SUBSTITUTED-DIHYDRO[1,4]OXAZINO[2,3,4-hi]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

Abstract

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

1 . A method of treating a central nervous system disorder relating to decreased cognition and memory in an Alzheimer's patient in need thereof, which method comprises providing to said patient a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 X is a bond, O, S, NR or CONR; 
 m is 0 or an integer of 1; 
 R is H or an optionally substituted alkyl group; 
 R 1  and R 7  are each independently H or an optionally substituted alkyl group; 
 R 2  is an alkyl, cycloalkyl, aryl or heteroaryl group each group optionally substituted or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; 
 R 3  and R 4  are each independently H, or an optionally substituted alkyl group; 
 n is 0 or an integer of 2, 3, 4, 5, or 6; 
 R 5  and R 6  are each independently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group each group optionally substituted or R 5  and R 6  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring optionally containing an additional heteroatom selected from NR, O or S; 
 R 8  is H, halogen, OR 9 , or an optionally substituted alkyl group; and 
 R 9  is H, alkyl or haloalkyl; or 
 
     a stereoisomer thereof or a pharmaceutically acceptable salt thereof; 
     wherein the optional substituents are selected from the group consisting of halogen atoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl and cycloalkyl groups. 
   
   
       2 . The method according to  claim 1  comprising enhancing cognition and memory in said Alzheimer's patient. 
   
   
       3 . The method according to  claim 1  wherein X is a bond and m and n are 0. 
   
   
       4 . The method according to  claim 1  wherein X is O; m is 0; and n is 2. 
   
   
       5 . The method according to  claim 1  wherein R 2  is an optionally substituted aryl or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; and R 5  and R 6  are each independently H or alkyl or R 5  and R 6  are taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring. 
   
   
       6 . A method of enhancing cognition and memory related to Alzheimer's disease in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 X is a bond, O, S, NR or CONR; 
 m is 0 or an integer of 1; 
 R is H or an optionally substituted alkyl group; 
 R 1  and R 7  are each independently H or an optionally substituted alkyl group; 
 R 2  is an alkyl, cycloalkyl, aryl or heteroaryl group each group optionally substituted or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; 
 R 3  and R 4  are each independently H, or an optionally substituted alkyl group; 
 n is 0 or an integer of 2, 3, 4, 5, or 6; 
 R 5  and R 6  are each independently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group each group optionally substituted or R 5  and R 6  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring optionally containing an additional heteroatom selected from NR, O or S; 
 R 8  is H, halogen, OR 9 , or an optionally substituted alkyl group; and 
 R 9  is H, alkyl or haloalkyl; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; 
 wherein the optional substituents are selected from the group consisting of halogen atoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl and cycloalkyl groups. 
 
   
   
       7 . The method according to  claim 6  wherein X is a bond and m and n are 0. 
   
   
       8 . The method according to  claim 6  wherein X is O; m is 0; and n is 2 
   
   
       9 . The method according to  claim 6  wherein R 2  is an optionally substituted aryl or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; and R 5  and R 6  are each independently H or alkyl or R 5  and R 6  are taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring. 
   
   
       10 . A method of treating Alzheimer's disease in a patient, which method comprises providing to said patient a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 X is a bond, O, S, NR or CONR; 
 m is 0 or an integer of 1; 
 R is H or an optionally substituted alkyl group; 
 R 1  and R 7  are each independently H or an optionally substituted alkyl group; 
 R 2  is an alkyl, cycloalkyl, aryl or heteroaryl group each group optionally substituted or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; 
 R 3  and R 4  are each independently H, or an optionally substituted alkyl group; 
 n is 0 or an integer of 2, 3, 4, 5, or 6; 
 R 5  and R 6  are each independently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group each group optionally substituted or R 5  and R 6  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring optionally containing an additional heteroatom selected from NR, O or S; 
 R 8  is H, halogen, OR 9 , or an optionally substituted alkyl group; and 
 R 9  is H, alkyl or haloalkyl; or 
 
     a stereoisomer thereof or a pharmaceutically acceptable salt thereof; 
     wherein the optional substituents are selected from the group consisting of halogen atoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl and cycloalkyl groups. 
   
   
       11 . The method according to  claim 10  comprising enhancing cognition and memory in said Alzheimer's patient. 
   
   
       12 . The method according to  claim 10  wherein X is a bond and m and n are 0. 
   
   
       13 . The method according to  claim 10  wherein X is O; m is 0; and n is 2. 
   
   
       14 . The method according to  claim 10  wherein R 2  is an optionally substituted aryl or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S; and R 5  and R 6  are each independently H or alkyl or R 5  and R 6  are taken together with the atom to which they are attached to form an optionally substituted 3- to 7-membered ring.