SUBSTITUTED IMIDAZO[1,5-a]PYRAZINES AS CGRP RECEPTOR ANTAGONISTS

Abstract

The disclosure generally relates to the novel compounds of formula I, including pharmaceutically acceptable salts, which arc CGRP-receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         where: 
         R 1  is hydrogen, alkyl, cycloalkyl, or (Ar 2 )alkyl; 
         R 2  is piperidinyl substituted with 1 substituent selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; 
         R 4  is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; 
         Ar 1  is indazolyl substituted with 0-1 substituents selected from the group consisting of halo, alkyl, and haloalkyl; 
         Ar 2  is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and 
         X is O, CH 2 , or NH; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of  claim 1  where R 1  is hydrogen, alkyl, cycloalkyl, or (Ar 2 )alkyl; R 2  is piperidinyl substituted with 1 substituent selected from the group consisting of 
       
         
           
           
               
               
           
         
         R 3  is hydrogen; R 4  is hydrogen; Ar 1  is indazolyl substituted with 1 alkyl substituent; 
         Ar 2  is phenyl; and X is O; or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of  claim 1  where R 1  is hydrogen, ethyl, cyclohexyl, or benzyl;
 R 2  is piperidinyl substituted with 1 
 
       
         
           
           
               
               
           
         
         substituent; R 3  is hydrogen; R 4  is hydrogen; Ar 1  is indazolyl substituted with 1 methyl substituent; Ar 2  is phenyl; and X is O; or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A compound of  claim 1  where R 1  is hydrogen, ethyl, cyclohexyl, or benzyl. 
     
     
         5 . A compound of  claim 1  where R 2  is piperidinyl 4-substituted with 1 substituent selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of  claim 1  where Ar 1  is indazolyl substituted with 1 alkyl substituent. 
     
     
         7 . A compound of  claim 1  where Ar 2  is phenyl. 
     
     
         8 . A compound of claim I where X is O. 
     
     
         9 . A composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         10 . A method of treating a condition associated with aberrant levels of CORP comprising the administration of a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a patient. 
     
     
         11 . The method of  claim 10  where the condition is migraine.