1-Aryl-or 1-alkylsulfonylbenzazole 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.

What is claimed is:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 W is SO 2 , CO, CONH, CSNH or CH 2 ;  
 X is CR 7  or N;  
 Y is CR 8  or N with the proviso that when X is N, then Y must be CR 8 ;  
 Z is O, SO p  or NR 9 ;  
 R 1  and R 2  are each independently H or C 1 -C 6 alkyl;  
 n is an integer of 2, 3 or 4;  
 R 3  and R 4  are each independently H, CNR 10 NR 11 R 12 , 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, or R 3  and R 4  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;  
 R 5  is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22  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;  
 m is an integer of 1, 2 or 3;  
 p and q are each independently 0 or an integer of 1 or 2;  
 R 6  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 7  and R 8  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 9  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 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 19  are each independently H or C 1 -C 4 alkyl;  
 R 13  is H, COR 23  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 14  is H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted;  
 R 20  and R 21  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 22  and R 23  are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein W is SO 2 .  
     
     
         3 . The compound according to  claim 1  wherein Z is O.  
     
     
         4 . The compound according to  claim 1  wherein n is 2.  
     
     
         5 . The compound according to  claim 1  wherein R 6  is an aryl or heteroaryl group each optionally substituted.  
     
     
         6 . The compound according to  claim 1  wherein X is CR 7  and R 5  and R 7  are H.  
     
     
         7 . The compound according to  claim 2  wherein R 1  and R 2  are H; Z is O; and n is 2.  
     
     
         8 . The compound according to  claim 6  wherein W is SO 2 ; Z is O; and R 3  and R 4  are taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom.  
     
     
         9 . The compound according to  claim 6  selected from the group consisting of: 
 2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethylamine;  
 4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-1H-indole;  
 1-(phenylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indole;  
 N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine;  
 N,N-bis(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 N-(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 N,N-dimethyl-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 1-(phenylsulfonyl)-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethylamine;  
 N-(2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine;  
 N-(2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-thiopyran-4-amine;  
 1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 1-[(4-fluorophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 4-({4-[2-(1-piperidinyl)ethoxy]-1H-indaazol-1-yl}sulfonyl)aniline; and  
 a pharmaceutically acceptable salt 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 is CR 7  or N;  
 Y is CR 8  or N with the proviso that when X is N, then Y must be CR 8 ;  
 Z is O, SO p  or NR p ;  
 R 1  and R 2  are each independently H or C 1 -C 6 alkyl;  
 n is an integer of 2, 3 or 4;  
 R 3  and R 4  are each independently H, CNR 10 NR 11 R 12 , 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, or R 3  and R 4  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;  
 R 5  is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22  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;  
 m is an integer of 1, 2 or 3;  
 p and q are each independently 0 or an integer of 1 or 2;  
 R 6  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 7  and R 8  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 9  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 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 19  are each independently H or C 1 -C 4 alkyl;  
 R 13  is H, COR 23  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 14  is H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted;  
 R 20  and R 21  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 22  and R 23  are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; or  
 a pharmaceutically acceptable salt 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 cognitive disorder is attention deficit disorder.  
     
     
         14 . The method according to  claim 11  wherein said cognitive disorder is Alzheimer's disease or Parkinson's disease.  
     
     
         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 is CR 7  or N;  
 Y is CR 8  or N with the proviso that when X is N, then Y must be CR 8 ;  
 Z is O, SO p  or NR 9 ;  
 R 1  and R 2  are each independently H or C 1 -C 6 alkyl;  
 n is an integer of 2, 3 or 4;  
 R 3  and R 4  are each independently H, CNR 10 NR 11 R 12 , 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, or R 3  and R 4  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;  
 R 5  is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R   16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22  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;  
 m is an integer of 1, 2 or 3;  
 p and q are each independently 0 or an integer of 1 or 2;  
 R 6  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 7  and R 8  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 9  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 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 19  are each independently H or C 1 -C 4 alkyl;  
 R 13  is H, COR 23  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 14  is H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted;  
 R 20  and R 21  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 22  and R 23  are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . The composition according to  claim 15  wherein W is SO 2 ; Z is O; and n is 2.  
     
     
         17 . The composition according to  claim 16  wherein R 6  is an aryl or heteroaryl group each optionally substituted.  
     
     
         18 . The composition according to  claim 17  wherein X is CR 7  and R 1 , R 2 , R 5 , and R 7  are H.  
     
     
         19 . The composition according to  claim 18  having a formula I compound selected from the group consisting of: 
 2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethylamine;  
 4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-1H-indole;  
 1-(phenylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indole;  
 N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine;  
 N,N-bis(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 N-(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 N,N-dimethyl-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;  
 1-(phenylsulfonyl)-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 2-{[1-(phenylsulfonyl)-1H-indazole-4-yl]oxy}ethylamine;  
 N-(2-{[1-(phenylsulfonyl)-1H-indazole-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine;  
 N-(2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-thiopyran-4-amine;  
 1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 1-[(4-fluorophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;  
 4-({4-[2-(1-piperidinyl)ethoxy]-1H-indazole-1-yl}sulfonyl)aniline; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         20 . A method for the preparation of a compound of formula Ia  
       
         
           
           
               
               
           
         
       
       wherein 
 X is CR 7  or N;  
 Y is CR 8  or N with the proviso that when X is N, then Y must be CR 8 ;  
 Z is O, SO p  or NR 9 ;  
 R 1  and R 2  are each independently H or C 1 -C 6 alkyl;  
 n is an integer of 2, 3 or 4;  
 R 3  and R 4  are each independently H, CNR 10 NR 11 R 12 , 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, or R 3  and R 4  may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;  
 R 5  is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22  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;  
 m is an integer of 1, 2 or 3;  
 p and q are each independently 0 or an integer of 1 or 2;  
 R 6  is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group;  
 R 7  and R 8  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 9  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 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 19  are each independently H or C 1 -C 4 alkyl;  
 R 13  is H, COR 23  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 14  is H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted;  
 R 20  and R 21  are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and  
 R 22  and R 23  are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group which method comprises reacting a compound of formula V′ 
                     
 wherein Hal is Cl, Br or I and X, Y, Z, n, m, R 1 , R 2 , R 5  and R 6  are as defined hereinabove with an amine, HNR 3 R 4 , wherein R 3  and R 4  are defined hereinabove optionally in the presence of a solvent to give the desired compound of formula Ia.