Heterocyclyloxy-, -thioxy-and-aminobenzazole 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 n  or NR 11 ;  
 Y is CR 12  or N;  
 Z is CR 13  or N with the proviso that when Y is N then Z must be CR 13 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 Q is  
                     
 with the proviso that when Q is piperidinyl then one of Y and Z must be N;  
 R 1  is halogen, CN, OR 14 , CO 2 R 15 , CONR 16 R 17 , CNR 18 NR 19 R 20 , SO 2 NR 21 R 22 , SO p R 23  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  is H, CNR 24 NR 25 R 26  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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 28  and R 29  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 10  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 n and p are each independently 0 or an integer of 1 or 2;  
 R 11  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 12  and R 13  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 14  is H, COR 27  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 15  and R 27  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 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25  and R 26  are each independently H or an optionally substituted  
 C 1 -C 6 alkyl group;  
 R 21  and R 22  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 23  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 2  wherein Q is an optionally substituted 3-pyrrolidinyl group.  
     
     
         5 . The compound according to  claim 4  wherein X is O and R 10  is an optionally substituted aryl or heteroaryl group.  
     
     
         6 . The compound according to  claim 5  wherein Y is CR 12 .  
     
     
         7 . The compound according to  claim 6  wherein Z is N.  
     
     
         8 . The compound according to  claim 6  selected from the group consisting of: 
 1-(phenylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indole;    4-(3-pyrrolidinyloxy)1-(thien-2-ylsulfonyl)-1H-indole;    4-{[4-(3-pyrrolidinyloxy)-1H-indol-1-yl]sulfonyl}aniline;    1-(1-naphthylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indole;    1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indole;    1-(phenylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indazole;    1-(1-naphthylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(2-chlorophenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(2-fluorophenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[3,4-dimethoxyphenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    N-(2-chloro-4-{[4-(3-pyrrolidinyloxy)-1H-indazol-1-yl]sulfonyl}phenyl)acetamide;    N-(4-{[4-(3-pyrrolidinyloxy)-1H-indazol-1y}]sulfonyl)-phenyl)acetamide;    8-{[4-(3-pyrrolidinyloxy)-1H-indazol-1-yl]sulfonyl}-quinoline;    1-(1-naphthylsulfonyl)-4-(piperidin-4-yloxy)-1H-indazole;    1-(1-naphthylsulfonyl)-4-(piperidin-3-yloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-4-yloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-3-yloxy)-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indole;    1-(phenylsulfonyl)-6-(pyrrolidin-3-yloxy)-1H-indole;    1-(phenylsulfonyl)-6-(pyrrolidin-3-yloxy)-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole;    the stereoisomers thereof; and    the pharmaceutically acceptable salts thereof.    
     
     
         9 . 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 n  or NR 11 ;  
 Y is CR 12  or N;  
 Z is CR 13  or N with the proviso that when Y is N then Z must be CR 13 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 Q is  
                     
 R 1  is halogen, CN, OR 14 , CO 2 R 15 , CONR 16 R 17 , CNR 18 NR 19 R 20 , SO 2 NR 21 R 22 , SO p R 23  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  is H, CNR 24 NR 25 R 26  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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 28  and R 29  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 10  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 n and p are each independently 0 or an integer of 1 or 2;  
 R 11  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 12  and R 13  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 14  is H, COR 27  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 15  and R 27  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 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25  and R 26  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 21  and R 22  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 23  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or  
 the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         10 . The method according to  claim 9  wherein said disorder is a motor disorder, anxiety disorder or cognitive disorder.  
     
     
         11 . The method according to  claim 9  wherein said disorder is schizophrenia or depression.  
     
     
         12 . The method according to  claim 10  wherein said disorder is Alzheimer's disease or Parkinson's disease.  
     
     
         13 . The method according to  claim 10  wherein said disorder is attention deficit disorder.  
     
