Heterocycle derivatives and their use for the treatment of cns disorders

Abstract

The present application relates to novel heterocycle derivatives of Formula (I), to processes for preparing them, pharmaceutical compositions containing them, and their use thereof in the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer' disease, cognitive disorders and/or memory deficits, as well as chronic and acute pain and other related CNS disorders.

1 . A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer or optical isomer, or combination thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of C 1 -C 6  lower alkyl, C 1 -C 6  lower alkoxy, C 1 -C 6  lower alkyl-ester, C 1 -C 6  lower alkyl-amide, C 1 -C 6  lower alkyl-acid, C 1 -C 6  lower haloalkyl, C 1 -C 6 -lower haloalkoxy, C 1 -C 6 -lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl, alkynyl, aryl-alkynyl, cycloalkenyl, heterocycloalkenyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, and alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, each R 1  group being optionally substituted with one or more independently-selected groups R 5 ; 
         R 2  and R 3  are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or 
         R 2  and R 3  connect to form, together with the carbon atom to which they are attached, a three to seven-membered carbocyclic or heterocyclic ring; and 
         R 4  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
         X and Q are independently selected from CH 2 , O, NR 7 , S, SO and SO 2 , 
         R 5  is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO 2 R 6 , CONHR 6 , CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , C 1 -C 6  lower alkyl, C 1 -C 6  lower alkoxy, C 1 -C 6  lower alkyl-ester, C 1 -C 6  lower alkyl-amide, C 1 -C 6  lower alkyl-acid, C 1 -C 6  lower haloalkyl, C 1 -C 6  lower haloalkoxy, C 1 -C 6  lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl and alkylene-O-alkylene-heterocycloalkyl; and 
         R 6  and R 7  are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
         provided that at least one of R 1 , R 2  and R 3  comprises a fluorine atom. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of aryl, heteroaryl, C 1 -C 6 alkylene-aryl and C 1 -C 6 alkylene-heteroaryl, each R 1  group being optionally substituted with one to three independently-selected groups R 5 , wherein R 5  is selected from the group consisting of hydroxy, halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, and C 1 -C 6 alkylene-O—C 1 -C 6 alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is C 1 -C 4 alkylene-aryl optionally substituted with one R 5  group, wherein R 5  is selected from the group consisting of Cl, F, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl and C 1 -C 4 fluoroalkoxy. 
     
     
         4 . The compound of  claim 3 , wherein the R 5  group is located at the para position. 
     
     
         5 . The compound of  claim 1 , wherein R 2  and R 3  are each independently selected from the group consisting of hydrogen, Cl, F, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. 
     
     
         6 . The compound of  claim 5 , wherein R 2  and R 3  are both H or are both F, or one of R 2  and R 3  is H and the other is F. 
     
     
         7 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. 
     
     
         8 . The compound of  claim 7  wherein R 4  is selected from the group consisting of hydrogen and CH 3 . 
     
     
         9 . The compound of  claim 1 , wherein X and Q are independently selected from O and NR 7 , wherein R 7  is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. 
     
     
         10 . The compound of  claim 9 , wherein X and Q are independently selected from O and NR 7 , wherein R 7  is selected from the group consisting of hydrogen and CH 3 . 
     
     
         11 . The compound of  claim 1 , wherein X is O. 
     
     
         12 . The compound of  claim 10 , wherein Q is selected from O and NR 7 . 
     
     
         13 . The compound of  claim 1 , wherein Q is O. 
     
     
         14 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of hydrogen and C 1 -C 4 alkyl. 
     
     
         15 . The compound of  claim 1 , wherein R 1  comprises a difluoromethoxy or a trifluoromethoxy substituent. 
     
     
         16 . The compound of  claim 1 , wherein R 2  and R 3  are both F. 
     
     
         17 . The compound of  claim 1 , selected from:
 7-benzyloxy-4H benzo[1,4]oxazin-3-one,   7-(4-fluoro-benzyloxy)-4H-benzo[1,4]oxazin-3-one,   7-(4-difluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one,   7-(4-trifluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one, and   7-benzyloxy-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, or   a pharmaceutically-acceptable salt, solvate, tautomer or optical isomer, or combination thereof.   
     
     
         18 . A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier and/or excipient. 
     
     
         19 . A method for treating at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1 .