NOVEL AZOLE DERIVATIVES AS APELIN RECEPTOR AGONIST

Abstract

The present invention relates to a novel azole derivative as an apelin receptor agonist and a method for treating cardiovascular disease, diabetic disease, renal disease, hypertension, and arteriosclerosis, etc., using the same. The present invention provides a compound represented by formula (I) or a pharmacologically acceptable salt thereof wherein X.sup.1 represents —N═ or —CH═, X.sup.2 represents —CH═ or —N═, R.sup.1 and R.sup.2 each represent a C.sub.1 to C.sub.6 alkoxy group or the like, R.sup.3 represents a heteroaryl group (the heteroaryl group is optionally substituted by a methyl group or the like) or the like, and R.sup.4 represents a C.sub.1 to C.sub.6 alkylthio group or a C.sub.2 to C.sub.6 alkenyl group (the C.sub.1 to C.sub.6 alkylthio group and the C.sub.2 to C.sub.6 alkenyl group are each optionally substituted by one carboxy group or the like) or the like.

##STR00001##

Claims

1-39. (canceled)

40. A pharmaceutical composition comprising a compound represented by formula (I), or a pharmacologically acceptable salt thereof: ##STR00195## wherein X.sup.1 is —N═ or —CH═, X.sup.2 is —CH═ or —N═, R.sup.1 and R.sup.2 are each independently a C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, or a halogeno group, wherein the C.sub.1 to C.sub.6 alkyl group and the C.sub.1 to C.sub.6 alkoxy group are each optionally substituted by 1 to 3 fluoro groups; R.sup.3 is an aryl group, a heteroaryl group, a C.sub.1 to C.sub.6 alkyl group, or a C.sub.3 to C.sub.8 cycloalkyl group, wherein the aryl group and the heteroaryl group are each optionally substituted by 1 to 3 identical or different groups selected from the group consisting of: a C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, a trifluoromethyl group, and a halogeno group; and R.sup.4 is a C.sub.1 to C.sub.6 alkylthio group, an aryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.2 to C.sub.6 alkenyl group, an aryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.2 to C.sub.6 alkynyl group, an aryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.1 to C.sub.6 alkyl group, an aryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, an aryl-C.sub.1 to C.sub.6 alkoxy group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, an aryl group, a heteroaryl group, a heterocycloalkyl group, a thiol group, a methylsulfonyl group, a halogeno group, or a hydrogen, wherein the C.sub.1 to C.sub.6 alkylthio group, the aryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.2 to C.sub.6 alkenyl group, the aryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.2 to C.sub.6 alkynyl group, the aryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.1 to C.sub.6 alkyl group, the aryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, the C.sub.1 to C.sub.6 alkoxy group, the aryl-C.sub.1 to C.sub.6 alkoxy group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the aryl group, the heteroaryl group, and the heterocycloalkyl group are each optionally substituted by one group, and the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, and the heteroaryl group are each optionally substituted at the heteroaryl group moiety by 1 to 4 identical or different groups selected from an oxo group, a C.sub.1 to C.sub.6 alkyl group, and a halogeno group; as an active ingredient.

41. The pharmaceutical composition according to claim 40, wherein X.sup.1 is —N═; and X.sup.2 is —CH═.

42. The pharmaceutical composition according to claim 40, wherein R.sup.1 and R.sup.2 are each independently a C.sub.1 to C.sub.6 alkoxy group or a C.sub.1 to C.sub.6 alkyl group.

43. The pharmaceutical composition according to claim 40, wherein R.sup.3 is a furyl group, a thienyl group, a pyridyl group, a phenyl group, a n-butyl group, or a cyclopentyl group, wherein the furyl group, the thienyl group, the pyridyl group, and the phenyl group are each optionally substituted by 1 or 2 groups each independently selected from a methyl group and a halogeno group.

44. The pharmaceutical composition according to claim 40, wherein R.sup.3 is a 5-methylfuran-2-yl group.

45. The pharmaceutical composition according to claim 40, wherein the compound is represented by formula (II): ##STR00196## or a pharmacologically acceptable salt thereof.

46. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a C.sub.1 to C.sub.6 alkylthio group, an aryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.2 to C.sub.6 alkenyl group, an aryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.2 to C.sub.6 alkynyl group, an aryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.1 to C.sub.6 alkyl group, an aryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, an aryl-C.sub.1 to C.sub.6 alkoxy group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group, wherein the C.sub.1 to C.sub.6 alkylthio group, the aryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.2 to C.sub.6 alkenyl group, the aryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.2 to C.sub.6 alkynyl group, the aryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.1 to C.sub.6 alkyl group, the aryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, the C.sub.1 to C.sub.6 alkoxy group, the aryl-C.sub.1 to C.sub.6 alkoxy group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the aryl group, the heteroaryl group, and the heterocycloalkyl group are each optionally substituted by one group selected from a carboxy group, a triazolylsulfonyl group, a carboxymethoxy group, a methylsulfonylamino group, a, a (2S)-2-carboxypyrrolidin-1-ylcarbonyl group, a (2S, 4R)-2-carboxy-4-hydroxypyrrolidin-1-ylcarbonyl group, a benzenesulfonylaminocarbonyl group, a phosphoryl group, an amino group, a carbamoyl group, a dimethylcarbamoyl group, an oxo group, a hydroxy group, and a cyano group, and the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, and the heteroaryl group are each optionally substituted at the heteroaryl group moiety by 1 to 4 identical or different groups selected from an oxo group, a C.sub.1 to C.sub.6 alkyl group, and a halogeno group.

47. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a C.sub.1 to C.sub.6 alkylthio group, an aryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.2 to C.sub.6 alkenyl group, an aryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.2 to C.sub.6 alkynyl group, an aryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.1 to C.sub.6 alkyl group, an aryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, an aryl-C.sub.1 to C.sub.6 alkoxy group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group, wherein the C.sub.1 to C.sub.6 alkylthio group, the aryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.2 to C.sub.6 alkenyl group, the aryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.2 to C.sub.6 alkynyl group, the aryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.1 to C.sub.6 alkyl group, the aryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, the C.sub.1 to C.sub.6 alkoxy group, the aryl-C.sub.1 to C.sub.6 alkoxy group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, the aryl group, the heteroaryl group, and the heterocycloalkyl group are each substituted by one group selected from a carboxy group, a triazolylsulfonyl group, a carboxymethoxy group, a methylsulfonylamino group, a 4-methylbenzenesulfonylamino group, a (2S)-2-carboxypyrrolidin-1-ylcarbonyl group, a (2S, 4R)-2-carboxy-4-hydroxypyrrolidin-1-ylcarbonyl group, a benzenesulfonylaminocarbonyl group, and a phosphoryl group.

48. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a C.sub.1 to C.sub.6 alkylthio group, an aryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, a C.sub.1 to C.sub.6 alkoxy group, an aryl-C.sub.1 to C.sub.6 alkoxy group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, or a heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group, and wherein the C.sub.1 to C.sub.6 alkylthio group, the aryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkylthio group, the C.sub.1 to C.sub.6 alkoxy group, the aryl-C.sub.1 to C.sub.6 alkoxy group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkoxy group, and the heterocycloalkyl-C.sub.1 to C.sub.6 alkoxy group are each substituted by one group selected from a carboxy group, a benzenesulfonylaminocarbonyl group, and a phosphoryl group.

49. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a C.sub.2 to C.sub.6 alkenyl group, an aryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, a C.sub.2 to C.sub.6 alkynyl group, an aryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, a C.sub.1 to C.sub.6 alkyl group, an aryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, a heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, an aryl group, a heteroaryl group, or a heterocycloalkyl group, wherein the C.sub.2 to C.sub.6 alkenyl group, the aryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkenyl group, the C.sub.2 to C.sub.6 alkynyl group, the aryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the heterocycloalkyl-C.sub.2 to C.sub.6 alkynyl group, the C.sub.1 to C.sub.6 alkyl group, the aryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the C.sub.3 to C.sub.8 cycloalkyl-C.sub.1 to C.sub.6 alkyl group, the heterocycloalkyl-C.sub.1 to C.sub.6 alkyl group, the aryl group, the heteroaryl group, and the heterocycloalkyl group are each substituted by one group selected from a carboxy group, a triazolylsulfonyl group, a carboxymethoxy group, a methylsulfonylamino group, a 4-methylbenzenesulfonylamino group, a (2S)-2-carboxypyrrolidin-1-ylcarbonyl group, and a (2S, 4R)-2-carboxy-4-hydroxypyrrolidin-1-ylcarbonyl group.

