Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group ii metabotropic glutamate receptors

Abstract

Pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) and pharmaceutical compositions containing them are disclosed. The compounds of formula (I) and the compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signaling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signaling in mammals. These pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.

1 . A pharmaceutical composition, comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 A is —CH; 
 R 1 , R 2  and R 4  are each independently selected from the group consisting of R 7 , halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , —NR 7 COOR 8 , aryl, and heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from the group consisting of R 7 , halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , and —NR 7 COOR 8 ; 
 R 3  is selected from the group consisting of hydrogen, halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , —NR 7 COOR 8 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, cycloalkyl and heterocycloalkyl, wherein said C 1 -C 4  alkyl and said C 2 -C 4  alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C 1 -C 4  alkyl; halogen; —CF 3 ; —CN; —OH; —O(C 1 -C 4  alkyl); C 1 -C 4  alkyl substituted with one or more —OH groups; —NH 2 ; —NH(C 1 -C 4  alkyl); and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl); 
 R 5  is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R 7 , halogen, —CN, —NR 7 R 8 , —CONR 7 R 8 , —COR 7 , —OR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , and —COOR 7 ; 
 R 6  is selected from the group consisting of C 1 -C 4  alkyl, cycloalkyl, and heterocycloalkyl, wherein said C 1 -C 4  alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, —CF 3 , —CN, —OH and —O(C 1 -C 4  alkyl), and further wherein, if R 6  is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, cycloalkyl, halogen, —CF 3 , —CN, —OH and —O(C 1 -C 4  alkyl); and 
 each R 7 , R 8  and R 9  is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C 1 -C 4  alkyl and said C 2 -C 4  alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF 3 , —CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), and further wherein, if R 7 , R 8  or R 9  is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: C 1 -C 4  alkyl; halogen; —CF 3 ; —CN; —OH; —O(C 1 -C 4  alkyl); C 1 -C 4  alkyl substituted with one or more —OH groups; —NH 2 ; —NH(C 1 -C 4  alkyl); and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl); 
 
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, 
         and a pharmaceutically acceptable excipient. 
       
     
     
         2 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 A is —CH; 
 R 1 , R 2  and R 4  are each independently selected from the group consisting of R 7 , halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , —NR 7 COOR 8 , aryl, and heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from the group consisting of R 7 , halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , and —NR 7 COOR 8 ; 
 R 3  is selected from the group consisting of hydrogen, halogen, —CN, —OR 7 , —NR 7 R 8 , —COOR 7 , —SO 3 H, —B(OH) 2 , —CONR 7 R 8 , —COR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , —NR 7 C(O)NR 8 R 9 , —NR 7 C(S)NR 8 R 9 , —NR 7 COOR 8 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, cycloalkyl and heterocycloalkyl, wherein said C 1 -C 4  alkyl and said C 2 -C 4  alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C 1 -C 4  alkyl; halogen; —CF 3 ; —CN; —OH; —O(C 1 -C 4  alkyl); C 1 -C 4  alkyl substituted with one or more —OH groups; —NH 2 ; —NH(C 1 -C 4  alkyl); and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl); 
 R 5  is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R 7 , halogen, —CN, —NR 7 R 8 , —CONR 7 R 8 , —COR 7 , —OR 7 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —NR 7 SO 2 R 8 , —OCOR 7 , and —COOR 7 ; 
 R 6  is selected from the group consisting of C 1 -C 4  alkyl, cycloalkyl, and heterocycloalkyl, wherein said C 1 -C 4  alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, —CF 3 , —CN, —OH and —O(C 1 -C 4  alkyl), and further wherein, if R 6  is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, cycloalkyl, halogen, —CF 3 , —CN, —OH and —O(C 1 -C 4  alkyl); and 
 each R 7 , R 8  and R 9  is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C 1 -C 4  alkyl and said C 2 -C 4  alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, —CF 3 , —CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), and further wherein, if R 7 , R 8  or R 9  is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: C 1 -C 4  alkyl; halogen; —CF 3 ; —CN; —OH; —O(C 1 -C 4  alkyl); C 1 -C 4  alkyl substituted with one or more —OH groups; —NH 2 ; —NH(C 1 -C 4  alkyl); and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl); 
 
         or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
         wherein the “heterocycloalkyl” is a saturated ring group which may be a monocyclic ring or a bridged ring, spiro ring and/or fused ring system, wherein said ring group contains one or more ring heteroatoms, wherein said ring heteroatoms are independently selected from the group consisting of O, S and N, and wherein one or more S ring atoms, if present, and/or one or more N ring atoms, if present, may be oxidized. 
       
