Imidazoyl pyridine compounds and salts thereof

Abstract

A compound represented by the formula (I): or a pharmacologically acceptable salt thereof, wherein Ar 1 represents an imidazolyl group or the like which may be substituted with a C1-6 alkyl group, Ar 2 represents a phenyl group or the like which may be substituted with a C1-6 alkoxy group, X 1 represents a double bond or the like and Het represents a triazolyl group or the like which may be substituted with a C1-6 alkyl group or the like, is effective as a therapeutic or prophylactic agent for a disease caused by Aβ.

1 . A compound represented by the formula (I-1): 
       
         
           
           
               
               
           
         
         or a pharmacologically acceptable salt thereof, 
         wherein 
         X 1  represents —CR 1 ═CR 2 — (wherein R 1  and R 2  are the same or different and each represent (1) a hydrogen atom, (2) a C1-6 alkyl group or (3) a halogen atom) and Het represents a group which may be substituted with 1 to 3 substituents selected from a C1-6 alkyl group, a halogen atom, a hydroxyl group and a cyano group, and is represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are the same or different and each represents a substituent selected from Substituent Group A1, X 2  represents a methylene group which may be substituted with a substituent selected from Substituent Group A1, or an oxygen atom and n a  represents an integer of 0 to 2; 
         Substituent Group A1: 
         (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A2, and (6) A*(wherein A* represents an aromatic hydrocarbon ring selected from a phenyl group and a naphthyl group, and a benzodioxolyl group, which may be substituted with 1 to 3 substituents selected from Substituent Group A2; 
         Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 halogen atoms) and (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl group which may be substituted with 1 to 3 halogen atoms). 
       
     
     
         2 . The compound or pharmacologically acceptable salt thereof according to  claim 1 , wherein Het represents a group which may be substituted with 1 to 3 substituents selected from a C1-6 alkyl group, a halogen atom, a hydroxyl group and a cyano group, and is represented by one of the following formulas: 
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         3 . The compound or pharmacologically acceptable salt thereof according to  claim 1 , wherein Het represents a group which may be substituted with 1 to 3 substituents selected from a C1-6 alkyl group, a halogen atom, a hydroxyl group and a cyano group, and is represented by one of the following formulas: 
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         4 . The compound or pharmacologically acceptable salt thereof according to  claim 2 , wherein R 3  is selected from the group consisting of a phenyl group and a naphthyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a methyl group, trifluoromethyl group and trifluoromethoxy group, and R 4  is selected from the group consisting of a hydrogen atom, a hydroxyl group, a cyano group and a methyl group. 
     
     
         5 . The compound or pharmacologically acceptable salt thereof according to  claim 2 , wherein the compound is selected from the group consisting of:
 1) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyridine,   2) (−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   3) (−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   4) (−)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   5) (+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   6) (+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   7) (−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   8) (−)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   9) (+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   10) (−)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   11) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   12) (+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   13) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   14) (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   15) (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,   16) (−)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   17) (−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   18) (−)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   19) (−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   20) (−)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   21) (−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   22) (−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   23) (5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   24) (5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   25) (S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole, and   26) (S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,   27) (−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   28) (−)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   29) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine, and   30) (−)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine.   
     
     
         6 . The compound or pharmacologically acceptable salt thereof according to  claim 2 , wherein the compound is selected from the group consisting of:
 1) (−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   2) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   3) (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   4) (−)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   5) (−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   6) (−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   7) (−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   8) (5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   9) (5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   10) (−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,   11) (−)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,   12) (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine, and   13) (−)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine.   
     
     
         7 . A pharmaceutical composition comprising:
 the compound or pharmacologically acceptable salt thereof according to  claim 1  as an active ingredient; and   a pharmaceutically acceptable carrier.