Phenyloxadiazole derivatives as pgds inhibitors

Abstract

This invention is directed to a compound of formula (I): wherein R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising the compound, intermediates and processes for making said compounds, and the use of the compound to treat allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD) and age-related macular degeneration (AMD).

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
        wherein
 R1 is hydrogen or C 1 -C 6 alkyl; 
 R2 is hydrogen, halogen or C 1 -C 3 alkyl; and 
 R3 is hydroxyalkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R1 is hydrogen, R2 is hydrogen and R3 is hydroxyalkyl. 
     
     
         3 . The compound of  claim 2  which is 2-pyridin-2-yl-pyrimidine-5-carboxylic acid 3-5-(1-hydroxy-1methyl-ethyl)[1,2,4]oxadiazol-3-yl]benzyl amide. 
     
     
         4 . The compound of  claim 1 , where R1 is C 1 -C 6 alkyl, R2 is hydrogen and R3 is hydroxyalkyl. 
     
     
         5 . The compound of  claim 4  selected from the group consisting of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((S)-1- f 3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide and 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((R)-1- f 3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide. 
     
     
         6 . A pharmaceutical composition comprising the compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . A method for treating an allergic or inflammatory disorder in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1 . 
     
     
         8 . The method according to  claim 7 , wherein the allergic or inflammatory disorder is selected from the group consisting of allergic rhinitis, asthma, chronic obstructive pulmonary disease and age-related macular degeneration. 
     
     
         9 . A process for preparing a compound according to  claim 1   comprising the step of reacting a compound of formula XI                         wherein R1, R2 and R3 are as defined in  claim 1 ,   with an acid compound of formula                          in the presence of a suitable coupling reagent.   
     
     
         10 . The process of  claim 9 , wherein the compound according to  claim 1  is
                     
 and the compound of formula XI is 
                     
. 
     
     
         11 . The process of  claim 10 , wherein the suitable coupling reagent is selected from the group consisting of DMTMM, CDI, and TBTU. 
     
     
         12 . A process for preparing a compound according to  claim 1   comprising the step of reacting a compound of formula XI                         wherein R1, R2 and R3 are as defined in  claim 1 ,   with an ester compound of formula                         wherein R4 is C 1 -C 3 alkyl,   in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).   
     
     
         13 . The process of  claim 12 , wherein the compound according to  claim 1  is 
       
         
           
           
               
               
           
         
       
        and the compound of formula XI is 
       
         
           
           
               
               
           
         
       
       . 
     
     
         14 . The process of  claim 13 , wherein R4 of the ester compound is CH 3 . 
     
     
         15 . A process for preparing a compound according to  claim 1  comprising the step of reacting a compound of formula XI
                     
 wherein R1, R2 and R3 are as defined in  claim 1 , 
 with an acid chloride compound of formula 
 
       
         
           
           
               
               
           
         
       
       . 
     
     
         16 . The process of  claim 15 , wherein the compound according to  claim 1  is
                     
 and the compound of formula XI is 
                     
. 
     
     
         17 - 20 . (canceled) 
     
     
         21 . A compound of formula
                       wherein R2 is hydrogen, halogen or C 1 -C 3 alkyl; and   R3 is hydroxyalkyl;   or an acid addition salt thereof.   
     
     
         22 . The compound of  claim 21  that is
                     
 or an acid addition salt thereof. 
. 
     
     
         23 . The compound of  claim 22 , wherein the acid salt is the hydrochloride salt. 
     
     
         24 . A process for preparing a compound of formula
                       wherein R2 is hydrogen, halogen or C 1 -C 3 alkyl; and   R3 is hydroxyalkyl;   comprising the step of reducing an oxime compound of formula                         wherein R2 is hydrogen, halogen or C 1 -C 3 alkyl; and   R3 is hydroxyalkyl.