Aryl carboxamide derivatives as TTX-S blockers

摘要

The present invention relates to aryl carboxamide derivatives of formula (I), wherein Ar1 is phenyl; Ar2 is aryl; n is 1-4; X is —O—, —S—, —SO— or —SO2—, a prodrug thereof or a pharmaceutically acceptable salt thereof, which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of such disorders and diseases as pain in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases as pain in which voltage gated sodium channels are involved.;

主权项

1. A compound of formula (I) wherein Ar1 is phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of
(1) halogen, (2) C1-C4 alkyl-Oi—, (3) C3-C8 cycloalkyl-Oi—, (4) C1-C4 haloalkyl-Oi—, (5) hydroxy, (6) C3-C8 cycloalkyl-C1-C4 alkyl-Oi—, (7) C1-C4 alkylthio, (8) nitro, (9) R1N(R2)—C0-4 alkyl-Oi— (10) cyano, (11) hydroxy C1-C4 alkyl-Oi—, (12) C1-C4 alkyl-O—C1-C4 alkyl-Oi—, (13) C1-C4 alkylsulfonyl, (14) R1N(R2)—SO2—C0-4 alkyl-Oi—, (15) C1-C4 alkyl C(═O)—, (16) HO—C(═O)—, (17) C1-C4 alkyl-O—C(═O)—, (18) R1N(R2)C(═O)—C0-4 alkyl-Oi—, (19) C1-C4 alkyl-SO2—NH—C0-4 alkyl-Oi—, (20) R1—Oi—C(═O)N(R2)—C0-4 alkyl-Ok—, (21) NH2(HN═)C—,Ar2 is selected from; 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, benzofurazanyl, benzimidazolonyl, 3-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl, 6-benzoimidazolyl, 7-benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, 3-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 3-benzothiophenyl, 4-benzothiophenyl, 5-benzothiophenyl, 6-benzothiophenyl, 7-benzothiophenyl, benzotriazolyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolinyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, isochromanyl, isoquinolyl, isoxazolopyridyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 5-pyridyl, 6-pyridyl, pyrimidyl, pyridazinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1-methyl-4-oxo-1,4-dihydroquinolyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and 5,6,7,8-tetrahydro-1,6-naphthyridyl wherein said 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, benzofurazanyl, benzimidazolonyl, 3-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl, 6-benzoimidazolyl, 7-benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, 3-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 3-benzothiophenyl, 4-benzothiophenyl, 5-benzothiophenyl, 6-benzothiophenyl, 7-benzothiophenyl, benzotriazolyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolinyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, isochromanyl, isoquinolyl, isoxazolopyridyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 5-pyridyl, 6-pyridyl, pyrimidyl, pyridazinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinoxalinyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1-methyl-4-oxo-1,4-dihydroquinolyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and 5,6,7,8-tetrahydro-1,6-naphthyridyl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of (1) halogen, (2) C1-C4 alkyl-Oi—, (3) C3-C8 cycloalkyl-Oi—, (4) C1-C4 haloalkyl-Oi—, (5) hydroxy, (6) C3-C8 cycloalkyl-C1-C4 alkyl-Oi—, (7) C1-C4 alkylthio, (8) nitro, (9) R1N(R2)—C0-4 alkyl-Oi— (10) cyano, (11) hydroxy C1-C4 alkyl-Oi—, (12) C1-C4 alkyl-Oi, (15) C1-C4 alkyl C(═O)—, (16) HO—C(═O)—, (17) C1-C4 alkyl-O—C(═O)—, (18) R1N(R2)C(═O)—C0-4 alkyl-Oi—, (19) C1-C4 alkyl-SO2—NH—C0-4 alkyl-Oi—, (20) R1—Oi—C(═O)N(R2)—C0-4 alkyl-Ok—, (21) NH2(HN═)C—, (22) NH2C(═O)NH—, (23) phenyl-Oi—C0-C4 alkyl-Ok—; wherein said phenyl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C7 cycloalkyl C0-6 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkylthio, C1-C4 alkylsulfonyl, R1N(R2)C(═O)—, C1-C4 alkyl-SO2—NH—, and nitro; said quinolyl may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of
(1) halogen, (2) C1-C4 alkyl-Oi—, (3) C3-C8 cycloalkyl-Oi—, (4) C1-C4 haloalkyl-Oi—, (5) 2-hydroxyl, (6) 3-hydroxyl, (7) 5-hydroxyl, (8) 6-hydroxyl, (9) 7-hydroxyl, (10) 8-hydroxyl, (11) C3-C8 cycloalkyl-C1-C4 alkyl-Oi—, (12) C1-C4 alkylthio, (13) nitro, (14) R1N(R2)—C0-4 alkyl-Oi— (15) cyano, (16) hydroxy C1-C4 alkyl-Oi—, (17) C1-C4 alkyl-Oi—, (20) C1-C4 alkyl C(═O)—, (21) HO—C(═O)—, (22) C1-C4 alkyl-O—C(═O)—, (23) R1N(R2)C(═O)—C0-4 alkyl-Oi—, (24) C1-C4 alkyl-SO2—NH—C0-4 alkyl-Oi—, (25) R1—O, —C(═O)N(R2)—C0-4 alkyl-Ok—, (26) NH2(HN═)C—, (27) NH2C(═O)NH—, (28) phenyl-Oi—C0-C4 alkyl-Ok—; wherein said phenyl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C7 cycloalkyl C0-6 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkylthio, C1-C4 alkylsulfonyl, R1N(R2)C(═O)—, C1-C4 alkyl-SO2—NH—; n is 3; i is 0 or 1; k is 0 or 1; R1 and R2 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6 alkyl, (3) hydroxy C1-C4 alkyl, (4) C1-C4 alkoxy C1-C4 alkyl, (5) amino C1-C4 alkyl, (6) C1-C4 haloalkyl, (7) C1-C4 haloalkoxy, (8) C3-6 alkenyl, (9) C3-8 cycloalkyl C0-6 alkyl, (10) phenyl, which is unsubstituted or substituted with R3, and (11) phenyl C0-C4 alkyl; wherein said phenyl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C7 cycloalkyl C0-6 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkylthio, and nitro; or R1 and R2 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring, where the ring may contain one to four heteroatom(s) independently selected from nitrogen, oxygen, and sulfur; where the ring may be saturated or partially saturated or unsaturated; and the ring is unsubstituted or substituted one or more substituents selected from R3; R3 is selected from the group consisting of: (1) hydroxy, (2) halogen, (3) C1-6 alkyl, (4) —C3-8 cycloalkyl, (5) —O—C1-6 alkyl, (6) —O(C═O)—C1-6 alkyl, (7) —NH—C1-6 alkyl, (8) phenyl, (9) heterocyclic group, (10) —CO2H, and (11) —CN; X is —O—, —S—, —SO—, or —SO2—; or a pharmaceutically acceptable salt thereof.