Benzimidazole-carboxamide compounds as 5-ht4 receptor agonists

Abstract

The invention relates to benzimidazole-carboxamide 5-HT 4 receptor agonist compounds of formula (I) wherein R 1 and X are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention also relates to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

1 - 22 . (canceled) 
     
     
         23 . A method of studying a biological system or sample comprising a 5-HT 4  receptor, the method comprising:
 (a) contacting the biological system or sample with a compound of formula (I):   
       
         
           
           
               
               
           
         
         R 1  is C 3-4 alkyl; and 
         X is selected from:
 (a) —C(O)OR 2  wherein R 2  is C 1-3 alkyl or phenyl; 
 (b) —C(O)R 3  wherein R 3  is phenyl, optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl, halo, and —CF 3 ; furanyl; or thiophenyl; 
 (c) —C(O)NR 4 R 5  wherein R 4  is hydrogen and R 5  is phenyl optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl and halo; 
 (d) —C(O)C(R 6 R 7 )R 8  wherein R 6  is hydrogen and R 7  is hydrogen, —OH, or methyl; or R 6  and R 7  taken together form oxo or —(CH 2 ) 2 —; and R 8  is phenyl or cyclohexyl, wherein phenyl or cyclohexyl are optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl and halo; 
 (e) —C(O)C(HR 9 )OR 10  wherein R 9  is hydrogen or methyl and R 10  is phenyl optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl and halo; and 
 (f) —S(O) 2 R 11  wherein R 11  is methyl or phenyl, optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl and halo; 
 
         or a pharmaceutically-acceptable salt thereof; and 
         (b) determining the effect caused by the compound on the biological system or sample. 
       
     
     
         24 . The method of  claim 23  wherein in the compound of formula (I),
 R 1  is isopropyl or tert-butyl; and 
 X is selected from:
 (a) —C(O)OR 2  wherein R 2  is methyl or phenyl; 
 (b) —C(O)R 3  wherein R 3  is phenyl, optionally substituted with 1 or 2 substituents selected from methyl, chloro, fluoro, and —CF 3 ; furan-2-yl; or thiophen-2-yl; and 
 (c) —C(O)NR 4 R 5  wherein R 4  is hydrogen and R 5  is phenyl optionally substituted with 1 fluoro or chloro.