Heterocyclylindazole and -azaindazole compounds as 5-hydroxytryptamine-6 ligands

Abstract

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

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 Q is SO 2 , CO, CONR 24 , CSNR 25  or CH 2 ;  
 W is N or CR 6 ;  
 X is N or CR 7 ;  
 Y is NR 8  or CR 9 R 10 ;  
 n is 0or an integer of 2;  
 Z is NR 11  or CR 12 R 13  with the proviso that when Y is NR 8  then Z must be CR 12 R 13  and at least one of Y and Z must be NR 8  or NR 11 ;  
 R 1 , R 2  and R 7  are each independently H, halogen, CN, OCO 2 R 14 , CO 2 R 15 , CONR 29 R 30 , CNR 16 NR 17 R 18 , SO m R 19 , NR 20 R 21 , OR 22 , COR 23  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 9 , R 10 , R 12  and R 13  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 5  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 m is 0 or an integer of 1 or 2;  
 R 6  is H, halogen, or an optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl group;  
 R 8  and R 11  are each independently H, CNR 26 NR 27 R 28  or a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;  
 R 14 , R 15 , R 22  and R 23  are each independently H or an optionally substituted 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;  
 R 16 , R 17 , R 18 , R 20 , R 21 , R 26 , R 27 , R 28 , R 29  and R 30  are each independently H or C 1 -C 4 alkyl;  
 R 19  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 24  and R 25  are each independently H or an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; and  
    represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein Y is NR 8 .  
     
     
         3 . (canceled)  
     
     
         4 . The compound according to  claim 1  wherein W is N.  
     
     
         5 . (canceled)  
     
     
         6 . The compound according to  claim 4  wherein Z is NR 11 .  
     
     
         7 . The compound according to  claim 2  wherein Q is SO 2  and R 5  is an optionally substituted aryl or heteroaryl group.  
     
     
         8 . The compound according to  claim 7  wherein X is CH and   represents a single bond.  
     
     
         9 . The compound according to  claim 1  selected from the group consisting of: 
 1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;    1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-indole;    1-phenylsulfonyl-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-b]pyridine;    1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-5-fluoro-3-( 1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-pyrrolo[2,3-b]pyridine;    3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indole;    1-(benzo[b]thien-4-ylsulfonyl)-5-fluoro-3-( 1-methylazepan-4-yl)-1H-indole;    8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indole;    8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline;    8-[5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indole;    1-(naphth-1-ylsulfonyl)-3-(1-phenethyl-azepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;    3-azepan-4-yl-1-(naphth-1-ylsulfonyl)-1H-indole;    3-azepan-4-yl-1-(3-chloro-5-methyl-benzo[b]thien-2-ylsulfonyl)-5-fluoro-1H-indole;    8-[3-(1-phenethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    3-[1-(3,3-dimethylbutyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl]-1-(naphth-2-ylsulfonyl)-1H-indole;    1-(2,3-dichlorophenylsulfonyl)-3-( 1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-]pyridine;    1-[(3-chloro-5-methoxyphenylsulfonyl)]-3-(2,2-dimethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-5-fluoro-1H-indole;    3-azepan-4-yl-5-fluoro-1-(naphth-2-ylsulfonyl)-1H-indole;    
     
     
         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 said patient with a therapeutically effective amount of a compound of formula I                          wherein    Q is SO 2 , CO, CONR 24 , CSNR 25  or CH 2 ;    W is N or CR 6 ;    X is N or CR 7 ;    Y is NR 8  or CR 9 R 10 ;    n is 0or an integer of 1 or 2;    Z is NR 1 , or CR 12 R 13  with the proviso that when n is 1, Q is SO 2 , CO or CH 2  and W is CR 6  then Z must be CR 12 R 13  and with the further provisos that when Y is NR 8  then Z must be CR 12 R 13  and at least one of Y and Z must be NR 8  or NR 11 ;    R 1 , R 2  and R 7  are each independently H, halogen, CN, OCO 2 R 14 , CO 2 R 15 , CONR 29 R 30 , CNR 16 NR 17 R 18 , SO m R 19 , NR 20 R 21 , OR 22 , COR 23  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 9 , R 10 , R 12  and R 13  are each independently H or an optionally substituted C 1 -C 6 alkyl group;    R 5  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;    m is 0 or an integer of 1 or 2;    R 6  is H, halogen, or an optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl group;    R 8  and R 11  are each independently H, CNR 26 NR 27 R 28  or a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;    R 14 , R, 5 , R 22 and R 23  are each independently H or an optionally substituted 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;    R 16 , R 17 , R 18 , R 20 , R 21 , R 26 , R 27 , R 28 , R29 and R 30  are each independe C 4 alkyl;    R 19  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;    R 24  and R 25  are each independently H or an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; and       represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.    
     
     
         11 . The method according to  claim 10  wherein said disorder is a mood disorder, a motor disorder, or a cognitive disorder.  
     
     
         12 . The method according to  claim 10  wherein said disorder is schizophrenia.  
     