50. The pharmaceutical composition according to claim 40, wherein R.sup.4 is: ##STR00197## ##STR00198## ##STR00199## or a pharmacologically acceptable salt thereof.

51. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, or a heteroaryl group, wherein the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, and the heteroaryl group are each optionally substituted at the heteroaryl group moiety by 1 to 4 identical or different groups selected from an oxo group, a C.sub.1 to C.sub.6 alkyl group, and a halogeno group.

52. The pharmaceutical composition according to claim 40, wherein R.sup.4 is a heteroaryl-C.sub.1 to C.sub.6 alkylthio group, a heteroaryl-C.sub.2 to C.sub.6 alkenyl group, a heteroaryl-C.sub.2 to C.sub.6 alkynyl group, a heteroaryl-C.sub.1 to C.sub.6 alkyl group, a heteroaryl-C.sub.1 to C.sub.6 alkoxy group, or a heteroaryl group, wherein the heteroaryl-C.sub.1 to C.sub.6 alkylthio group, the heteroaryl-C.sub.2 to C.sub.6 alkenyl group, the heteroaryl-C.sub.2 to C.sub.6 alkynyl group, the heteroaryl-C.sub.1 to C.sub.6 alkyl group, the heteroaryl-C.sub.1 to C.sub.6 alkoxy group, and the heteroaryl group are each optionally substituted at the heteroaryl group moiety by 1 or 2 oxo groups.

53. The pharmaceutical composition according to claim 40, or a pharmacologically acceptable salt thereof, wherein R.sup.4 is ##STR00200##

54. The pharmaceutical composition according to claim 40, wherein the compound is selected from the group consisting of: {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, 4-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoic acid, {[5-(5-Bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, {[4-(2,6-Diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, {[4-(2,4-Dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-2-methylpropanoic acid, {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(naphthalen-1-yl)acetic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoic acid, {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]oxy}acetic acid, 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-N-(phenylsulfonyl)acetamide, ({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)phosphonic acid, (2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid, 3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]propanoic acid, 3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid, 4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid, (2Z)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid, {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methoxy}acetic acid, 4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole, N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}methanesulfonamide, N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}-4-methylbenzenesulfonamide, 1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-L-proline, (4R)-1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-4-hydroxy-L-proline, 6-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrimidine-2,4(1H,3H)-dione, 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, 4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyridin-2(1H)-one, 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1H-tetrazole, 3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2,4-oxadiazol-5(2H)-one, 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3,4-oxadiazol-2(3H)-one, and 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2-dihydro-3H-pyrazol-3-one; or a pharmacologically acceptable salt thereof.

55. A method for treating or preventing a disease in a subject, comprising administering the pharmaceutical composition of claim 40 to the subject.

56. A method for treating or preventing a disease in a subject, comprising administering the pharmaceutical composition of claim 54 to the subject.

57. The method according to claim 56, wherein the disease is cardiovascular disease, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling, myocardial remodeling after infarction, myocardial remodeling after cardiac surgery, valvular heart disease, metabolic disease, metabolic syndrome, insulin resistance, diabetes mellitus, diabetic late complications, diabetic macrovasculopathy, diabetic microvasculopathy, diabetic nephropathy, diabetic retinopathy, diabetic neuropathies, cardiac autonomic neuropathy, CNS-dependent disturbed fluid homeostasis, CNS-independent disturbed fluid homeostasis, acute renal failure, chronic renal failure, hypertension, pulmonary hypertension, portal hypertension, systolic hypertension, vascular disease, vascular hypertrophy, vascular remodeling, vascular stiffness, atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis, thrombosis, vascular permeability disorder, cardiac, renal, or retinal disorder caused by ischemia, or cardiac, renal, or retinal disorder caused by reperfusion.

58. A method for agonizing apelin receptor activity in a subject, comprising administering a pharmaceutical composition according to claim 40 to the subject.

59. A method for treating a disease or condition in a subject, comprising administering to the subject a pharmaceutical composition according to claim 40, wherein the disease or condition is treatable by agonizing apelin receptors.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0202] Hereinafter, the present invention will be described in detail with reference to Examples, etc. However, the scope of the present invention is not intended to be limited by them.

[0203] Elution in column chromatography in Examples was carried out under observation by thin layer chromatography (TLC). In the TLC observation, silica gel 60F.sub.254 (Merck KGaA) was used as a TLC plate; a solvent used as an eluting solvent in column chromatography was used as a developing solvent; and a UV detector or a chromogenic method using a coloring agent (e.g., a ninhydrin coloring solution, an anisaldehyde coloring solution, an ammonium phosphomolybdate coloring solution, a cerium ammonium nitrate coloring solution, or an alkaline permanganate coloring solution) was used as a detection method.

[0204] Silica gel SK-85 (230-400 mesh) (Merck KGaA), silica gel 60 N (40-50 μm) (Kanto Chemical Co., Inc.), or Chromatorex NH (200-350 mesh) (Fuji Silysia Chemical Ltd.) was used as silica gel for columns.

[0205] In addition to general column chromatography, an automatic chromatography apparatus such as Purif-α2 or Purif-espoir2 (Shoko Scientific Co., Ltd.), W-Prep 2XY (Yamazen Corp.), Isolera One (Biotage Japan Ltd.), or CombiFlash Rf (Teledyne Isco, Inc.) was appropriately used. The eluting solvent was determined on the basis of the TLC observation.

[0206] In Examples, nuclear magnetic resonance (.sup.1H NMR) spectra were indicated by chemical shift 6 values (ppm) determined with tetramethylsilane (TMS) as a standard. CDCl.sub.3, DMSO-d.sub.6, and CD.sub.3OD in the parentheses means deuterated chloroform, deuterated dimethylsulfoxide, and deuterated methanol used as a measurement solvent. Multiplicity in .sup.1H-NMR means s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br s=broad singlet, and br m=broad multiplet.

[0207] Mass spectrometry (MS) was conducted by electron spray ionization (ESI), or atmospheric pressure chemical ionization (APCI) method by using liquid chromatography mass spectrometry (LCMS) device.

[0208] In each step of Examples, the preparation of a reaction solution and reaction were carried out at room temperature unless the temperature is otherwise specified.

EXAMPLES

Example 1

4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

Step 1

2-Isothiocyanato-1,3-dimethoxybenzene

[0209] ##STR00026##

[0210] To a mixed solution of dichloromethane (500 mL) and water (500 mL), 2,6-dimethoxyaniline (75.8 g, 495 mmol) and sodium hydrogen carbonate (83.1 g, 990 mmol) were added, and thiophosgene (62.6 g, 544 mmol) was added in small portions with stirring under ice cooling. The mixture was stirred for 10 minutes under ice cooling and then stirred at room temperature for 1 hour. An organic layer was separated, and dichloromethane was added to the aqueous layer to extract organic matter. The organic layers were combined, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, n-hexane was added to the obtained solid, and the resulting solid was collected by filtration to obtain the title compound (88.5 g, 454 mmol, 92%) as a white solid.

[0211] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.89 (6H, s), 6.54 (2H, d, J=8.5 Hz), 7.14 (1H, t, J=8.5 Hz). MS (APCI): m/z 182 [M+H].sup.+.

Step 2

N-(2,6-Dimethoxyphenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide

[0212] ##STR00027##

[0213] To a suspension of 2-isothiocyanato-1,3-dimethoxy-benzene (62.7 g, 321 mmol) in tetrahydrofuran (642 mL), 5-methylfuran-2-carbohydrazide (45.0 g, 321 mmol) was added at room temperature, and the mixture was heated to reflux for 1.5 hours. The solvent in the reaction solution was distilled off under reduced pressure to obtain the partially purified title compound (107.7 g, 321 mmol, quantitative) as a faint yellow amorphous form. The obtained faint yellow amorphous form was used in the next reaction without being purified.

[0214] MS (APCI): m/z 336 [M+H].sup.+.

Step 3

4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

[0215] ##STR00028##

[0216] To N-(2,6-dimethoxyphenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide (107.7 g, 321 mmol), 1 mol/L aqueous sodium hydroxide solution (642 mL, 642 mmol) was added at room temperature, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, 1 mol/L hydrochloric acid (642 mL, 642 mmol) was added in small portions thereto with stirring, and the mixture was stirred at room temperature for 30 minutes. The resulting white precipitate was collected by filtration, fully washed with water and n-hexane, and then dried under reduced pressure at 50° C. to obtain the title compound (96.2 g, 303 mmol, 94%) as a white solid.

[0217] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.32 (3H, s), 3.78 (6H, s), 5.79 (1H, d, J=3.6 Hz), 5.88-5.92 (1H, m), 6.73 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz), 10.63 (1H, s). MS (APCI): m/z 318 [M+H].sup.+.

