Isoxazolo-pyrazine derivatives

Abstract

The invention relates to isoxazolo-pyrazine derivatives and their pharmaceutically acceptable salts having affinity and selectivity for the GABA A α5 receptor binding site, their manufacture, and pharmaceutical compositions containing them. The compounds of present invention are inverse agonists of GABA A α5. The invention also relates to methods for enhancing cognition and for treating cognitive disorders like Alzheimer's disease.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       X is O or NH; 
       R 1  is phenyl, optionally substituted with one, two or three halo, 
       R 2  is H, C 1-4  alkyl or C 1-4  haloalkyl; 
       R 3  and R 4  each are independently
 H, 
 C 1-7  alkyl, optionally substituted with one or more halo, cyano, or hydroxy, 
 C 1-7  alkoxy, optionally substituted with one or more halo, 
 CN, 
 halo, 
 NO 2 , 
 —C(O)—R a , wherein R a  is hydroxy, C 1-7  alkoxy, C 1-7  alkyl, phenoxy or phenyl, —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, 
 C 1-7  alkyl, optionally substituted with one or more halo, hydroxy, or cyano, 
 —(CH 2 ) z —C 3-7  cycloalkyl, optionally substituted by one or more B, and z is 0, 1, 2, 3 or 4, 
 —(CH 2 ) y -heterocyclyl, wherein y is 0, 1, 2, 3 or 4, and wherein heterocyclyl is optionally substituted by one or more A 
 R b  and R c  together with the nitrogen to which they are bound form a heterocyclyl moiety, optionally substituted with one or more A, or 
 
 or R 3  and R 4  together form an annelated benzo ring, the benzo ring is optionally substituted by one or more E; 
 
       A is hydroxy, oxo, C 1-7  alkyl, C 1-7  alkoxy, C 1-7  haloalkyl, C 1-7  hydroxyalkyl, halo, or CN; 
       B is halo, hydroxy, CN, C 1-4  alkyl, or C 1-4  haloalkyl; 
       E is halo, CN, NO 2 , hydroxy, C 1-7  alkyl, C 1-7  alkoxy, C 1-7  haloalkyl, C 1-7  hydroxyalkyl, C 1-7  cyanoalkyl, C 1-7  haloalkoxy, or C 3-7  cycloalkyl, 
       or a pharmaceutically acceptable salt thereof.