Indole and azaindole modulators of the alpha 7 nAChR

Abstract

This invention relates to modulation of the α7 nicotinic acetylcholine receptor (nAChR) by a compound of formula (I): or a pharmaceutically acceptable salt thereof.

1 - 26 . (canceled) 
     
     
         27 . A method of treating a psychotic disorder in a human comprising administering an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is independently selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl and halo; 
 R 2  is independently selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, halo, acetyl, cyano, CH 2 CN and cyclopropyl; and 
 X is CH or N; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         28 . The method of  claim 27 , wherein R 1  is H, fluoro or methyl. 
     
     
         29 . The method of  claim 27 , wherein R 2  is haloC 1-6 alkyl. 
     
     
         30 . The method of  claim 27 , wherein R 2  is selected from C 2-3 alkyl, fluoroC 1-3 alkyl, chloro, acetyl, cyano, CH 2 CN and cyclopropyl. 
     
     
         31 . The method of  claim 27 , wherein X is N. 
     
     
         32 . The method of  claim 27 , wherein the compound is of the formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 27 , wherein the compound is:
 6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinecarbonitrile;   6-(1,1-dimethylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   [6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinyl]acetonitrile;   1-[6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinyl]ethanone;   6-(1,1-difluoroethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoroethyl)-N-{([2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(difluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(fluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-chloro-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-cyclopropyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoro-1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-5-fluoro-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-chloro-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-ethyl-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoroethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1,1-difluoroethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   5-methyl-6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(difluoromethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(fluoromethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-cyclopropyl-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   or a pharmaceutically acceptable salt thereof.   
     
     
         34 . The method of  claim 27 , wherein the compound is:
 6-(1-fluoroethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-(1-fluoro-1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   or a pharmaceutically acceptable salt thereof.   
     
     
         35 . A method of treating cognitive impairment in a human comprising administering an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is independently selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl and halo; 
 R 2  is independently selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, halo, acetyl, cyano, CH 2 CN and cyclopropyl; and 
 X is CH or N; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         36 . The method of  claim 35 , wherein R 1  is H, fluoro or methyl. 
     
     
         37 . The method of  claim 35 , wherein R 2  is haloC 1-6 alkyl. 
     
     
         38 . The method of  claim 35 , wherein R 2  is selected from C 2-3 alkyl, fluoroCl 1-3 alkyl, chloro, acetyl, cyano, CH 2 CN and cyclopropyl. 
     
     
         39 . The method of  claim 35 , wherein X is N. 
     
     
         40 . The method of  claim 35 , wherein the compound is of the formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         41 . The method of  claim 35 , wherein the compound is:
 6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinecarbonitrile;   6-(1,1-dimethylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   [6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinyl]acetonitrile;   1-[6-({[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}amino)-4-pyrimidinyl]ethanone;   6-(1,1-difluoroethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoroethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(difluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(fluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-chloro-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-cyclopropyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoro-1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-5-fluoro-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}4-pyrimidinamine;   6-chloro-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-ethyl-N-{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}-4-pyrimidinamine;   6-ethyl-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-fluoroethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(1-(fluoroethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   5-methyl-6-(trifluoromethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(difluoromethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   6-(fluoromethyl)-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-cyclopropyl-5-methyl-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   or a pharmaceutically acceptable salt thereof.   
     
     
         42 . The method of  claim 35 , wherein the compound is:
 6-(1-fluoroethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine; or   6-(1-fluoro-1-methylethyl)-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine;   or a pharmaceutically acceptable salt thereof.   
     
     
         43 . A method of treating pain in a human comprising administering an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is independently selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl and halo; 
 R 2  is independently selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, halo, acetyl, cyano, CH 2 CN and cyclopropyl; and 
 X is CH or N; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         44 . The method of  claim 36 , wherein the pain is neuropathic pain.