Example 2

2-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0218] ##STR00029##

[0219] To a mixture of 2-(chloromethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one (44.0 mg, 0.208 mmol), 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (60.0 mg, 0.189 mmol), and potassium carbonate (33.0 mg, 0.236 mmol), acetone (1.0 mL) was added, and the mixture was stirred at 65° C. for 1.5 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate/methanol=30/70/0-0/100/0-0/90/10 (V/V)] to obtain the title compound (82 mg, 0.168 mmol, 89%) as a white solid.

[0220] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 2.42 (3H, s), 3.71 (6H, s), 4.41 (2H, s), 5.87-5.90 (1H, m), 5.91 (1H, d, J=3.6 Hz), 6.51 (1H, s), 6.66 (2H, d, J=8.5 Hz), 7.43 (1H, t, J=8.5 Hz), 7.52 (1H, d, J=9.1 Hz), 7.58 (1H, dd, J=9.1, 1.8 Hz), 8.81 (1H, s). MS (APCI): m/z 490 [M+H].sup.+.

Example 3

7-Chloro-2-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-4H-pyrido[1,2-a]pyrimidin-4-one

[0221] ##STR00030##

[0222] The title compound (92 mg, 0.181 mmol, 96%) was obtained as a white solid from 7-chloro-2-(chloromethyl)pyrido[1,2-a]pyrimidin-4-one (47.6 mg, 0.208 mmol) and 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (60.0 mg, 0.189 mmol) in the same way as in Example 2.

[0223] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.71 (6H, s), 4.38 (2H, s), 5.88-5.90 (1H, m), 5.92 (1H, d, J=3.6 Hz), 6.56 (1H, s), 6.67 (2H, d, J=8.5 Hz), 7.44 (1H, t, J=8.5 Hz), 7.53 (1H, d, J=9.1 Hz), 7.64 (1H, dd, J=9.4, 2.1 Hz), 9.01 (1H, d, J=1.8 Hz). MS (APCI): m/z 510 [M+H].sup.+.

Example 4

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0224] ##STR00031##

[0225] To a mixture of bromoacetic acid ethyl ester (40 μL, 0.352 mmol), 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (93 mg, 0.294 mmol), and potassium carbonate (51 mg, 0.367 mmol), acetone (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite to remove insoluble matter. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=60/40-30/70 (V/V)] to obtain the title compound (110 mg, 0.273 mmol, 93%) as a white solid.

[0226] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.26 (3H, t, J=7.1 Hz), 2.27 (3H, s), 3.73 (6H, s), 4.05 (2H, s), 4.18 (2H, q, J=7.1 Hz), 5.88-5.90 (1H, m), 5.92 (1H, d, J=3.0 Hz), 6.68 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 404 [M+H].sup.+.

Example 5

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0227] ##STR00032##

[0228] To ethyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (101 mg, 0.251 mmol), ethanol was added, then 1 mol/L aqueous sodium hydroxide solution (0.50 mL, 0.50 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Ethanol in the reaction solution was distilled off, then the residue was diluted by the addition of water, and 1 mol/L hydrochloric acid (0.50 mL, 0.50 mmol) was added to the mixture. Ethyl acetate was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (83 mg, 0.221 mmol, 88%) as a white solid.

[0229] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.75 (6H, s), 4.12 (2H, s), 5.92-5.95 (1H, m), 6.02 (1H, d, J=3.0 Hz), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 376 [M+H].sup.+.

Example 6

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0230] ##STR00033##

[0231] To a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (96.1 g, 303 mmol) in dichloromethane (388 mL), a solution of hydrogen peroxide (62.4 mL, 757 mmol) in acetic acid (173 mL, 3029 mmol) was added dropwise with stirring under ice cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was stirred under ice cooling. The pH of the aqueous layer was rendered neutral by the addition of 1 mol/L aqueous sodium hydroxide solution (500 mL) and 28% aqueous ammonia solution, and the mixture was stirred at room temperature for 30 minutes (the disappearance of peroxide was confirmed using potassium iodide starch paper). An organic layer was separated, followed by further extraction twice by the addition of dichloromethane. The organic layers were combined, washed with an aqueous sodium hydrogensulfite solution (approximately 500 mL) and saturated saline, and dried over anhydrous magnesium sulfate. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography [elution solvent: dichloromethane] to obtain a light brown solid. The solid was crystallized from dichloromethane-ethyl acetate to obtain the title compound (46.1 g, 161 mmol, 53%) as a white solid.

[0232] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.71 (6H, s), 5.91-5.93 (1H, m), 6.02 (1H, d, J=3.0 Hz), 6.68 (2H, d, J=8.5 Hz), 7.44 (1H, t, J=8.5 Hz), 8.04 (1H, s). MS (APCI): m/z 286 [M+H].sup.+.

Example 7

[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanol

[0233] ##STR00034##

[0234] To 4-(2,6-dimethoxyphenyl)-3-(5-methylfuran-2-yl)-4H-1,2,4-triazole (38.8 g, 136 mmol), a 36% aqueous formaldehyde solution (131 mL, 2720 mmol) was added, and the mixture was heated and stirred at 90° C. for 1 hour under the nitrogen atmosphere. The reaction solution was diluted by the addition of dichloromethane and washed with 1 mol/L aqueous sodium hydroxide solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/ethyl acetate=70/30-30/70 (V/V))] to obtain the title compound (26.9 g, 85.3 mmol, 63%) as a white solid.

[0235] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 2.37 (1H, t, J=6.4 Hz, —OH), 3.73 (6H, s), 4.56 (2H, d, J=6.4 Hz), 5.87 (1H, d, J=3.6 Hz), 5.89-5.92 (1H, m), 6.71 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz). MS (APCI): m/z 316 [M+H].sup.+.

Example 8

Ethyl (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

Step 1

4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde

[0236] ##STR00035##

[0237] To a solution of [4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanol (33.3 g, 106 mmol) in dichloromethane (530 mL), Dess-Martin periodinane (53.8 g, 127 mmol) was added in small portions with stirring under ice cooling, and the mixture was then stirred for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution under ice cooling, and the mixture was stirred for 15 minutes. Insoluble matter was filtered off through celite, and an organic layer was separated. Dichloromethane was added to the aqueous layer for extraction, and the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/ethyl acetate=95/5-50/50 (V/V)] to obtain the title compound (19.4 g, 62.1 mmol, 59%) as a white solid.

[0238] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.33 (3H, s), 3.69 (6H, s), 5.96-5.98 (1H, m), 6.05 (1H, d, J=3.6 Hz), 6.69 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz), 10.04 (1H, s). MS (APCI): m/z 314 [M+H].sup.+ and 332, [M+H.sub.2O+H].sup.+.

Step 2

Ethyl (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

[0239] ##STR00036##

[0240] To a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-carbaldehyde (19.38 g, 61.86 mmol) in toluene (620 mL), ethyl (triphenylphosphoranylidene)acetate (25.86 g, 74.23 mmol) was added, and the mixture was stirred at 90° C. for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/ethyl acetate=100/0-80/20 (V/V)] to obtain the title compound (18.8 g, 49.0 mmol, 79%) as a white solid.

[0241] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.28 (3H, t, J=7.0 Hz), 2.29 (3H, s), 3.70 (6H, s), 4.20 (2H, q, J=7.0 Hz), 5.89-5.93 (2H, m), 6.70 (2H, d, J=8.5 Hz), 6.86 (1H, d, J=15.8 Hz), 7.10 (1H, d, J=15.8 Hz), 7.49 (1H, t, J=8.5 Hz). MS (APCI): m/z 384 [M+H].sup.+.

Example 9

(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid

[0242] ##STR00037##

[0243] To a solution of ethyl (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate (469 mg, 1.22 mmol) in ethanol, 1 mol/L aqueous sodium hydroxide solution (2.50 mL, 2.50 mmol) was added, and the mixture was stirred for 1.5 hours. 1 mol/L hydrochloric acid (2.50 mL, 2.50 mmol) was added thereto under ice cooling, and ethanol was then distilled off under reduced pressure. The resulting white solid was collected by filtration to obtain the title compound (389 mg, 1.10 mmol, 90%).

[0244] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.71 (6H, s), 5.91-5.94 (1H, m), 5.98 (1H, d, J=3.6 Hz), 6.71 (2H, d, J=8.5 Hz), 7.14 (2H, br s), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+.

