Heterocyclylalkoxy-, -alkylthio- and -alkylaminobenzazole derivatives as 5-hydroxytryptamine-6 ligands

Abstract

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 W is SO 2 , CO, CONH, CSNH or (CH 2 ) x ;  
 X is O, SO y  or NR 13 ;  
 Y is CR 14  or N;  
 Z is CR 15  or N with the proviso that when Y is N then Z must be CR 15 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 n and p are each independently an integer of 1, 2 or 3 with the proviso that when p is an integer of 1 then one of Y and Z must be N;  
 R 1  is halogen, CN, OR 16 , CO 2 R 17 , CONR 18 R 19 , CNR 20 NR 21 R 22 , SO 2 NR 23 R 24 , SO w R 25 , or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;  
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 4  is H, CNR 26 NR 27 R 28  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 12  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 y and w are each 0 or an integer of 1 or 2;  
 R 13  is 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 14  and R 15  are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;  
 R 16  is H, COR 29  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;  
 R 17  and R 29  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 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27  and R 28  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 23  and R 24  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 25  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein W is SO 2 .  
     
     
         3 . The compound according to  claim 1  wherein X is O.  
     
     
         4 . The compound according to  claim 1  wherein Y is CR 14 .  
     
     
         5 . The compound according to  claim 1  wherein n is 1.  
     
     
         6 . The compound according to  claim 2  wherein R 12  is an aryl or heteroaryl group each optionally substituted.  
     
     
         7 . The compound according to  claim 6  wherein X is O and n is 1.  
     
     
         8 . The compound according to  claim 7  wherein Y is CR 14  and p is 1.  
     
     
         9 . The compound according to  claim 7  selected from the group consisting of 
 1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;    1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;    2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;    1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;    4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;    4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;    4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;    4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;    1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole;    the stereoisomers thereof; and    the pharmaceutically acceptable salts thereof.    
     
     
         10 . A method for the treatment of a disorder of the central nervous system 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 SO 2 , CO, CONH, CSNH or (CH 2 ) x ;  
 X is O, SO y  or NR 13 ;  
 Y is CR 14  or N;  
 Z is CR 15  or N with the proviso that when Y is N then Z must be CR 15 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 n and p are each independently an integer of 1, 2 or 3;  
 R 1  is halogen, CN, OR 16 , CO 2 R 17 , CONR 18 R 19 , CNR 20 NR 21 R 22 , SO 2 NR 23 R 24 , SO w R 25 , or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;  
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 4  is H, CNR 26 NR 27 R 28  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 12  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 y and w are each 0 or an integer of 1 or 2;  
 R 13  is 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 14  and R 15  are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;  
 R 16  is H, COR 29  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;  
 R 17  and R 29  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 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27  and R 28  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 23  and R 24  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 25  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         11 . The method according to  claim 10  wherein said disorder is a motor disorder, anxiety disorder or cognitive disorder.  
     
     
         12 . The method according to  claim 10  wherein said disorder is schizophrenia or depression.  
     
     
         13 . The method according to  claim 11  wherein said disorder is Alzheimer's disease or Parkinson's diease.  
     
     
         14 . The method according to  claim 11  wherein said disorder is attention deficit disorder.  
     
     
         15 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 W is SO 2 , CO, CONH, CSNH or (CH 2 ) x ;  
 X is O, SO y  or NR 13 ;  
 Y is CR 14  or N;  
 Z is CR 15  or N with the proviso that when Y is N then Z must be CR 15 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 n and p are each independently an integer of 1, 2 or 3 with the proviso that when p is an integer of 1 then one of Y and Z must be N;  
 R 1  is halogen, CN, OR 16 , CO 2 R 17 , CONR 18 R 19 , CNR 20 NR 21 R 22 , SO 2 NR 23 R 24 , SO w R 25 , or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;  
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 4  is H, CNR 26 NR 27 R 28  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 12  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 y and w are each 0 or an integer of 1 or 2;  
 R 13  is 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 14  and R 15  are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;  
 R 16  is H, COR 29  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;  
 R 17  and R 29  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 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27  and R 28  are each independently H or an optional substituted C 1 -C 6 alkyl group;  
 R 23  and R 24  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 25  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         16 . The composition according to  claim 15  having a formula I compound wherein W is SO 2 .  
     
     
         17 . The composition according to  claim 16  having a formula I wherein X is O.  
     
     
         18 . The composition according to  claim 16  having a formula I compound wherein Y is CR 14  and n is 1.  
     
     
         19 . The composition according to  claim 18  having a formula I compound selected from the group consisting of: 
 1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;    1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;    2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;    1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;    4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;    4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;    4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;    4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;    4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;    1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole;    the stereoisomers thereof; and    the pharmaceutically acceptable salts thereof.    
     
     
         20 . A process for the preparation of a compound of formula Ie  
       
         
           
           
               
               
           
         
       
       wherein X, Y, Z, m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are defined in  claim 1  which comprises reacting a compound of formula XVI  
       
         
           
           
               
               
           
         
       
       wherein X, Y, Z, m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are as defined hereinabove with a sulfonyl chloride, R 12 SO 2 Cl, wherein R 12  is as defined hereinabove in the presence of a base optionally in the presence of a solvent.  
     
     
         21 . A compound of formula XVI  
       
         
           
           
               
               
           
         
       
       wherein 
 X is O, SO y  or NR 13 ;  
 Y is CR 14  or N;  
 Z is CR 15  or N with the proviso that when Y is N then Z must be CR 15 ;  
 m is 0 or an integer of 1, 2 or 3;  
 n and p are each independently an integer of 1, 2 or 3;  
 R 1  is halogen, CN, OR 16 , CO 2 R 17 , CONR 18 R 19 , CNR 20 NR 21 R 22 , SO 2 NR23R 24 , SO w R 25 , or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;  
 R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 4  is H, CNR 26 NR 27 R 28  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or cycloheteroalkyl group each optionally substituted;  
 R 13  is 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 14  and R 15  are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;  
 R 16  is H, COR 29  or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;  
 R 17  and R 29  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 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27  and R 28  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 23  and R 24  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 25  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         22 . The compound according to  claim 21  wherein X is O; Y is CR 14 ; and n is 1.  
     
     
         23 . The compound according to  claim 22  wherein Z is CR 15 .