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein R 3  is selected from the group consisting of hydrogen, halogen, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, —CN, C 1 -C 4  alkyl, cycloalkyl, heterocycloalkyl, —OH, —O(C 1 -C 4  alkyl), —O-cycloalkyl, —O-heterocycloalkyl, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —NH-cycloalkyl, —N(C 1 -C 4  alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C 1 -C 4  alkyl)-heterocycloalkyl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—N H 2 , —CO—NH(C 1 -C 4  alkyl), —CO—N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —CO—NH-cycloalkyl, —CO—N(C 1 -C 4  alkyl)-cycloalkyl, —CO—NH-heterocycloalkyl, —CO—N(C 1 -C 4  alkyl)-heterocycloalkyl, —NH—CO-cycloalkyl, —N(C 1 -C 4 alkyl)-CO-cycloalkyl, —NH—CO-heterocycloalkyl, and —N(C 1 -C 4  alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of: C 1 -C 4  alkyl; halogen; —CF 3 ; —CN; —OH; —O(C 1 -C 4  alkyl); C 1 -C 4  alkyl substituted with one or more —OH groups; —NH 2 ; —NH(C 1 -C 4  alkyl); and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl). 
     
     
         6 . (canceled) 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein R 1 , R 2  and R 4  are each independently selected from hydrogen, halogen, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, —CN, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C 1 -C 4  alkyl), —O—(C 1 -C 4  alkylene)-OH, —O—(C 1 -C 4  alkylene)-O(C 1 -C 4  alkyl), —O-cycloalkyl, —O—(C 1 -C 4  alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C 1 -C 4  alkylene)-heterocycloalkyl, —O-aryl, —O—(C 1 -C 4  alkylene)-aryl, —O-heteroaryl, —O—(C 1 -C 4  alkylene)-heteroaryl, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —NH-cycloalkyl, —N(C 1 -C 4  alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C 1 -C 4  alkyl)-heterocycloalkyl, —NH—(C 1 -C 4  alkylene)-cycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-cycloalkyl, —NH—(C 1 -C 4  alkylene)-heterocycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heterocycloalkyl, —NH-aryl, —N(C 1 -C 4  alkyl)-aryl, —NH-heteroaryl, —N(C 1 -C 4  alkyl)-heteroaryl, —NH—(C 1 -C 4  alkylene)-aryl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-aryl, —NH—(C 1 -C 4  alkylene)-heteroaryl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heteroaryl, —CO—(C 1 -C 4  alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C 1 -C 4  alkylene)-cycloalkyl, —CO—(C 1 -C 4  alkylene)-heterocycloalkyl, —CO-aryl, —CO-heteroaryl, —CO—(C 1 -C 4  alkylene)-aryl, —CO—(C 1 -C 4  alkylene)-heteroaryl, —CO—NH 2 , —CO—NH(C 1 -C 4  alkyl), —CO—N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —CO—NH-cycloalkyl, —CO—N(C 1 -C 4  alkyl)-cycloalkyl, —CO—NH—(C 1 -C 4  alkylene)-cycloalkyl, —CO—N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-cycloalkyl, —CO—NH-heterocycloalkyl, —CO—N(C 1 -C 4  alkyl)-heterocycloalkyl, —CO—NH—(C 1 -C 4  alkylene)-heterocycloalkyl, —CO—N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heterocycloalkyl, —CO—NH-aryl, —CO—N(C 1 -C 4  alkyl)-aryl, —CO—NH—(C 1 -C 4  alkylene)-aryl, —CO—N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-aryl, —CO—NH-heteroaryl, —CO—N(C 1 -C 4  alkyl)-heteroaryl, —CO—NH—(C 1 -C 4  alkylene)-heteroaryl, —CO—N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heteroaryl, —NH—CHO, —N(C 1 -C 4  alkyl)-CHO, —NH—CO(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)-CO(C 1 -C 4  alkyl), —NH—CO-cycloalkyl, —N(C 1 -C 4  alkyl)-CO-cycloalkyl, —NH—CO—(C 1 -C 4  alkylene)-cycloalkyl, —N(C 1 -C 4  alkyl)-CO—(C 1 -C 4  alkylene)-cycloalkyl, —NH—CO-heterocycloalkyl, —N(C 1 -C 4  alkyl)-CO-heterocycloalkyl, —NH—CO—(C 1 -C 4  alkylene)-heterocycloalkyl, —N(C 1 -C 4  alkyl)-CO—(C 1 -C 4  alkylene)-heterocycloalkyl, —NH—CO-aryl, —N(C 1 -C 4  alkyl)-CO-aryl, —NH—CO—(C 1 -C 4  alkylene)-aryl, —N(C 1 -C 4  alkyl)-CO—(C 1 -C 4  alkylene)-aryl, —NH—CO-heteroaryl, —N(C 1 -C 4  alkyl)-CO-heteroaryl, —NH—CO—(C 1 -C 4  alkylene)-heteroaryl, and —N(C 1 -C 4  alkyl)-CO—(C 1 -C 4  alkylene)-heteroaryl, wherein said aryl, said heteroaryl, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl). 
     