Example 10

4-(2,6-Dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol

Step 1

N-(2,6-Dimethoxyphenyl)-2-(thiophen-2-ylcarbonyl)hydrazinecarbothioamide

[0245] ##STR00038##

[0246] The partially purified title compound (1.32 g, 3.90 mmol, quantitative) was obtained as a white amorphous form from 2-thiophenecarboxylic hydrazide (554 mg, 3.90 mmol) in the same way as in step 2 of Example 1. The obtained white solid was used in the next reaction without being purified.

[0247] MS (APCI): m/z 338 [M+H].sup.+.

Step 2

4-(2,6-Dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol

[0248] ##STR00039##

[0249] The title compound (1.00 g, 80%) was obtained as a white solid from N-(2,6-dimethoxyphenyl)-2-(thiophen-2-ylcarbonyl)hydrazinecarbothioamide (1.32 g, 3.90 mmol) in the same way as in step 3 of Example 1.

[0250] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 3.70 (6H, s), 6.88 (2H, d, J=8.5 Hz), 6.98 (1H, dd, J=3.7, 1.2 Hz), 7.04 (1H, dd, J=4.9, 3.7 Hz), 7.55 (1H, t, J=8.5 Hz), 7.65-7.68 (1H, m), 14.01 (1H, s). MS (APCI): m/z 320 [M+H].sup.+.

Example 11

[2-({[4-(2,6-Dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0251] ##STR00040##

[0252] The title compound (124.3 mg, 0.253 mmol, 79%) was obtained as a white solid from 2-(chloromethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one (73.0 mg, 0.350 mmol) and 4-(2,6-dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol (102 mg, 0.318 mmol) in the same way as in Example 2.

[0253] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.41 (3H, s), 3.71 (6H, s), 4.42 (2H, s), 6.55 (1H, s), 6.67 (2H, d, J=8.5 Hz), 6.89-6.95 (1H, m), 7.12 (1H, d, J=3.0 Hz), 7.25 (1H, d, J=4.9 Hz), 7.46 (1H, t, J=8.5 Hz), 7.52 (1H, d, J=9.1 Hz), 7.59 (1H, d, J=9.1 Hz), 8.81 (1H, s). MS (APCI): m/z 492 [M+H].sup.+.

Example 12

Ethyl 3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]propanoate

[0254] ##STR00041##

[0255] To a solution of ethyl (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate (469 mg, 1.22 mmol) in methanol (20 mL), a 10% palladium carbon catalyst (112 mg, 0.1223 mmol) was added, and the mixture was stirred at room temperature for 5 hours under the hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/ethyl acetate=90/10-30/70 (V/V)] to obtain the title compound (223 mg, 0.579 mmol, 47%) as a white solid.

[0256] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 1.16 (3H, t, J=7.1 Hz), 2.23 (3H, s), 2.56-2.62 (2H, m), 2.64-2.71 (2H, m), 3.71 (6H, s), 4.03 (2H, q, J=7.1 Hz), 5.81 (1H, d, J=3.0 Hz), 6.07-6.09 (1H, m), 6.92 (2H, d, J=8.5 Hz), 7.57 (1H, t, J=8.5 Hz). MS (APCI): m/z 386 [M+H].sup.+.

Example 13

3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]propanoic acid

[0257] ##STR00042##

[0258] The title compound 3-[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-4H-1,2,4-triazol-3-yl]propanoic acid (176 mg, 0.493 mmol, 89%) was obtained as a white solid from ethyl 3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]propanoate (214 mg, 0.556 mmol) in the same way as in Example 9.

[0259] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.26 (3H, s), 2.82 (2H, t, J=7.3 Hz), 2.97 (2H, t, J=7.3 Hz), 3.73 (6H, s), 5.87-5.91 (2H, m), 6.70 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz). MS (APCI): m/z 358 [M+H].sup.+.

Example 14

6-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrimidine-2,4(1H,3H)-dione

[0260] ##STR00043##

[0261] The title compound (31 mg, 0.071 mmol, 45%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (51 mg, 0.159 mmol) and 6-chloromethyluracil (31 mg, 0.191 mmol) in the same way as in Example 2.

[0262] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.74 (6H, s), 3.96 (2H, s), 5.52 (1H, s), 5.92-5.94 (1H, m), 6.01 (1H, d, J=3.0 Hz), 6.69 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz), 7.90 (1H, br s), 11.49 (1H, br s). MS (APCI): m/z 442 [M+H].sup.+.

Example 15

6-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

[0263] ##STR00044##

[0264] The title compound (37 mg, 0.079 mmol, 50%) was obtained as a pale yellow solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (50 mg, 0.157 mmol) and 6-(chloromethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (36 mg, 0.188 mmol) in the same way as in Example 2.

[0265] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.30 (3H, s), 3.42 (3H, s), 3.72 (6H, s), 4.21 (2H, s), 5.74 (1H, s), 5.90-5.93 (1H, m), 5.97 (1H, d, J=3.6 Hz), 6.69 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz). MS (APCI): m/z 470 [M+H].sup.+.

Example 16

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0266] ##STR00045##

[0267] The title compound (53 mg, 0.114 mmol, 74%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (49 mg, 0.154 mmol) and 5-(chloromethyl)-4H,7H-pyrazolo[1,5-a]pyrimidin-7-one (34 mg, 0.185 mmol) in the same way as in Example 2.

[0268] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.31 (3H, s), 3.73 (6H, s), 4.13 (2H, s), 5.72 (1H, s), 5.92-5.98 (2H, m), 6.21 (1H, d, J=1.2 Hz), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz), 7.88 (1H, s). MS (APCI): m/z 465 [M+H].sup.+.

Example 17

4-(2,6-Dimethoxyphenyl)-3-ethyl-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

Step 1

4-(2,6-Dimethoxyphenyl)-3-ethenyl-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0269] ##STR00046##

[0270] A suspension of methyltriphenylphosphonium bromide (89 mg, 0.249 mmol) in tetrahydrofuran (2.0 mL) was stirred under ice cooling, and potassium tert-butoxide (28 mg, 0.249 mmol) was added thereto. After stirring for 1 hour, a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (60 mg, 0.192 mmol) in tetrahydrofuran (2.0 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/methanol=100/0-95/5 (V/V)] to obtain the title compound (58 mg, 0.187 mmol, 98%) as a colorless oil.

[0271] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.70 (6H, s), 5.41 (1H, dd, J=10.9, 1.8 Hz), 5.84-5.87 (1H, m), 5.88-5.90 (1H, m), 6.13 (1H, dd, J=18.2, 1.8 Hz), 6.23 (1H, dd, J=18.2, 10.9 Hz), 6.69 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 312 [M+H].sup.+.

Step 2

4-(2,6-Dimethoxyphenyl)-3-ethyl-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0272] ##STR00047##

[0273] The title compound (44 mg, 0.141 mmol, 76%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-3-ethenyl-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole (58 mg, 0.187 mmol) in the same way as in Example 12.

[0274] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.20 (3H, t, J=7.5 Hz), 2.28 (3H, s), 2.52 (2H, q, J=7.5 Hz), 3.71 (6H, s), 5.78 (1H, d, J=3.0 Hz), 5.85-5.88 (1H, m), 6.69 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 314 [M+H].sup.+.

Example 18

4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyridin-2(1H)-one

[0275] ##STR00048##

[0276] The title compound (55 mg, 0.129 mmol, 79%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (52 mg, 0.163 mmol) and 4-(chloromethyl)-1H-pyridin-2-one (28.1 mg, 0.195 mmol) in the same way as in Example 2.

[0277] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.70 (6H, s), 4.17 (2H, s), 5.88-5.90 (1H, m), 5.92 (1H, d, J=3.0 Hz), 6.30 (1H, dd, J=6.7, 1.8 Hz), 6.42 (1H, s), 6.67 (2H, d, J=8.5 Hz), 7.23 (1H, d, J=7.3 Hz), 7.45 (1H, t, J=8.5 Hz), 12.83 (1H, br s). MS (APCI): m/z 425 [M+H].sup.+.

Example 19

(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enamide

[0278] ##STR00049##

[0279] To a suspension of (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (51 mg, 0.143 mmol) in dichloromethane (2.0 mL), triethylamine (26 μL, 0.186 mmol) was added, and isobutyl chloroformate (24 μL, 0.179 mmol) was added dropwise with stirring under ice cooling. After stirring for 20 minutes, ammonia (ca. 4% in methanol) (0.72 mL, 1.43 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/methanol=100/0-95/5 (V/V)] to obtain the title compound (42 mg, 0.119 mmol, 83%) as a white solid.

