Quinuclidine Compounds as Alpha-7 Nicotinic Acetylcholine Receptor Ligands

Abstract

The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

1 . A compound of formula I, or a stereoisomer thereof, 
       
         
           
           
               
               
           
         
       
       wherein R 1  is pyrrolotriazinyl substituted with 1 halo substituent; or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound of  claim 1 , or a stereoisomer thereof, wherein R 1  is N-(halopyrrolo[1,2-f][1,2,4]triazin-4-yl); or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A compound of  claim 1 , or a stereoisomer thereof, wherein R 1  is N-(7-halopyrrolo[1,2-f][1,2,4]triazin-4-yl); or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1 : (R)—N-(7-Bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         6 . The composition of  claim 5  where the compound of  claim 1  is (R)—N-(7-Bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         7 . A method for the treatment of schizophrenia, Alzheimer's Disease, cognitive disorders, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's Disease, or diabetes comprising administering a therapeutically affective amount of a compound of  claim 1  to a patient. 
     
     
         8 . The method of  claim 7  directed to schizophrenia. 
     
     
         9 . The method of  claim 8  where the compound of  claim 1  is (R)—N-(7-Bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 7  directed to Alzheimer's disease. 
     
     
         11 . The method of  claim 10  where the compound of  claim 1  is (R)—N-(7-Bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.