1-aryl- or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands

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.

• 28
• wherein
• W is SO2, CO, CONH, CSNH or CH2;
• X is CR7 or N;
• Y is CR8 or N with the proviso that when X is N, then Y must be CR8;
• Z is O, SOp or NR9;
• R1 and R2 are each independently H or C1-C6alkyl;
• n is an integer of 2, 3 or 4;
• R3 and R4 are each independently H, CNR1, NR11R12, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 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;
• R5 is H, halogen, CN, OR13, CO2R14, CONR16R16, CNR17NR18R19, SO2NR2OR21, SOqR22 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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;
• R6 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
• R7 and R8 are each independently H, halogen or a C1-C6 alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
• R9 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R10, R11, R12, R15, R16, R17, R18 and R19 are each independently H or C1-C4alkyl;
• R13 is H, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
• R14 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• R20 and R21 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• and
• R22 and R23 are each independently an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
• or
• a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I.

• 29
• wherein
• W is SO2, CO, CONH, CSNH or CH2;
• X is CR7 or N;
• Y is CR8 or N with the proviso that when X is N, then Y must be CR8;
• Z is O, SOP or NR8;
• R1 and R2 are each independently H or C1-C6alkyl;
• n is an integer of 2, 3 or 4;
• R3 and R4 are each independently H, CNR10NR11R12, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 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;
• R5 is H, halogen, CN, OR13, Co2R14, CONR15 R16 CNR17NR18R19, SO2NR2OR21, SOqR22 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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;
• R6 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
• R7 and R8 are each independently H, halogen or a C1-C6 alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
• R9 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R10, R11, R12, R15, R16, R17, R18 and R19 are each independently H or C1-C4alkyl;
• R13 is H, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
• R14 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• R20 and R21 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• and
• R22 and R23 are each independently an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
• or
• a pharmaceutically acceptable salt thereof.

A method for the preparation of a compound of formula Ia

• 30
• wherein
• X is CR7 or N;
• Y is CR8 or N with the proviso that when X is N, then Y must be CR8;
• Z is O, SOP or NR9;
• R1 and R2 are each independently H or C1-C6alkyl;
• n is an integer of 2, 3 or 4;
• R3 and R4 are each independently H, CNR10NR11R12, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 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;
• R5 is H, halogen, CN, OR13, CO2R14, CONR15R16, CNR11NR18R19, SO2NR2OR21, SOqR22 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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;
• R6 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
• R7 and R8 are each independently H, halogen or a C1-C6 alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
• R9 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R10, R11, R12, R15, R16, R17, R18 and R19 are each independently H or C1-C4alkyl;
• R13 is H, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
• R14 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• R20 and R21 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
• and
• R22 and R23 are each independently an optionally substituted C1-C6alkyl, aryl or heteroaryl group which method comprises reacting a compound of formula V′
• 31
• wherein Hal is Cl, Br or I and X, Y, Z, n, m, R1, R2, R5 and R6 are as defined hereinabove with an amine, HNR3R4, wherein R3 and R4 are defined hereinabove optionally in the presence of a solvent to give the desired compound of formula Ia.