     
         8 . (canceled) 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein R 5  is heteroaryl having 5 or 6 ring members and comprising one or more ring heteroatoms independently selected from the group consisting of O, S and N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, C 2 -C 4  alkenyl, halogen, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C 1 -C 4  alkyl), —O-cycloalkyl, —O—(C 1 -C 4  alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C 1 -C 4  alkylene)-heterocycloalkyl, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —NH-cycloalkyl, —N(C 1 -C 4  alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C 1 -C 4  alkyl)-heterocycloalkyl, —NH—(C 1 -C 4  alkylene)-cycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-cycloalkyl, —NH—(C 1 -C 4  alkylene)-heterocycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heterocycloalkyl, —CO—(C 1 -C 4  alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C 1 -C 4  alkylene)-cycloalkyl, and —CO—(C 1 -C 4  alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl). 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein R 5  is pyridinyl which is optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, C 2 -C 4  alkenyl, halogen, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —O(C 1 -C 4  alkyl), —O-cycloalkyl, —O—(C 1 -C 4  alkylene)-cycloalkyl, —O-heterocycloalkyl, —O—(C 1 -C 4  alkylene)-heterocycloalkyl, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —NH-cycloalkyl, —N(C 1 -C 4  alkyl)-cycloalkyl, —NH-heterocycloalkyl, —N(C 1 -C 4  alkyl)-heterocycloalkyl, —NH—(C 1 -C 4  alkylene)-cycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-cycloalkyl, —NH—(C 1 -C 4  alkylene)-heterocycloalkyl, —N(C 1 -C 4  alkyl)-(C 1 -C 4  alkylene)-heterocycloalkyl, —CO—(C 1 -C 4  alkyl), —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—(C 1 -C 4  alkylene)-cycloalkyl, and —CO—(C 1 -C 4  alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from the group consisting of C 1 -C 4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl) and —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl). 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein R 5  is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin-4-yl, wherein said one or two substituent group(s) is/are selected independently from the group consisting of C 1 -C 4  alkyl, C 2 -C 4  alkenyl, halogen, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, —CN, cycloalkyl, heterocycloalkyl, —O(C 1 -C 4  alkyl), —O-cycloalkyl, and —O-heterocycloalkyl. 
     
     
         12 . (canceled) 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein R 5  is 2-trifluoromethyl-pyridin-4-yl. 
     
     
         14 . (canceled) 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein R 6  is methyl. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising the compound as defined in  claim 2  or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating and/or preventing a condition associated with altered glutamatergic signaling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signaling, the method comprising the administration of the pharmaceutical composition of  claim 1  to a subject in need of such treatment or prevention. 
     
     
         22 . The method of  claim 21 , wherein the condition to be treated or prevented is selected from the group consisting of: epilepsy; dementias; parkinsonism and movement disorders; motor neuron disease or amyotrophic lateral sclerosis; neurodegenerative and/or hereditary disorders of the nervous system; disorders of the peripheral nervous system; multiple sclerosis and other demyelinating diseases of the nervous system; infantile cerebral palsy; paralytic syndromes including hemiplegia and hemiparesis; cerebrovascular disorders; migraine; headache; myoneural disorders; disorders of the eye and visual pathways; intracranial trauma/injury and their sequels; trauma/injury to nerves and spinal cord and their sequels; poisoning and toxic effects of nonmedicinal substances; accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; neurological and psychiatric adverse effects of drugs, medicinal and biological substances; disturbance of sphincter control and sexual function; mental disorders; delirium and cognitive disorders; substance related disorders; schizophrenia and psychotic disorders; mood disorders; anxiety disorders; eating disorders; sleep disorders and sleep/wake disorders; medication-induced movement disorders; endocrine and metabolic diseases; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; cancers; and autism spectrum disorders. 
     
     
         23 . The method of  claim 21 , wherein the condition to be treated or prevented is selected from the croup consisting of dementias, parkinsonism and movement disorders, acute or chronic pain, anxiety disorders, schizophrenia, mood disorders, endocrine or metabolic diseases, and cancers. 
     
     
         24 . The method of  claim 23 , wherein said dementias are selected from the group consisting of: dementias of the Alzheimer's type (DAT); Alzheimer's disease; Pick's disease; vascular dementias; Lewy-body disease; dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency; AIDS-dementia complex; Creutzfeld-Jacob disease; and atypical subacute spongiform encephalopathy. 
     
     
         25 - 31 . (canceled) 
     
     
         32 . A method of treating and/or preventing Alzheimer's disease, the method comprising the administration of the pharmaceutical composition of  claim 1  to a subject in need of such treatment or prevention. 
     
     
         33 . The method of  claim 21 , wherein said subject is a human. 
     
     
         34 . A method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), comprising the following steps:
 (a) contacting mGluR2 with the compound of  claim 2 , wherein said compound is radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating bound, labeled compound;   (b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent;   (c) contacting the bound, labeled compound with a test agent;   (d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and   (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2.