Imidazopyridine compounds as 5-HT4 receptor modulators

Abstract

This invention provides a compound of the formula (I): or the pharmaceutically acceptable salts thereof wherein R 1 is hydrogen, halo or alkyl; R 2 and R 3 are independently hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl or hydroxyalkyl; or R 2 and R 3 taken together with the nitrogen atom to which they are E attached may form hetrocyclic; R 4 is hydrogen, halo, acyl, amino, amido, aryl, arylalkyl, or heteroaryl; R 5 is hydrogen, halo, alkyl, alkenyl, alkynyl, acyl, amino, amido, aryl, arylalkyl, or heteroaryl; R 6 is hydrogen, alkyl or alkoxyalkyl; X is NR 9 wherein R 9 is hydrogen or alkyl; and Y is (CR 7 R 8 ) n wherein n is an integer from 0 to 5. These compounds have 5-HT 4 receptor binding activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans. This invention also provides a pharmaceutical composition comprising the above compound.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts thereof wherein 
 R 1  is hydrogen, halo or C 1-6  alkyl;  
 R 2  and R 3  are independently hydrogen, C 1-6  alkyl C 2-6  alkenyl, C 2-6  alkynyl, mono- or di-(C 1-5 )alkyl amino, amino(C 1-5 )alkyl or hydroxy(C 1-5 )alkyl; or R 2  and R 3  taken together with the nitrogen atom to which they are attached may form substituted or non-substituted nitrogen-containing hetrocyclic;  
 R 4  is hydrogen, halo, C 1-8  acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C 1-6 )alkyl, or substituted or non-substituted heterocyclic;  
 R 5  is hydrogen, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-8  acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C 1-6 )alkyl, or substituted or non-substituted heterocyclic;  
 R 6  is hydrogen, C 1-6  alkyl or C 1-6  alkoxy (C 1-6 )alkyl;  
 X is NR 9  wherein R 9  is hydrogen or C 1-6  alkyl; and  
 Y is (CR 7 R 8 ) n  wherein R 7  and R 8  are independently hydrogen or C 1-6  alkyl, and n is an integer from 0 to 5.  
 
     
     
         2 . A compound according to  claim 1 , wherein 
 R 1  is hydrogen, halo or C 1-3  alkyl;    R 2  and R 3  are independently hydrogen, C 1-3  alkyl, mono- or di-(C 1-5 )alkyl amino, amino(C 1-5 )alkyl or hydroxy(C 1-5 )alkyl; or R 2  and R 3  taken together with the nitrogen atom to which they are attached may form substituted or non-substituted nitrogen containing hetrocyclic;    R 4  is hydrogen, halo, C 1-3  acyl, substituted or non-substituted aryl, substituted or non-substituted aryl(C 1-3 )alkyl, or substituted or non-substituted heterocyclic;    R 5  is hydrogen, halo, C 1-3  alkyl, C 1-3  acyl, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C 1-3 )alkyl, or substituted or non-substituted heterocyclic;    R 6  is hydrogen, C 1-5  alkyl or C 1-3  alkoxy (C 1-5 )alkyl;    X is NR 9 ; and Y is (CR 7 R 8 ) n , wherein R 7 , R 8  and R 9  are independently hydrogen or C 1-3  alkyl, and n is an integer from 0 to 3.    
     
     
         3 . A compound according to  claim 1 , wherein 
 R 1  is hydrogen or halo;    R 2  and R 3  are independently hydrogen or C 1-3  alkyl; or R 2  and R 3  taken together with the nitrogen atom to which they are attached may form hetrocyclic selected from morpholino, piperazino, piperidino, pyrrolidino, azetidino, pyrazolidino, (1,2,3,4)-tetrahydroisoqunolino and perhydroisoquinolino, which may be optionally substituted with halo, C 1-3  alkyl, C 1-3  alkoxy, mono- or di-(C 1-3 )alkyl amino or C 1-3  alkoxy(C 1-3 ) alkyl;    R 4  is hydrogen, halo, C 1-3  acyl, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C 1-3  alkyl and naphthyl C 1-3  alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C 1-3  alkyl, C 1-3  alkoxy, mono- or di-(C 1-3 )alkyl amino or C 1-3  alkoxy(C 1-3 ) alkyl;    R 5  is hydrogen, halo, C 1-3  alkyl, C 1-3  acyl, amido, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C 1-3  alkyl and naphthyl C 1-3  alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C 1-3  alkyl, C 1-3  alkoxy, mono- or di-(C 1-3 )alkyl amino or C 1-3  alkoxy(C 1-3 ) alkyl;    R 6  is C 1-5  alkyl or C 1-3  alkoxy (C 1-5 )alkyl;    X is NR 9 ; and Y is (CR 7 R 8 ) n , wherein R 7 , R 8 , and R 9  are independently hydrogen or methyl, and n is an integer from 0 to 2.    
     
     
         4 . A compound according to  claim 1 , wherein 
 R 1  is halo;    R 2  and R 3  are independently hydrogen or C 1-3  alkyl; or R 2  and R 3  taken together with the nitrogen to which they are attached may form hetrocyclic selected from morpholino, piperazino and piperidino;    R 4  is hydrogen, halo, C 1-3  acyl, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrrolyl;    R 5  is hydrogen, halo, C 1-3  alkyl, C 1-3  acyl, amido, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrrolyl;    R 6  is C 1-4  alkyl or C 1-3  alkoxy (C 1-4 )alkyl;    X is NH; and    Y is chemical bond or methylene.    
     
     
         5 . A compound according to  claim 1 , wherein 
 R 1  is chloro;    R 2  and R 3  are independently hydrogen or C 1-3  alkyl;    R 4  is hydrogen or halo;    R 5  is hydrogen, halo or C 1-3  alkyl;    R 6  is C 3-4  alkyl or methoxy (C 1-4 )alkyl;    X is NH; and    Y is methylene.    
     
     
         6 . A compound according to  claim 1  selected from 
 5-amino-N-[(1-butyl -4-piperidinyl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide;  
 5-amino-N-[(1-butyl-4-piperidinyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;  
 5-amino-6-chloro-N-[(1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide;  
 5-amino-N-[(1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide;  
 5-Amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxamide;  
 5-Amino-6-chloro-2-methyl-N-{1-[3-(methyloxy)propyl]-4-piperidinyl}imidazo[1,2-a]pyridine-8-carboxamide;  
 5-Amino-6-chloro-2-methyl-N-({1-[3-(methyloxy)propyl]-4-piperidinyl}methyl)imidazolo[1,2-a]pyridine-8-carboxyamide; and  
 salts thereof.  
 
     
     
         7 . A compound according to  claim 6  selected from 
 5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide;  
 5-amino-6-chloro-N-[(1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide; and  
 salts thereof.  
 
     
     
         8 . A pharmaceutical composition for the treatment or prevention of disease conditions mediated by 5-HT 4  receptor activity, in a mammalian subject, which comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         9 . A pharmaceutical composition for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, aausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder, which comprises a therapeutically effective amount of a compound of claim  1  and a pharmaceutically acceptable carrier.  
     
     
         10 . A method for the treatment or prevention of disease conditions mediated by 5-HT 4  receptor activity, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         11 . A method for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, aausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder, which comprises administering to said subject a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         12 . Use of a compound according to  claim 1  in the manufacture of a medicament for the treatment or prevention of disease conditions mediated by 5-HT 4  receptor activity, in a mammalian subject.  
     
     
         13 . Use of a compound according to  claim 12 , wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, aausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder.