Diazole derivatives

Abstract

The present invention relates to diazole derivatives of the general formula wherein A, E, R 1 , R 2 and R 3 are as defined in application and pharmaceutical compositions containing them. The invention also relates to use of such compounds for the treatment of diseases mediated by the metabotropic glutamate receptors (mGluR), such as anxiety, chronic and acute pain, protection against liver damage, urinary incontinence, obesity, Fragile-X and autism, Alzheimer's disease, epilepsy, schizophrenia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDs, and Parkinson's disease.

1 . A compound of the formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 one of A or E is N and the other is C;  
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by  
 piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, oh, c 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound according to  claim 1  which is formula Ia:  
     
       
         
         
             
             
         
       
     
   
   
       3 . A compound according to  claim 1  which is formula Ib:  
     
       
         
         
             
             
         
       
     
   
   
       4 . A compound according to  claim 1 , wherein 
 R 1  is halogen;    R 2  is methyl or i-propyl;    R 3  is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl each of which is optionally substituted by one, two, or three chloro, fluoro, lower alkyl, lower alkoxy, cyano, lower haloalkyl, lower haloalkoxy or cycloalkyl; and    R 4  is CHF 2  or CH 2 R 5  wherein R 5  is hydrogen, OH or C 1 -C 6 -alkyl;    or a pharmaceutically acceptable salt thereof.    
   
   
       5 . A compound of formula Ia according to  claim 2 , wherein R 3  is unsubstituted or substituted heteroaryl, and wherein the substituents are selected from chloro, fluoro, CF 3 , and lower alkyl.  
   
   
       6 . A compound of formula Ia according to  claim 5  which is selected from the group consisting of: 
 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-5-methyl-pyridine;    2-Chloro-5-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-pyridine;    2-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-6-methyl-4-trifluoromethyl-pyridine;    2-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-pyrazine;    2-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-6-methyl-pyridine;    2-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-6-(trifluoromethyl)-pyridine; and    3-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1H-imidazol-1-yl]-5-fluoro-pyridine.    
   
   
       7 . A compound of formula Ia according to  claim 2 , wherein R 3  is aryl, substituted by one, two, or three chloro, fluoro, CF 3 , lower alkyl, lower alkoxy, CF 3 O or 1-morpholinyl.  
   
   
       8 . A compound of formula Ia in accordance with  claim 7  which is selected from the group consisting of: 
 2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(2,4-difluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3,5-difluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(4-fluoro-2-methyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(4-fluoro-3-methyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-(2,5-dimethyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine;    2-Chloro-4-[1-(3-chloro-4-methyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-fluoro-4-methoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(4-methoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(3-trifluoromethoxy-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(3-methyl-4-trifluoromethoxy-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(4-chloro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-chloro-2-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[5-difluoromethyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine;    [5-(2-Chloro-pyridin-4-ylethynyl)-3-(4-fluoro-phenyl)-2-methyl-3H-imidazol-4-yl]-methanol;    2-Chloro-4-[1-(4-methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3,5-difluoro-4-methoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(4-methoxy-3-trifluoromethoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-methoxy-4-trifluoromethoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    4-{3-[4-(2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-5-fluoro-phenyl}-morpholine;    2-Chloro-4-[1-(4-fluoro-2-trifluoromethoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(2-fluoro-4-trifluoromethoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(4-methyl-3-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(3-methyl-4-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[2,5-dimethyl-1-(3-methyl-5-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-methoxy-5-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-methoxy-4-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3,5-dichloro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-chloro-5-methyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-fluoro-5-methyl-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;    2-Chloro-4-[1-(3-chloro-5-methoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine; and    2-Chloro-4-[1-(3-fluoro-5-methoxy-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.    
   
   
       9 . A compound of formula Ib according to  claim 3 , wherein R 3  is aryl substituted by one, two, or three fluoro atoms.  
   
   
       10 . A compound of formula Ib in accordance with  claim 9 , which is 2-Chloro-4-[5-(4-fluoro-phenyl)-1,4-dimethyl-1H-pyrazol-3-ylethynyl]-pyridine.  
   
   
       11 . A process for preparing a compound of formula Ia which process comprises reacting a compound of formula II  
     
       
         
         
             
             
         
       
     
     with a compound of formula III  
     
       
         
         
             
             
         
       
     
     to obtain the compound of formula Ia;  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl.  
 X is halogen.  
 
   
   
       12 . A process for preparing a compound of formula Ia which process comprises reacting a compound of formula IV  
     
       
         
         
             
             
         
       
     
     with a compound of formula V  
     
       
         
         
             
             
         
       
     
     to obtain the compound of formula Ia;  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl.  
 X is halogen.  
 
   
   
       13 . A process for preparing a compound of formula Ia which process comprises reacting a compound of formula Ic  
     
       
         
         
             
             
         
       
     
     with a compound of formula VI  
       R 4 -X  (VI)  
     to obtain the compound of formula Ia;  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl.  
 X is halogen.  
 
   
   
       14 . A process for preparing a compound of formula Ib which process comprises reacting a compound of formula XXVI  
     
       
         
         
             
             
         
       
     
     with a compound of formula XXVII  
     
       
         
         
             
             
         
       
     
     to obtain a compound of formula XXVIII  
     
       
         
         
             
             
         
       
     
     and converting the compound of formula XXVIII into the compound of formula Ib;  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl.  
 
   
   
       15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 one of A or E is N and the other is C;  
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl;  
 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.  
 
   
   
       16 . A pharmaceutical composition according to  claim 15 , wherein the compound is a compound of formula Ia  
     
       
         
         
             
             
         
       
     
   
   
       17 . A pharmaceutical composition according to  claim 16 , wherein the compound is a compound of formula Ib  
     
       
         
         
             
             
         
       
     
   
   
       18 . A method of treating a disease selected from the group consisting of anxiety, chronic and acute pain, protection against liver damage, urinary incontinence, obesity, Fragile-X and autism comprising administering to an individual a therapeutically effective amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 one of A or E is N and the other is C;  
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       19 . A method of treating a disease selected from the group consisting of Alzheimer's disease, epilepsy, schizophrenia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDs, and Parkinson's disease comprising administering to an individual a therapeutically effective amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 one of A or E is N and the other is C;  
 R 1  is halogen or cyano;  
 R 2  is lower alkyl;  
 R 3  is aryl or heteroaryl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl, lower haloalkoxy, cyano, NR′R″ or by  
 1-morpholinyl or by  
 1-pyrrolidinyl, optionally substituted by (CH 2 ) m OR, or by piperidinyl, optionally substituted by (CH 2 ) m OR, or by  
 1,1-dioxo-thiomorpholinyl or by piperazinyl, optionally substituted by lower alkyl or (CH 2 ) m -cycloalkyl;  
 R is hydrogen, lower alkyl or (CH 2 ) m -cycloalkyl;  
 R′ and R″ are each independently hydrogen, lower alkyl, (CH 2 ) m -cycloalkyl or (CH 2 ) n OR;  
 m is 0 or 1;  
 n is 1 or 2; and  
 R 4  is CHF 2 , CF 3 , C(O)H, or CH 2 R 5  wherein R 5  is hydrogen, OH, C 1 -C 6 -alkyl or C 3 -C 12 -cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.