[0280] .sup.1H-NMR (400 MHz, CD.sub.3OD) δ (ppm): 2.27 (3H, s), 3.76 (6H, s), 6.05-6.08 (2H, m), 6.89 (1H, d, J=15.8 Hz), 6.92 (2H, d, J=8.5 Hz), 7.02 (1H, d, J=15.8 Hz), 7.63 (1H, t, J=8.5 Hz). MS (APCI): m/z 355 [M+H].sup.+.

Example 20

(3E)-4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]but-3-en-2-one

[0281] ##STR00050##

[0282] To a mixture of (acetylmethylene)triphenylphosphorane (196 mg, 0.617 mmol) and 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (149 mg, 0.474 mmol), toluene (5.0 mL) and tetrahydrofuran (1.0 mL) were added, and the mixture was stirred at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=30/70-10/90 (V/V)] to obtain the title compound (157 mg, 0.445 mmol, 94%) as a white solid.

[0283] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 2.30 (3H, s), 3.70 (6H, s), 5.88-5.93 (2H, m), 6.71 (2H, d, J=8.5 Hz), 6.97 (1H, d, J=15.9 Hz), 7.14 (1H, d, J=15.9 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 354 [M+H].sup.+.

Example 21

(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]-N,N-dimethylprop-2-enamide

[0284] ##STR00051##

[0285] The title compound (49 mg, 0.128 mmol, 84%) was obtained as a white solid from (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (54 mg, 0.152 mmol) and dimethylamine (2.0 M solution in tetrahydrofuran, 0.76 mL, 1.52 mmol) in the same way as in Example 19.

[0286] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.02 (3H, s), 3.17 (3H, s), 3.69 (6H, s), 5.86 (1H, d, J=3.1 Hz), 5.89-5.92 (1H, m), 6.68 (2H, d, J=8.5 Hz), 7.00 (1H, d, J=15.3 Hz), 7.46 (1H, t, J=8.5 Hz), 7.61 (1H, d, J=15.3 Hz). MS (APCI): m/z 383 [M+H].sup.+.

Example 22

4-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoic acid

Step 1

Ethyl 4-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoate

[0287] ##STR00052##

[0288] The title compound (66 mg, 0.154 mmol, 58%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (85 mg, 0.267 mmol) and 4-bromo-n-butyric acid ethyl ester (46 μL, 0.321 mmol) in the same way as in Example 4.

[0289] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.23 (3H, t, J=7.0 Hz), 1.98-2.05 (2H, m), 2.28 (3H, s), 2.39 (2H, t, J=7.3 Hz), 3.18 (2H, t, J=7.0 Hz), 3.72 (6H, s), 4.10 (2H, q, J=7.0 Hz), 5.87-5.90 (2H, m), 6.68 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz).

[0290] MS (APCI): m/z 432 [M+H].sup.+.

Step 2

4-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoic acid

[0291] ##STR00053##

[0292] The title compound (58 mg, 0.145 mmol, 97%) was obtained as a white solid from 4-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoate (64 mg, 0.148 mmol) in the same way as in Example 5.

[0293] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.02-2.09 (2H, m), 2.26 (3H, s), 2.54 (2H, t, J=7.0 Hz), 3.23 (2H, t, J=7.0 Hz), 3.73 (6H, s), 5.89-5.92 (1H, m), 5.98 (1H, d, J=3.0 Hz), 6.69 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz). MS (APCI): m/z 404 [M+H].sup.+.

Example 23

(3E)-4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]but-3-en-2-ol

[0294] ##STR00054##

[0295] To a solution of (3E)-4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]but-3-en-2-one (66 mg, 0.187 mmol) and cerium chloride anhydrous (55 mg, 0.224 mmol) in methanol (2.0 mL), sodium borohydride (9.2 mg, 0.261 mmol) was added in small portions with stirring under ice cooling, and the mixture was stirred at 0° C. for 15 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/methanol=100/0-85/15 (V/V)] to obtain the title compound (48 mg, 0.136 mmol, 73%) as a white solid.

[0296] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.28 (3H, d, J=6.7 Hz), 2.28 (3H, s), 3.68 (6H, s), 4.39-4.45 (1H, m), 5.82 (1H, d, J=3.6 Hz), 5.88 (1H, d, J=3.6 Hz), 6.08 (1H, d, J=16.4 Hz), 6.69 (2H, d, J=8.5 Hz), 6.82 (1H, dd, J=16.4, 5.2 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+.

Example 24

4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]butan-2-one

[0297] ##STR00055##

[0298] The title compound (24 mg, 0.069 mmol, 29%) was obtained as a white solid (crystals) from (3E)-4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]but-3-en-2-one (84 mg, 0.237 mmol) in the same way as in Example 12.

[0299] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.17 (3H, s), 2.28 (3H, s), 2.66-2.71 (2H, m), 3.03-3.09 (2H, m), 3.71 (6H, s), 5.79 (1H, d, J=3.0 Hz), 5.86-5.88 (1H, m), 6.68 (2H, d, J=8.5 Hz), 7.45 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+.

Example 25

4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]butan-2-ol

[0300] ##STR00056##

[0301] To a solution of 4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]butan-2-one (52 mg, 0.145 mmol) in methanol (3.0 mL), sodium borohydride (7.3 mg, 0.174 mmol) was added with stirring under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane/methanol=100/0-80/20 (V/V)] to obtain the title compound (45 mg, 0.126 mmol, 87%) as a white solid.

[0302] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.16 (3H, d, J=6.7 Hz), 1.72-1.87 (2H, m), 2.27 (3H, s), 2.53-2.70 (2H, m), 3.71 (3H, s), 3.72 (3H, s), 3.80-3.89 (1H, m), 5.81 (1H, d, J=3.0 Hz), 5.86-5.89 (1H, m), 6.70 (2H, dd, J=8.5, 1.8 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 358 [M+H].sup.+.

Example 26

{[5-(5-Bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

2-[(5-Bromofuran-2-yl)carbonyl]-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide

[0303] ##STR00057##

[0304] The partially purified title compound (4.10 g, 10.3 mmol, quantitative) was obtained as a white amorphous form 5-bromofuran-2-carbohydrazide (2.11 g, 10.3 mmol) and 2-isothiocyanato-1,3-dimethoxy-benzene (2.00 g, 10.3 mmol) in the same way as in step 2 of Example 1. The obtained white amorphous form was used in the next reaction without being purified.

[0305] MS (APCI): m/z 400 [M+H].sup.+.

Step 2

5-(5-Bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazole-3-thiol

[0306] ##STR00058##

[0307] The title compound (3.88 g, 10.2 mmol, 99%) was obtained from 2-[(5-bromofuran-2-yl)carbonyl]-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide (4.10 g, 10.3 mmol) in the same way as in step 3 of Example 1.

[0308] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.79 (6H, s), 5.93 (1H, d, J=3.6 Hz), 6.25 (1H, d, J=3.6 Hz), 6.73 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz), 10.90 (1H, s). MS (APCI): m/z 382 [M+H].sup.+.

Step 3

Ethyl {[5-(5-bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0309] ##STR00059##

[0310] The title compound (3.53 g, 7.53 mmol, 93%) was obtained as a white solid from 5-(5-bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (3.10 g, 8.11 mmol) and ethyl 2-chloroacetate (1.04 mL, 9.73 mmol) in the same way as in Example 4.

[0311] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.26 (3H, t, J=7.3 Hz), 3.75 (6H, s), 4.06 (2H, s), 4.19 (2H, q, J=7.3 Hz), 6.21 (1H, d, J=3.6 Hz), 6.25 (1H, d, J=3.6 Hz), 6.68 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 468 [M+H].sup.+.

[Step 4]

{[5-(5-Bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0312] ##STR00060##

[0313] To ethyl {[5-(5-bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (90 mg, 0.192 mmol), tetrahydrofuran (1.0 mL) and ethanol (1.0 mL) were added, then 1 mol/L aqueous sodium hydroxide solution (0.384 mL, 0.384 mmol) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour. 1 mol/L hydrochloric acid (0.38 mL, 0.38 mmol) was added to the reaction solution, and the solvent was concentrated under reduced pressure. The deposited solid was collected by filtration to obtain the title compound (77 mg, 0.174 mmol, 91%) as a white solid.

[0314] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.77 (6H, s), 3.93 (2H, s), 6.28-6.31 (2H, m), 6.70 (2H, d, J=8.5 Hz), 7.51 (1H, t, J=8.5 Hz). MS (APCI): m/z 440 [M+H].sup.+.

