1-heterocyclylalkyl-3-sulfonylazaindole or -azaindazole 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 for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       W is N or CR 2 ; 
       X is N or CR 9 ; 
       Y is N or CR 10 ; 
       Z is N or CR 11 ; 
       Q is N or CR 12  with the proviso that at least one and not more than two of X, Y, Z and Q must be N; 
       R 1  is an optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 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; 
       R 2  is H, halogen, or a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 3  and R 4  are each independently H or an optionally substituted C 1 -C 6 alkyl group; 
       R 5  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 6  is a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       R 7  and R 8  are each independently H or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       m and n are each independently 0 or an integer of 1, 2 or 3; 
       p is 0 or an integer of 1 or 2; 
       R 9 , Ri 10 , R 11 , and R 12  are each independently H, halogen, CN, OCO 2 R 13 , CO 2 R 14 , CONR 15 R 16 , SO x R 17 , NR 18 R 19 , OR 20 , COR 21  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 13 , R 14 , R 17  and R 2 , are each independently H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 15 , R 16 , R 18  and R 19  are each independently H or an optionally substituted C 1 -C 4 alkyl group or R 15  and R 16  or R 18  and R 19  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR 22  or SO q ; 
       R 20  is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       x and q are each independently 0 or an integer of 1 or 2; and 
       R 22  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteraryl group each optionally substituted; or 
       the stereoisomers thereof or the pharmaceutically acceptable salts thereof. 
     
   
   
       2 . The method according to  claim 1  wherein said disorder is a motor disorder, anxiety disorder or cognitive disorder. 
   
   
       3 . The method according to  claim 1  wherein said disorder is a neurodegenerative disorder. 
   
   
       4 . The method according to  claim 2  wherein said disorder is selected from the group consisting of: attention deficit disorder; obsessive compulsive disorder; and withdrawal from drug, alcohol or nicotine addiction. 
   
   
       5 . The method according to  claim 3  wherein said disorder is stroke or head trauma. 
   
   
       6 . 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 
       W is N or CR 2 ; 
       X is N or CR 9 ; 
       Y is N or CR 10 ; 
       Z is N or CR 11 ; 
       Q is N or CR 12  with the proviso that at least one and not more than two of X, Y, Z and Q must be N; 
       R 1  is an optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 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; 
       R 2  is H, halogen, or a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 3  and R 4  are each independently H or an optionally substituted C 1 -C 6 alkyl group; 
       R 5  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 6  is a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       R 7  and R 8  are each independently H or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       m and n are each independently 0 or an integer of 1, 2 or 3; 
       p is 0 or an integer of 1 or 2; 
       R 9 , R 10 , R 11  and R 12  are each independently H, halogen, CN, OCO 2 R 13 , CO 2 R 14 , CONR 15 R 16 , SO x R 17 , NR 18 R 19 , OR 20 , COR 21  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 13 , R 14 , R 17  and R 21  are each independently H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 15 , R 16 , R 18  and R 19  are each independently H or an optionally substituted C 1 -C 4 alkyl group or R 15  and R16 or R 18  and R 19  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR 22  or SO q ; 
       R 20  is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       x and q are each independently 0 or an integer of 1 or 2; and 
       R 22  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteraryl group each optionally substituted; or 
       the stereoisomers thereof or the pharmaceutically acceptable salts thereof. 
     
   
   
       7 . The method of  claim 6  comprising enhancing cognition and memory in said Alzheimer's patient. 
   
   
       8 . 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 
       W is N or CR 2 ; 
       X is N or CR 9 ; 
       Y is N or CR 10 ; 
       Z is N or CR 11 ; 
       Q is N or CR 12  with the proviso that at least one and not more than two of X, Y, Z and Q must be N; 
       R 1  is an optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, or heteroaryl group or an optionally substituted 8- to 1 3-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, 0 or S; 
       R 2  is H, halogen, or a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 3  and R 4  are each independently H or an optionally substituted C 1 -C 6 alkyl group; 
       R 5  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 6  is a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       R 7  and R 8  are each independently H or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 
       m and n are each independently 0 or an integer of 1, 2 or 3; 
       p is 0 or an integer of 1 or 2; 
       R 9 , R 10 , R 11  and R 12  are each independently H, halogen, CN, OCO 2 R 13 , CO 2 R 14 , CONR15R 16 , SO x R 17 , NR 18 R 19 , OR 20 , COR 21  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
       R 13 , R 14 , R 17  and R 21  are each independently H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       R 15 , R 16 , R 18  and R 19  are each independently H or an optionally substituted C 1 -C 4 alkyl group or R 15  and R 16  or R 18  and R 19  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR 22  or SO q ; 
       R 20  is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 
       x and q are each independently 0 or an integer of 1 or 2; and 
       R 22  is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloheteroalkyl, aryl or heteraryl group each optionally substituted; or 
       the stereoisomers thereof or the pharmaceutically acceptable salts thereof.