     
         14 . 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 n  or NR 11 ;  
 Y is CR 12  or N;  
 Z is CR 13  or N with the proviso that when Y is N then Z must be CR 13 ;  
 m and x are each independently 0 or an integer of 1, 2 or 3;  
 Q is  
                     
 with the proviso that when Z is piperidinyl then one of Y and Z must be N;  
 R 1  is halogen, CN, OR 14 , CO 2 R 15 , CONR 16 R 17 , CNR 18 NR 19 R 20 , SO 2 NR 21 R 22 , SO p R 23  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  is H, CNR 24 NR 25 R 26  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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 28  and R 29  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 10  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 n and p are each independently 0 or an integer of 1 or 2;  
 R 11  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 12  and R 13  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 14  is H, COR 27  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 15  and R 27  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 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25  and R 26  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 21  and R 22  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 23  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         15 . The composition according to  claim 14  having a formula I compound wherein W is SO 2 .  
     
     
         16 . The composition according to  claim 14  having a formula I compound wherein X is O.  
     
     
         17 . The composition according to  claim 15  having a formula I compound wherein Y is CR 12 .  
     
     
         18 . The composition according to  claim 17  having a formula I compound wherein X is O; Q is an optionally substituted 3-pyrrolidinyl group and R 10  is an optionally substituted aryl or heteroaryl group.  
     
     
         19 . The composition according to  claim 18  having a formula I compound selected from the group consisting of: 
 1-(phenylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indole;    4-(3-pyrrolidinyloxy)1-(thien-2-ylsulfonyl)-1H-indole;    4-{[4-(3-pyrrolidinyloxy)-1H-indol-1-yl]sulfonyl}aniline;    1-(1-naphthylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indole;    1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indole;    1-(phenylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indazole;    1-(1-naphthylsulfonyl)-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(2-chlorophenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(2-fluorophenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[3,4-dimethoxyphenyl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(3-pyrrolidinyloxy)-1H-indazole;    N-(2-chloro-4-{[4-(3-pyrrolidinyloxy)-1H-indazol-1-yl]sulfonyl}phenyl)acetamide;    N-(4-{[4-(3-pyrrolidinyloxy)-1H-indazol-1y}]sulfonyl)phenyl)acetamide;    8-{[4-(3-pyrrolidinyloxy)-1H-indazol-1-yl]sulfonyl}-quinoline;    1-(1-naphthylsulfonyl)-4-(piperidin-4-yloxy)-1H-indazole;    1-(1-naphthylsulfonyl)-4-(piperidin-3-yloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-4-yloxy)-1H-indazole;    1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-3-yloxy)-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indole;    1-(phenylsulfonyl)-6-(pyrrolidin-3-yloxy)-1H-indole;    1-(phenylsulfonyl)-6-(pyrrolidin-3-yloxy)-1H-indazole;    1-(phenylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole;    the stereoisomers thereof; and    the pharmaceutically acceptable salts thereof.    
     
     
         20 . A method for the preparation of a compound of formula Ie  
       
         
           
           
               
               
           
         
       
       wherein 
 X is O, SO n  or NR 11 ;  
 Y is CR 12  or N;  
 Z is CR 13  or N with the proviso that when Y is N then Z must be CR 13 ;  
 m is 0 or an integer of 1, 2 or 3;  
 Q is  
                     
 R 1  is halogen, CN, OR 14 , CO 2 R 15 , CONR 16 R 17 , CNR 18 NR 19 R 20 , SO 2 NR 21 R 22 , SO p R 23  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  is H, CNR 24 NR 25 R 26  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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 28  and R29 are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 10  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 n and p are each independently 0 or an integer of 1 or 2;  
 R 11  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 12  and R 13  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 14  is H, COR 27  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 15  and R 27  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 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25  and R 26  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 21  and R 22  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 23  is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group which process comprises reacting a compound of formula XIX  
                     
 wherein X, Y, Z, m and Q are as described hereinabove with a sulfonyl chloride, R 10 SO 2 Cl, wherein R 10  is as described hereinabove in the presence of a base to give the desired compound of formula Ie.