Example 27

{[4-(2,6-Dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

N-(2,6-Dimethoxyphenyl)-2-(pyridin-3-ylcarbonyl)hydrazinecarbothioamide

[0315] ##STR00061##

[0316] The partially purified title compound (0.343 g, 1.03 mmol, quantitative) was obtained as a faint yellow solid from nicotinic acid hydrazide (141 mg, 1.03 mmol) and 2-isothiocyanato-1,3-dimethoxy-benzene (201 mg, 1.03 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified.

[0317] MS (APCI): m/z 333 [M+H].sup.+.

Step 2

4-(2,6-Dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol

[0318] ##STR00062##

[0319] The title compound (296 mg, 0.940 mmol, 91%) was obtained as a white solid from N-(2,6-dimethoxyphenyl)-2-(pyridin-3-ylcarbonyl)hydrazinecarbothioamide (0.343 g, 1.03 mmol) in the same way as in step 3 of Example 1.

[0320] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.77 (6H, s), 6.66 (2H, d, J=8.5 Hz), 7.23-7.28 (1H, m), 7.43 (1H, t, J=8.5 Hz), 7.71-7.74 (1H, m), 8.62 (1H, dd, J=4.9, 2.1 Hz), 8.66 (1H, d, J=2.1 Hz), 10.63 (1H, br s). MS (APCI): m/z 315 [M+H].sup.+.

Step 3

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0321] ##STR00063##

[0322] The title compound (181 mg, 0.451 mmol, 99%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (144 mg, 0.458 mmol) and ethyl 2-chloroacetate (0.059 mL, 0.549 mmol) in the same way as in Example 4.

[0323] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.0 Hz), 3.71 (6H, s), 4.09 (2H, s), 4.21 (2H, q, J=7.0 Hz), 6.63 (2H, d, J=8.5 Hz), 7.21-7.27 (1H, m), 7.41 (1H, t, J=8.5 Hz), 7.88 (1H, dt, J=7.9, 1.8 Hz), 8.55 (1H, dd, J=4.9, 1.2 Hz), 8.62 (1H, d, J=1.8 Hz). MS (APCI): m/z 401 [M+H].sup.+.

Step 4

{[4-(2,6-Dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0324] ##STR00064##

[0325] The title compound (69 mg, 0.185 mmol, 82%) was obtained as a white solid from ethyl {[4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (91 mg, 0.226 mmol) in the same way as in step 4 of Example 26.

[0326] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.72 (6H, s), 3.95 (2H, s), 6.65 (2H, d, J=8.5 Hz), 7.30 (1H, dd, J=7.9, 4.9 Hz), 7.45 (1H, t, J=8.5 Hz), 7.87 (1H, d, J=7.9 Hz), 8.58-8.63 (2H, br m). MS (APCI): m/z 373 [M+H].sup.+.

Example 28

{[4-(2,6-Dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

2-Benzoyl-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide

[0327] ##STR00065##

[0328] The partially purified title compound (0.339 g, 1.03 mmol, quantitative) was obtained as a white solid from benzohydrazide (139 mg, 1.02 mmol) and 2-isothiocyanato-1,3-dimethoxy-benzene (200 mg, 1.02 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified.

[0329] MS (APCI): m/z 332 [M+H].sup.+.

Step 2

4-(2,6-Dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazole-3-thiol

[0330] ##STR00066##

[0331] The title compound (285 mg, 0.909 mmol, 89%) was obtained as a white solid from 2-benzoyl-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide (0.339 g, 1.02 mmol) in the same way as in step 3 of Example 1.

[0332] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.75 (6H, s), 6.65 (2H, d, J=8.5 Hz), 7.25-7.32 (2H, m), 7.35-7.44 (4H, m), 10.77 (1H, br s). MS (APCI): m/z 314 [M+H].sup.+.

Step 3

Ethyl {[4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0333] ##STR00067##

[0334] The title compound (117 mg, 0.293 mmol, 98%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazole-3-thiol (94 mg, 0.300 mmol) and ethyl 2-chloroacetate (0.038 mL, 0.360 mmol) in the same way as in Example 4.

[0335] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.1 Hz), 3.69 (6H, s), 4.07 (2H, s), 4.20 (2H, q, J=7.1 Hz), 6.62 (2H, d, J=8.5 Hz), 7.23-7.34 (3H, m), 7.39 (1H, t, J=8.5 Hz), 7.44-7.48 (2H, m). MS (APCI): m/z 400 [M+H].sup.+.

Step 4

{[4-(2,6-Dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0336] ##STR00068##

[0337] The title compound (67 mg, 0.180 mmol, 65%) was obtained as a white solid from ethyl 2-[[4-(2,6-dimethoxyphenyl)-5-phenyl-1,2,4-triazol-3-yl]sulfanyl]acetate (110 mg, 0.275 mmol) in the same way as in step 4 of Example 26.

[0338] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.70 (6H, s), 3.99 (2H, s), 6.64 (2H, d, J=8.5 Hz), 7.27-7.33 (2H, m), 7.34-7.47 (4H, m). MS (APCI): m/z 372 [M+H].sup.+.

Example 29

{[5-Butyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

N-(2,6-Dimethoxyphenyl)-2-pentanoylhydrazinecarbothioamide

[0339] ##STR00069##

[0340] The partially purified title compound (0.324 g, 1.04 mmol, quantitative) was obtained as a white solid from valeric acid hydrazide (121 mg, 1.04 mmol) and 2-isothiocyanato-1,3-dimethoxy-benzene (203.1 mg, 1.04 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified.

[0341] MS (APCI): m/z 312 [M+H].sup.+.

Step 2

5-Butyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazole-3-thiol

[0342] ##STR00070##

[0343] The title compound (222 mg, 0.757 mmol, 73%) was obtained as a white solid from N-(2,6-dimethoxyphenyl)-2-pentanoylhydrazinecarbothioamide (0.324 g, 1.04 mmol) in the same way as in step 3 of Example 1.

[0344] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.83 (3H, t, J=7.3 Hz), 1.24-1.35 (2H, m), 1.49-1.57 (2H, m), 2.34 (2H, t, J=7.6 Hz), 3.82 (6H, s), 6.71 (2H, d, J=8.5 Hz), 7.45 (1H, t, J=8.5 Hz), 10.29 (1H, br s). MS (APCI): m/z 294 [M+H].sup.+.

Step 3

Ethyl {[5-butyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0345] ##STR00071##

[0346] The title compound (57 mg, 0.151 mmol, 50%) was obtained as a white solid from 5-butyl-4-(2,6-dimethoxyphenyl)-1,2,4-triazole-3-thiol (88 mg, 0.300 mmol) and ethyl 2-chloroacetate (0.038 mL, 0.360 mmol) in the same way as in Example 4.

[0347] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.81 (3H, t, J=7.6 Hz), 1.22-1.33 (5H, m), 1.53-1.60 (2H, m), 2.45 (2H, t, J=7.9 Hz), 3.77 (6H, s), 3.94 (2H, s), 4.16 (2H, q, J=7.1 Hz), 6.67 (2H, d, J=8.5 Hz), 7.41 (1H, t, J=8.5 Hz). MS (APCI): m/z 380 [M+H].sup.+.

Step 4

{[5-Butyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0348] ##STR00072##

[0349] The title compound (42 mg, 0.120 mmol, 88%) was obtained as a white solid from ethyl 2-[[5-butyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl]acetate (51 mg, 0.135 mmol) in the same way as in step 4 of Example 26.

[0350] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.84 (3H, t, J=7.3 Hz), 1.24-1.36 (2H, m), 1.56-1.63 (2H, m), 2.48 (2H, t, J=7.6 Hz), 3.81 (6H, s), 3.88 (2H, s), 6.70 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 352 [M+H].sup.+.

Example 30

{[4-(2,6-Dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0351] ##STR00073##

[0352] The title compound (18 mg, 0.290 mmol, 94%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol (99 mg, 0.309 mmol) and ethyl 2-chloroacetate (40 μL, 0.371 mmol) in the same way as in Example 4.

[0353] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.0 Hz), 3.73 (6H, s), 4.05 (2H, s), 4.20 (2H, q, J=7.0 Hz), 6.69 (2H, d, J=8.5 Hz), 6.93 (1H, dd, J=5.5, 3.6 Hz), 7.12 (1H, dd, J=3.6, 1.2 Hz), 7.25 (2H, d, J=1.2 Hz), 7.49 (1H, t, J=8.5 Hz). MS (APCI): m/z 406 [M+H].sup.+.

Step 2

{[4-(2,6-Dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0354] ##STR00074##

[0355] The title compound (98 mg, 0.259 mmol, 94%) was obtained as a white solid from ethyl {[4-(2,6-dimethoxyphenyl)-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (112 mg, 0.276 mmol) in the same way as in step 4 of Example 26.

