Phenoxymethyl heterocyclic compounds

Abstract

Phenoxymethyl compounds that inhibit at least one phosphodiesterase 10 are described as are pharmaceutical compositions containing such compounds an methods for treating various CNS disorders by administering such compounds to a patient in need thereof.

What is claimed is: 
     
         1 . A compound of Formula (I) and pharmaceutically acceptable salts thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         HET is selected from A29 and A31 
       
       
         
           
           
               
               
           
         
         wherein the left most radical is connected to the X group in Formula (I); 
         X is selected from optionally substituted aryl and optionally substituted heteroaryl, wherein the substituents are selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, C 1 -C 4  alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4  cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro; and 
         Z is selected from pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl, each of which can be optionally substituted, wherein the substituents are selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, C 1 -C 4  alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4  cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro; and 
         each R 2  is independently selected from optionally fluoro substituted C 1 -C 4  alkyl or two R 2  groups taken together with the carbon to which they are attached form a 3 membered cycloalkyl ring. 
       
     
     
         2 - 35 . (canceled) 
     
     
         36 . A method for making 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof, the method comprising using Suzuki coupling to obtain 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof from 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one. 
     
     
         37 . The method of  claim 36 , conducted in a polar solvent mixture. 
     
     
         38 . The method of  claim 37 , wherein the polar solvent mixture comprises water. 
     
     
         39 . The method of  claim 36 , conducted in the presence of a catalyst. 
     
     
         40 . The method of  claim 39 , wherein the catalyst is a palladium(0) or palladium(II) catalyst. 
     
     
         41 . The method of  claim 36  conducted in the presence of a base. 
     
     
         42 . The method of  claim 41 , wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate. 
     
     
         43 . The method of  claim 36 , further comprising isolating 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof. 
     
     
         44 . A method for making 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof,
 the method comprising contacting 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one   with a compound of formula   
       
         
           
           
               
               
           
         
       
       to provide 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof. 
     
     
         45 . The method of  claim 44 , conducted in a polar solvent. 
     
     
         46 . The method of  claim 45 , wherein the polar solvent is CH 3 CN or DMF. 
     
     
         47 . The method of  claim 44  conducted in the presence of a base. 
     
     
         48 . The method of  claim 47 , wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate. 
     
     
         49 . The method of  claim 44 , further comprising isolating 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof. 
     
     
         50 . A method for making 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof,
 the method comprising reducing 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one to provide 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.   
     
     
         51 . The method of  claim 50 , conducted in the presence of a catalyst. 
     
     
         52 . The method of  claim 51 , wherein the catalyst is a palladium(0) or palladium(II) catalyst. 
     
     
         53 . The method of  claim 50 , conducted in the presence of hydrogen. 
     
     
         54 . The method of  claim 50 , further comprising isolating 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.