Acyl piperazine derivatives as TTX-S blockers

A compound of the following formula (I):

• wherein
• R is selected from the group consisting of:
• (1) C1-C6 alkyl and (2) C3-C8 cycloalkyl;
• which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of
• (1) halogen, (2) C1-C6 alkyl, (3) C3-C8 cycloalkyl, (4) hydroxy, (5) C1-C6 alkoxy, (6) amino, (7) C1-C6 alkylamino, (8) di(C1-C6 alkyl)amino, (9) hydroxy C1-C6 alkyl, (10) C1-C6 alkoxy C1-C6 alkyl, (11) C1-C6 alkylsulfonyl, (12) aminosulfonyl, (13) C1-C6 alkyl C(═O)—, (14) HO (O═)C—, (15) C1-C6 alkyl-O (O═)C—, (16) RAN(RB)C(═O)—, (17) C1-C6 alkylsulfonylamino, (18) RAC(═O)N(RB)—, (19) NH2(HN═)C—, and (20) 5 to 10 membered aryl C0-C6 alkyl;
• wherein said aryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkylthio, and nitro;
• W is aryl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of
• (1) halogen, (2) C1-C6 alkyl, (3) C3-C8 cycloalkyl, (4) C1-C6 haloalkyl, (5) hydroxy, (6) C1-C6 alkoxy, (7) C1-C6 haloalkoxy, (8) C1-C6 alkylthio, (9) nitro, (10) amino, (11) C1-C6 alkylamino, (12) di(C1-C6 alkyl)amino, (13) cyano, (14) hydroxy C1-C6 alkyl, (15) C1-C6 alkoxy C1-C6 alkyl, (16) C1-C6 alkylsulfonyl, (17) RAN(RB)SO2—, (18) C1-C6 alkyl C(═O)—, (19) HO (O═)C—, (20) C1-C6alkyl-O (O═)C—, (21) RAN(RB)C(═O)—, (22) C1-C6 alkylsulfonylamino, (23) C3-C8 cycloalkyl, (24) RAC(═O)N(RB)—, (25) NH2(HN═)C—, and (26) 5 to 10 membered aryl C0-C6 alkyl-O0-1—;
• wherein said aryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl C0-C6 alkyl, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkylthio, and nitro;
• RA and RB are independently selected from the group consisting of:
• (1) hydrogen, (2) C1-C6 alkyl, (3) hydroxy C1-C6 alkyl, (4) amino C1-C6 alkyl, (5) C1-C6 haloalkyl, (6) C1-C6 haloalkoxy, (7) C3-C6 alkenyl, (8) C3-C8 cycloalkyl C0-C6 alkyl, and (9) 5 to 10 membered aryl C0-C6 alkyl;
• wherein said aryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl C0-C6 alkyl, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkylthio, and nitro;
• R1 and R2 are independently selected from the group consisting of:
• (1)hydrogen, (2) hydroxy C0-C6 alkyl, (3) halogen, (4) C1-C6 alkyl, (5) C3-C8 cycloalkyl, and (6) C1-C6 alkoxy;
• or R1 and R2 taken together may form a 3 to 8 membered ring, where the ring may contain one to four heteroatom(s) independently selected from nitrogen, oxygen, and sulfur;
• and the ring may be substituted one or more substituents selected from RC;
• or R1 and R2 taken together may be an oxo group;
• RC is selected from the group consisting of:
• (1)hydrogen, (2) hydroxy C0-C6 alkyl, (3) halogen, (4) C1-C6 alkyl, (5) C3-C8 cycloalkyl, and (6) C1-C6 alkoxy;
• R3, R4, R5, and R6 are each independently selected from the group consisting of:
• (1) hydrogen, (2) hydroxy, (3) C1-C6 alkyl, (4) C3-C8 cycloalkyl, (5) C1-C6 alkoxy, (6) RAN(RB)—, (7) RAC(═O)N(RB)—, and (8) RAO—C(═O)N(RB)—;
• or R3 and R4 together may be an oxo group;
• or R5 and R6 together may be an oxo group;
• E is —CHR1—, —CHR1—CH2—, —CO—CH2—, or —CO—;
• p is 0, 1, or 2;
• when p is one or more than one, R3 and R4 may be same or different;
• q is 0, or 1;
• r is 0, 1, or 2;
• when r is one or more than one, R5 and R6 may be same or different;
• X is —O—, or —S—;
• M is —O—, —NRA—, —S—, —SO—, SO2—, NRA—SO2—, or —SO2—NRA—;
• or a pharmaceutically acceptable salt thereof.