1-6 -alkylamido, arylamido, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         X 2  is arylene or heteroarylene each of which is optionally substituted with one or more substituents, where said substituents independently are
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-6 -alkylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         X 3  is aryl or heteroaryl each of which is optionally substituted with one or more substituents, where said substituents are
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylcarbonyl, arylcarbonyl, C 1-6 -alkylsulfonyl, arylsulfonyl, C 1-6 -alkylsulfonyloxy, arylsulfonyloxy, C 1-6 -alkylamido, arylamido, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         Ar is arylene which is optionally substituted with one or more substituents, where said substituents are
 a) halogen, hydroxy or cyano; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio or C 3-6 -cycloalkylthio each of which is optionally substituted with one or more halogens; and 
 
         Y 1  is O or S; and 
         Y 2  is O or S; and 
         Z is —(CH 2 ) n — wherein n is 1, 2 or 3; and 
         R 1  is hydrogen, halogen or a substituent which is
 a) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio or C 3-6 -cycloalkylthio each of which is optionally substituted with one or more halogens; and 
 
         R 2  is hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl. 
       
     
     
         18 . The method according to  claim 17  wherein the compound is packaged in a unit dosage form, where the unit dosage form comprises from 0.05 mg to 1000 mg, or from 0.1 to 500 mg, or from 0.5 mg to 200 mg of the compound. 
     
     
         19 . The method according to  claim 17 , wherein X 1  is aryl or heteroaryl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, aryl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         20 . The method according to  claim 19 , wherein X 1  is phenyl, furyl, thienyl, benzothienyl or benzofuranyl optionally substituted with one or more substituents, where said substituents are
 a) halogen; or   b) C 1-6 -alkyl, aryl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         21 . The method according to  claim 17 , wherein X 2  is arylene or heteroarylene optionally substituted with one or more substituents, where said substituents are
 a) halogen; or   b) C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more halogens.   
     
     
         22 . The method according to  claim 21 , wherein X 2  is phenylene optionally substituted with one or more substituents, where said substituents independently are
 a) halogen; or   b) C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more halogens.   
     
     
         23 . The method according to  claim 17 , wherein X 3  is aryl or heteroaryl optionally substituted with one or more substituents selected from, where said substituents independently are
 a) halogen; or   b) C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         24 . The method according to  claim 23 , wherein X 3  is phenyl, furyl, thienyl, benzothienyl or benzofuranyl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         25 . A method for treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X 1  is aryl or heteroaryl each of which is optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylcarbonyl, arylcarbonyl, C 1-6 -alkylsulfonyl, arylsulfonyl, C 1-6 -alkylsulfonyloxy, arylsulfonyloxy, C 1-6 -alkylamido, arylamido, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         X 2  is arylene or heteroarylene each of which is optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-6 -alkylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         X 3  is aryl or heteroaryl each of which is optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen, hydroxy, cyano, amino or carboxy; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio, C 3-6 -cycloalkylthio, C 1-6 -alkylcarbonyl, arylcarbonyl, C 1-6 -alkylsulfonyl, arylsulfonyl, C 1-6 -alkylsulfonyloxy, arylsulfonyloxy, C 1-6 -alkylamido, arylamido, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylamino, C 1-6 -dialkylamino or C 3-6 -cycloalkylamino each of which is optionally substituted with one or more halogens; and 
 
         Ar is arylene which is optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen, hydroxy or cyano; or 
 b) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio or C 3-6 -cycloalkylthio each of which is optionally substituted with one or more halogens; and 
 
         Y 1  is O or S; and 
         Y 2  is O or S; and 
         Z is —(CH 2 ) n — wherein n is 1, 2 or 3; and 
         R 1  is hydrogen, halogen or a substituent which is
 a) C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aralkyl, heteroaralkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy, C 1-6 -alkylthio, arylthio or C 3-6 -cycloalkylthio each of which is optionally substituted with one or more halogens; and 
 
         R 2  is hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl. 
       
     
     
         26 . The method according to  claim 25  wherein the compound is packaged in a unit dosage form, where the unit dosage form comprises from 0.05 mg to 1000 mg, or from 0.1 to 500 mg, or from 0.5 mg to 200 mg of the compound. 
     
     
         27 . The method according to  claim 25 , wherein X i  is aryl or heteroaryl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, aryl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         28 . The method according to  claim 27 , wherein X i  is phenyl, furyl, thienyl, benzothienyl or benzofuranyl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, aryl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         29 . The method according to  claim 25 , wherein X 2  is arylene or heteroarylene optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more halogens.   
     
     
         30 . The method according to  claim 29 , wherein X 2  is phenylene optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more halogens.   
     
     
         31 . The method according to  claim 25 , wherein X 3  is aryl or heteroaryl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.   
     
     
         32 . The method according to claim  15 , wherein X 3  is phenyl, furyl, thienyl, benzothienyl or benzofuranyl optionally substituted with one or more substituents, where said substituents independently are:
 a) halogen; or   b) C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylsulfonyl or C 1-6 -alkylsulfonyloxy each of which is optionally substituted with one or more halogens.