Fluorinated amide derivatives and their uses as therapeutic agents

Abstract

The present application relates to novel fluorinated amide 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 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 H, 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, alkylene-O-alkylene-heterocycloalkyl, optionally substituted with one or more independently-selected groups R 6 ; 
         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 heteoaryl; 
         or R 2  and R 3  connect to form, together with the carbon atom to which they are attached, a three to seven-membered ring; and 
         R 4  and R 5  are each 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 heteoaryl; 
         or R 4  and R 5  connect to form, together with the nitrogen atom to which they are attached, a three to seven-membered ring; 
         Q is selected from O, NR 7 , S, SO and SO 2 ; 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 heteoaryl. 
       
     
     
         2 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy and C 1 -C 2 alkylene-O—C 1 -C 4 alkyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is selected from the group consisting of Cl, F, CH 3 , CF 3 , CH 3 O, CF 3 O and CH 2 OCH 3 . 
     
     
         5 . The compound of  claim 1 , wherein R 2  and R 3  are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl. 
     
     
         6 . The compound of  claim 1 , wherein at least one of R 2  and R 3  is H. 
     
     
         7 . The compound of  claim 1 , wherein R 2  and R 3  connect to form, together with the carbon atom to which they are attached, a cyclopropyl, cyclobutyl, cyclypentyl or cyclohexyl ring. 
     
     
         8 . The compound of  claim 1 , wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen and CH 3 . 
     
     
         10 . The compound of  claim 9 , wherein at least one of R 4  and R 5  is H. 
     
     
         11 . The compound of  claim 1 , wherein R 4  and R 5  connect to form, together with the nitrogen atom to which they are attached, an aziridine, azetidine, pyrrolidine or piperadine ring. 
     
     
         12 . The compound of  claim 1 , wherein Q is selected from O and NR 7 . 
     
     
         13 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 12 cycloalkyl. 
     
     
         14 . The compound of  claim 13 , wherein R 7  is selected from the group consisting of H and C 1 -C 4 alkyl. 
     
     
         15 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl. 
     
     
         16 . The compound of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof, or a stereoisomer thereof. 
     
     
         17 . The compound of  claim 16 , selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         18 . The compound of  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier and/or excipient. 
     
     
         20 . 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 .