     
         13 . The method according to  claim 11  wherein said disorder is anxiety or depression.  
     
     
         14 . The method according to  claim 11  wherein said disorder is memory loss or attention deficit disorder.  
     
     
         15 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 Q is SO 2 , CO, CONR 24 , CSNR 25  or CH 2 ;  
 W is N or CR 6 ;  
 X is N or CR 7 ;  
 Y is NR 8  or CR 9 R 10 ;  
 n is an integer of 2;  
 Z is NR 11  or CR 12 R 13  with the proviso that when Y is NR 8  then Z must be CR 12 R 13  and at least one of Y and Z must be NR 8  or NR 11 ;  
 R 1 , R 2  and R 7  are each independently H, halogen, CN, OCO 2 R 14 , CO 2 R 15 , CONR n R 30 , CNR 16 NR 17 R, 8 , SO m R 19 , NR 20 R 21 , OR 22 , COR 23  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 9 , R 10 , R 12  and R 13  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 5  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 m is 0 or an integer of 1 or 2;  
 R 6  is H, halogen, or an optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl group;  
 R 8  and R 11  are each independently H, CNR 26 NR 27 R 28  or a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;  
 R 14 , R 15 , R 22  and R 23  are each independently H or an optionally substituted 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;  
 R 16 , R 17 , R 18 , R 20 , R 21 , R 26 , R 27 , R 28 , R 29  and R 30  are each independently H or C 1 -C 4 alkyl;  
 R 19  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 24  and R 25  are each independently H or an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; and  
    represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.  
 
     
     
         16 . The composition according to  claim 15  having a formula I compound wherein Q is SO 2 ; Y is NR 8 ; and X is CR 7 .  
     
     
         17 . The composition according to  claim 15  having a formula I compound wherein Q is SO 2 ; X is CR 7 ; and Z is NR 11 .  
     
     
         18 . The composition according to  claim 16  having a formula I compound wherein R 5  is an optionally substituted aryl group and represents a single bond.  
     
     
         19 . The composition according to  claim 15  having a formula I compound selected from the group consisting of: 
 1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;    1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-indole;    1-phenylsulfonyl-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-b]pyridine;    1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;    3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-pyrrolo[2,3-b]pyridine;    3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indole;    1-(benzo[b]thien-4-ylsulfonyl)-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;    8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indole;    8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoliene;    8-[5-fluoro-3-( 1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indoline;    1-(naphth-1-ylsulfonyl)-3-(1-phenethyl-azepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;    3-azepan-4-yl-1-(naphth-1-ylsulfonyl)-1H-indole;    3-azepan-4-yl-1-(3-chloro-5-methyl-benzo[b]thien-2-ylsulfonyl)-5-fluoro-1H-indole;    8-[3-(1-phenethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;    3-[1-(3,3-dimethylbutyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl]-1-(naphth-2-ylsulfonyl)-1H-indole;    1-(2,3-dichlorophenylsulfonyl)-3-( 1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-]pyridine;    1-[(3-chloro-5-methoxyphenylsulfonyl)]-3-(2,2-dimethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-5-fluoro-1H-indole;    3-azepan-4-yl-5-fluoro-1-(naphth-2-ylsulfonyl)-1H-indole; and    the pharmaceutically acceptable salts thereof.    
     
     
         20 . A process for the preparation of a compound of formula If  
       
         
           
           
               
               
           
         
       
       wherein 
 W is N or CR 6 ;  
 X is N or CR 7 ;  
 Y is NR 8  or CR 9 R 10 ;  
 n is an integer of 2;  
 Z is NR 1 , or CR 12 R 13  with the proviso that when Y is NR 8  then Z must be CR 12 R 13  and at least one of Y and Z must be NR 8  or NR 11 ;  
 R 1 , R 2  and R 7  are each independently H, halogen, CN, OCO 2 R 14 , CO 2 R 15 , CONR 29 R 30 , CONR 29 R 30 , CNR 16 NR 17 R 18 , SO m R 19 , NR 20 R 21 , OR 22 , COR 23  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 9 , R 10 , R 12  and R 13  are each independently H or an optionally substituted C 1 -C 6 alkyl group;  
 R 5  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 m is 0 or an integer of 1 or 2;  
 R 6  is H, halogen, or an optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl group;  
 R 8  and R 1  are each independently H, CNR 26 NR 27 R 28  or a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;  
 R 14 , R 15 , R 22  and R 23  are each independently H or an optionally substituted 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;  
 R 16 , R 17 , R 18 , R 20 , R 21 , R 26 , R 27 , R 28 , R 29  and R 30  are each independently H or C 1 -C 4 alkyl;  
 R 19  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; and  
    represents a single bond or a double bond which process comprises reacting a compound of formula IVa  
                     
 wherein W, X, Y, Z, n, R 1 , R 2 , R 3  and R 4  are as defined above with a sulfonyl chloride, R 5 SO 2 Cl, wherein R 5  is defined above in the presence of a base