[0356] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.75 (6H, s), 3.94 (2H, s), 6.71 (2H, d, J=8.5 Hz), 6.97 (1H, dd, J=4.9, 3.6 Hz), 7.17 (1H, dd, J=3.6, 1.2 Hz), 7.33 (1H, dd, J=4.9, 1.2 Hz), 7.53 (1H, t, J=8.5 Hz). MS (APCI): m/z 378 [M+H].sup.+.

Example 31

{[4-(2,6-Diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

N-(2,6-Diethylphenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide

[0357] ##STR00075##

[0358] The partially purified title compound (0.497 g, 1.50 mmol, quantitative) was obtained as a white solid from 2,6-diethylphenyl isothiocyanate (287 mg, 1.50 mmol) and 5-methylfuran-2-carbohydrazide (210 mg, 1.50 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified.

[0359] MS (APCI): m/z 332 [M+H].sup.+.

Step 2

4-(2,6-Diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

[0360] ##STR00076##

[0361] The title compound (419 mg, 1.34 mmol, 89%) was obtained as a white solid from N-(2,6-diethylphenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide (497 mg, 1.50 mmol) in the same way as in step 3 of Example 1.

[0362] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.14 (6H, t, J=7.3 Hz), 2.30-2.34 (5H, m), 2.44-2.48 (2H, m), 5.43 (1H, d, J=3.0 Hz), 5.87-5.87 (1H, m), 7.32 (2H, d, J=7.3 Hz), 7.51-7.53 (1H, m), 11.01 (1H, br s). MS (APCI): m/z 314 [M+H].sup.+.

Step 3

Ethyl {[4-(2,6-diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0363] ##STR00077##

[0364] The title compound (114 mg, 0.285 mmol, 95%) was obtained as a colorless oil from 4-(2,6-diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (94 mg, 0.30 mmol) and ethyl 2-chloroacetate (0.038 mL, 0.36 mmol) in the same way as in Example 4.

[0365] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.07 (6H, t, J=7.6 Hz), 1.28 (3H, t, J=7.3 Hz), 2.17-2.39 (6H, m), 4.18 (2H, s), 4.21 (2H, q, J=7.3 Hz), 5.63 (1H, d, J=3.0 Hz), 5.84-5.88 (1H, m), 7.29 (2H, d, J=7.3 Hz), 7.49 (1H, t, J=7.3 Hz). MS (APCI): m/z 400 [M+H].sup.+.

Step 4

{[4-(2,6-Diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0366] ##STR00078##

[0367] The title compound (86 mg, 0.232 mmol, 85%) was obtained as a white solid from ethyl {[4-(2,6-diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (110 mg, 0.275 mmol) in the same way as in step 4 of Example 26.

[0368] .sup.1H-NMR (DMSO-d.sub.6) δ (ppm): 0.99 (6H, t, J=7.6 Hz), 2.08-2.28 (7H, m), 4.12 (2H, s), 5.61 (1H, d, J=3.6 Hz), 6.08-6.11 (1H, m), 7.40 (2H, d, J=7.9 Hz), 7.57 (1H, t, J=7.9 Hz). MS (APCI): m/z 372 [M+H].sup.+.

Example 32

{[4-(2,6-Dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

N-(2,6-Dichlorophenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide

[0369] ##STR00079##

[0370] The partially purified title compound (0.516 g, 1.50 mmol, quantitative) was obtained as a white solid from 2,6-dichlorophenyl isothiocyanate (306 mg, 1.50 mmol) and 5-methylfuran-2-carbohydrazide (210 mg, 1.50 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified. MS (APCI): m/z 344 [M+H].sup.+.

Step 2

4-(2,6-Dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

[0371] ##STR00080##

[0372] To N-(2,6-dichlorophenyl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide (0.516 g, 1.50 mmol), 1 mol/L aqueous sodium hydroxide solution (3.0 mL, 3.00 mmol) was added, and the mixture was heated to reflux for 1 hour. 5 mol/L hydrochloric acid (0.60 mL, 3.00 mmol) was added to the reaction solution with stirring under ice cooling, and the resulting white precipitate was collected by filtration to obtain the partially purified title compound (549 mg) as a white solid. The obtained compound was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=90/10-40/60 (V/V)] to obtain the title compound (259 mg, 0.795 mmol, 53%) as a white solid.

[0373] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 5.93-5.99 (2H, m), 7.48-7.54 (1H, m), 7.55-7.60 (2H, m), 11.41 (1H, br s). MS (APCI): m/z 326 [M+H].sup.+.

Step 3

Ethyl {[4-(2,6-dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0374] ##STR00081##

[0375] The title compound (113 mg, 0.273 mmol, 91%) was obtained as a colorless oil from 4-(2,6-dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (98 mg, 0.30 mmol) and ethyl 2-chloroacetate (0.038 mL, 0.360 mmol) in the same way as in Example 4.

[0376] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.3 Hz), 2.21 (3H, s), 4.14 (2H, s), 4.21 (2H, q, J=7.3 Hz), 5.95-5.98 (1H, m), 6.19 (1H, d, J=3.6 Hz), 7.46-7.57 (3H, m). MS (APCI): m/z 412 [M+H].sup.+.

Step 4

{[4-(2,6-Dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0377] ##STR00082##

[0378] The title compound (96 mg, 0.251 mmol, 95%) was obtained as a white solid from ethyl {[4-(2,6-dichlorophenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (109 mg, 0.264 mmol) in the same way as in step 4 of Example 26.

[0379] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 2.22 (3H, s), 4.04 (2H, d, J=1.8 Hz), 5.86 (1H, d, J=3.7 Hz), 6.11-6.15 (1H, m), 7.59-7.73 (2H, m), 7.96 (1H, dd, J=7.6, 1.5 Hz), 13.02 (1H, br s). MS (APCI): m/z 384 [M+H].sup.+.

Example 33

{[5-Cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

2-(Cyclopentylcarbonyl)-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide

[0380] ##STR00083##

[0381] The partially purified title compound (0.485 g, 1.50 mmol, quantitative) was obtained as a faint yellow solid from 2-isothiocyanato-1,3-dimethoxy-benzene (293 mg, 1.50 mmol) and cyclopentanecarbohydrazide (192 mg, 1.50 mmol) in the same way as in step 2 of Example 1. The obtained compound was used in the next reaction without being purified.

[0382] MS (APCI): m/z=324 [M+H].sup.+.

Step 2

5-Cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazole-3-thiol

[0383] ##STR00084##

[0384] The title compound (392 mg, 1.28 mmol, 86%) was obtained as a white solid from 2-(cyclopentylcarbonyl)-N-(2,6-dimethoxyphenyl)hydrazinecarbothioamide (0.485 g, 1.50 mmol) in the same way as in step 3 of Example 1.

[0385] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.46-1.56 (2H, m), 1.66-1.86 (6H, m), 2.59-2.66 (1H, m), 3.82 (6H, s), 6.70 (2H, d, J=8.5 Hz), 7.44 (1H, t, J=8.5 Hz), 10.47 (1H, s). MS (APCI): m/z=306 [M+H].sup.+.

Step 3

Ethyl {[5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0386] ##STR00085##

[0387] The title compound ethyl 2-[[5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl]acetate (81 mg, 0.207 mmol, 69%) was obtained as a colorless oil from 5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (92 mg, 0.300 mmol) and ethyl 2-chloroacetate (0.0384 mL, 0.360 mmol) in the same way as in Example 4.

[0388] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.25 (3H, t, J=7.3 Hz), 1.44-1.56 (2H, m), 1.69-1.80 (4H, m), 1.84-1.95 (2H, m), 2.66-2.74 (1H, m), 3.78 (6H, s), 3.96 (2H, s), 4.17 (2H, q, J=7.3 Hz), 6.67 (2H, d, J=8.5 Hz), 7.42 (1H, t, J=8.5 Hz). MS (APCI): m/z=392 [M+H].sup.+.

Step 4

{[5-Cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0389] ##STR00086##

[0390] The title compound (56 mg, 0.154 mmol, 74%) was obtained as a white solid from ethyl {[5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (81 mg, 0.207 mmol) in the same way as in step 4 of Example 26.

[0391] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.46-1.60 (2H, m), 1.71-1.93 (6H, m), 2.69-2.79 (1H, m), 3.80 (6H, s), 3.86 (2H, s), 6.69 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 364 [M+H].sup.+.

Example 34

{[4-(2,4-Dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

3-Isothiocyanato-2,4-dimethoxypyridine

[0392] ##STR00087##

[0393] The title compound (563 mg, 2.87 mmol, 89%) was obtained as a white solid from thiophosgene (274 μL, 3.568 mmol) and 2,4-dimethoxypyridin-3-amine (500 mg, 3.24 mmol) in the same way as in step 1 of Example 1.

