Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor

Abstract

The present invention relates to processes for preparing pyrazole derivatives of Formula (I) and salts and pharmaceutical compositions of the salts thereof, useful as modulators of 5-HT 2A serotonin receptor activity. The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to salts of compounds of Formula (I) and pharmaceutical compositions thereof.

1 . A process for preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, comprising: 
         (a) reacting a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         
           or a salt thereof, with a compound of Formula (VII): 
         
       
       
         
           
           
               
               
           
         
         
           or a salt thereof, to form a compound of Formula (III): 
         
       
       
         
           
           
               
               
           
         
         
           or a salt thereof; 
         
         (b) reacting a compound of Formula (IV): 
       
       
         
           
           
               
               
           
         
         
           with a compound of Formula (V): 
         
       
       
         
           
           
               
               
           
         
         
           or a salt thereof, to form a compound of Formula (II): 
         
       
       
         
           
           
               
               
           
         
         
           or a salt thereof; and 
         
         (c) reacting said compound of Formula (II) or a salt thereof, with said compound of Formula (III) or a salt thereof, to form said compound of Formula (I) or a salt thereof; 
         wherein:
 R 1  is a halogen 
 R 2  is a leaving group; and 
 R 3  is a halogen; 
 
         provided that R 2  is a leaving group other than 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy. 
       
     
     
         2 . A process for preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  is halogen; 
 
         comprising reacting a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a compound of Formula (III): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 2  is a leaving group; 
 
         to form said compound of Formula (I) or a salt thereof; provided that R 2  is a leaving group other than 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy. 
       
     
     
         3 . The process according to  claim 2 , wherein said compound of Formula (I) is the S enantiomer. 
     
     
         4 . The process according to  claim 2 , wherein R 1  is chloro and R 2  is 1H-imidazol-1-yl. 
     
     
         5 . The process according to  claim 2 , wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in the presence of a base. 
     
     
         6 . The process according to  claim 2 , wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in the presence of a catalyst. 
     
     
         7 . The process according to  claim 2 , wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out at a temperature of about 20° C. to about reflux temperature. 
     
     
         8 . The process according to  claim 2 , wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in an amide-forming solvent. 
     
     
         9 . A process for preparing a compound of Formula (II): 
       
         
           
           
               
               
           
         
         or a salt thereof, comprising reacting a compound of Formula (IV): 
       
       
         
           
           
               
               
           
         
         wherein:
 R 3  is halogen; 
 
         with a compound of Formula (V): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, to form said compound of Formula (II) or a salt thereof. 
       
     
     
         10 . The process according to  claim 9 , wherein R 3  is bromo. 
     
     
         11 . The process according to  claim 9  wherein said compound of Formula (V) is the S enantiomer. 
     
     
         12 . A process for preparing a compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  is halogen; and 
 R 2  is a leaving group; 
 
         comprising reacting a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, to form said compound of Formula (III) or a salt thereof. 
       
     
     
         13 . The process according to  claim 12 , wherein R 1  is chloro and R 2  is 1H-imidazol-1-yl. 
     
     
         14 . A process for preparing a salt of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is halogen; 
 
         comprising reacting said compound of Formula (I) with a salt-forming acid to form said salt of a compound of Formula (I). 
       
     
     
         15 . The process according to  claim 14 , wherein said compound of Formula (I) is the S enantiomer. 
     
     
         16 . The process according to  claim 14 , wherein said salt of a compound of Formula (I) is the hydrochloride salt. 
     
     
         17 . The process according to  claim 14 , wherein R 1  is chloro. 
     
     
         18 . The process according to  claim 14 , wherein said reacting said compound of Formula (I) with a salt-forming acid is carried out in a salt-forming solvent. 
     
     
         19 . The process according to  claim 14 , wherein said reacting said compound of Formula (I) with a salt-forming acid is carried out at a temperature of about −10° C. to about reflux temperature. 
     
     
         20 . The process according to  claim 14 , wherein said salt-forming acid is hydrochloric acid. 
     
     
         21 . A hydrochloride salt of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is halogen. 
 
       
     
     
         22 . The hydrochloride salt according to  claim 21 , wherein said compound of Formula (I) is the S enantiomer. 
     
     
         23 . The hydrochloride salt according to  claim 21 , wherein R 1  is chloro. 
     
     
         24 . The hydrochloride salt according to  claim 21 , wherein said hydrochloride salt is (S)-2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanone hydrochloride, represented by the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A pharmaceutical composition comprising the hydrochloride salt according to  claim 21  together with a pharmaceutically acceptable carrier. 
     
     
         26 . A method for treating a 5-HT 2A  mediated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a the hydrochloride salt according to  claim 21 . 
     
     
         27 . A method for treating a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of the hydrochloride salt according to  claim 21 . 
     
     
         28 . A method for treating a sleep disorder selected from: a dyssomnia, insomnia or a parasomnia; or for increasing slow wave sleep, improving sleep consolidation or improving sleep maintenance in an individual comprising administering to said individual in need thereof a therapeutically effective amount of the hydrochloride salt according to  claim 21 . 
     
     
         29 - 35 . (canceled) 
     
     
         36 . A process for preparing a composition comprising admixing the hydrochloride salt according to  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         37 . A hydrobromide salt of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The hydrobromide salt according to  claim 37 , wherein said compound of Formula (II) is the S enantiomer. 
     
     
         39 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  is halogen; and 
 R 2  is 1H-imidazol-1-yl. 
 
       
     
     
         40 . The compound according to  claim 39 , wherein R 1  is chloro.