[0394] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.94 (3H, s), 4.01 (3H, s), 6.55 (1H, d, J=6.1 Hz), 7.94 (1H, d, J=6.1 Hz). MS (APCI): m/z=197 [M+H].sup.+.

Step 2

N-(2,4-Dimethoxypyridin-3-yl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide

[0395] ##STR00088##

[0396] The partially purified title compound (0.506 g, 1.50 mmol, quantitative) was obtained as a faint yellow solid from 3-isothiocyanato-2,4-dimethoxypyridine (294 mg, 1.50 mmol) and 5-methylfuran-2-carbohydrazide (210 mg, 1.50 mmol) in the same way as in step 2 of Example 1.

[0397] MS (APCI): m/z=337 [M+H].sup.+.

Step 3

4-(2,4-Dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

[0398] ##STR00089##

[0399] The title compound (431 mg, 1.36 mmol, 90%) was obtained as a white solid from N-(2,4-dimethoxypyridin-3-yl)-2-[(5-methylfuran-2-yl)carbonyl]hydrazinecarbothioamide (0.506 g, 1.50 mmol) in the same way as in step 3 of Example 1.

[0400] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.86 (3H, s), 3.91 (3H, s), 5.94-5.97 (1H, m), 6.00 (1H, d, J=3.7 Hz), 6.73 (1H, d, J=6.1 Hz), 8.29 (1H, d, J=6.1 Hz), 10.90 (1H, s). MS (APCI): m/z=319 [M+H].sup.+.

Step 4

Ethyl {[4-(2,4-dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0401] ##STR00090##

[0402] The title compound (115 mg, 0.284 mmol, 95%) was obtained as a white solid from 4-(2,4-dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (96 mg, 0.300 mmol) and ethyl 2-chloroacetate (0.038 mL, 0.360 mmol) in the same way as in Example 4.

[0403] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.26 (3H, t, J=7.0 Hz), 2.24 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 4.00-4.11 (2H, m), 4.19 (2H, q, J=7.0 Hz), 5.94-5.96 (1H, m), 6.19 (1H, d, J=3.1 Hz), 6.69 (1H, d, J=6.1 Hz), 8.24 (1H, d, J=6.1 Hz). MS (APCI): m/z=405 [M+H].sup.+.

Step 5

{[4-(2,4-Dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0404] ##STR00091##

[0405] The title compound (77 mg, 0.204 mmol, 76%) was obtained as a white solid from ethyl {[4-(2,4-dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (109 mg, 0.269 mmol) in the same way as in step 4 of Example 26.

[0406] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.24 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 3.98-4.11 (2H, m), 5.98-6.01 (1H, m), 6.28 (1H, d, J=3.0 Hz), 6.71 (1H, d, J=6.1 Hz), 8.27 (1H, d, J=6.1 Hz). MS (APCI): m/z=377 [M+H].sup.+.

Example 35

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetic acid

Step 1

Methyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetate

[0407] ##STR00092##

[0408] To a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (59 mg, 0.186 mmol) in acetone (3.0 mL), potassium carbonate (32 mg, 0.232 mmol) and methyl alpha-bromophenylacetate (51 mg, 0.223 mmol) were added, and the mixture was heated to reflux for 1 hour. The reaction solution was allowed to cool to room temperature and then filtered through celite, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=40/60-20/85 (V/V)] to obtain the title compound (85 mg, 0.183 mmol, 99%) as a white solid.

[0409] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.26 (3H, s), 3.53 (3H, s), 3.72 and 3.75 (total 6H, each s), 5.61 (1H, s), 5.86-5.88 (1H, m), 5.89-5.92 (1H, m), 6.59 (1H, d, J=8.5 Hz), 6.67 (1H, d, J=8.5 Hz), 7.25-7.31 (3H, m), 7.38-7.45 (3H, m). MS (APCI): m/z 466 [M+H].sup.+.

Step 2

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetic acid

[0410] ##STR00093##

[0411] The title compound (75 mg, 0.166 mmol, 95%) was obtained as a white solid from methyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetate (81 mg, 0.174 mmol) in the same way as in step 4 of Example 26.

[0412] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.20 (3H, s), 3.55 and 3.70 (total 6H, each s), 5.63 (1H, s), 5.86 (1H, m), 5.91 (1H, m), 6.60 (1H, d, J=8.5 Hz), 6.65 (1H, d, J=8.5 Hz), 7.11-7.23 (3H, m), 7.35-7.49 (3H, m). MS (APCI): m/z 452 [M+H].sup.+.

Example 36

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-2-methylpropanoic acid

Step 1

Ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-2-methylpropanoate

[0413] ##STR00094##

[0414] The title compound (98 mg, 0.227 mmol, 75%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (97 mg, 0.305 mmol) and 2-bromoisobutyric acid ethyl ester (54 μL, 0.366 mmol) in the same way as in step 1 of Example 35.

[0415] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.23 (3H, t, J=7.0 Hz), 1.53 (6H, s), 2.27 (3H, s), 3.70 (6H, s), 4.12 (2H, q, J=7.0 Hz), 5.88-5.91 (1H, m), 5.96 (1H, d, J=3.0 Hz), 6.66 (2H, d, J=8.5 Hz), 7.45 (1H, t, J=8.5 Hz). MS (APCI): m/z 432 [M+H].sup.+.

Step 2

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-2-methylpropanoic acid

[0416] ##STR00095##

[0417] The title compound (80 mg, 0.197 mmol, 90%) was obtained as a white solid from ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-2-methylpropanoate (94 mg, 0.218 mmol) in the same way as in step 4 of Example 26.

[0418] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.59 (6H, s), 2.28 (3H, s), 3.73 (6H, s), 5.93 (1H, d, J=3.0 Hz), 6.00 (1H, d, J=3.0 Hz), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 404 [M+H].sup.+.

Example 37

Methyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(naphthalen-1-yl)acetate

[0419] ##STR00096##

[0420] The title compound (106 mg, 0.206 mmol, 67%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and alpha-bromo-1-naphthaleneacetic acid ethyl ester (152 mg, 0.519 mmol) in the same way as in step 1 of Example 35.

[0421] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.26 (3H, s), 3.39 (3H, s), 3.73 and 3.76 (total 6H, each s), 5.85-5.89 (1H, m), 5.92 (1H, d, J=3.6 Hz), 6.34 (1H, s), 6.49 (1H, d, J=8.5 Hz), 6.66 (1H, d, J=8.5 Hz), 7.34-7.42 (2H, m), 7.45-7.53 (2H, m), 7.61 (1H, d, J=7.3 Hz), 7.78 (1H, d, J=8.5 Hz), 7.81-7.85 (1H, m), 8.10 (1H, d, J=8.5 Hz). MS (APCI): m/z 516 [M+H].sup.+.

Example 38

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(naphthalen-1-yl)acetic acid

[0422] ##STR00097##

[0423] The title compound (93 mg, 0.184 mmol, 98%) was obtained as a white solid from methyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(naphthalen-1-yl)acetate (97 mg, 0.189 mmol) in the same way as in step 4 of Example 26.

[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.23 (3H, s), 3.52 and 3.56 (total 6H, each s), 5.91 and 5.92 (total 1H, each s), 6.09-6.12 (2H, m), 6.55 (2H, dd, J=12.1, 8.5 Hz), 7.39 (2H, t, J=8.5 Hz), 7.44-7.53 (2H, m), 7.66 (1H, d, J=6.7 Hz), 7.79 (1H, d, J=8.5 Hz), 7.81-7.85 (1H, m), 8.00-8.05 (1H, m). MS (APCI): m/z 502 [M+H].sup.+.

Example 39

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoic acid

Step 1

Ethyl 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoate

[0425] ##STR00098##

[0426] The title compound (144 mg, 0.291 mmol, 97%) was obtained as a white oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and ethyl 2-bromo-3-phenyl-propanoate (93 mg, 0.360 mmol) in the same way as in step 1 of Example 35.

[0427] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.07 (3H, t, J=7.0 Hz), 2.28 (3H, s), 3.15-3.30 (2H, m), 3.697 and 3.701 (total 6H, each s), 3.98-4.06 (2H, m), 4.48-4.53 (1H, m), 5.89-5.91 (1H, m), 5.94 (1H, d, J=3.0 Hz), 6.67 (2H, d, J=8.5 Hz), 7.14-7.27 (5H, m), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z=494 [M+H].sup.+.

Step 2

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoic acid

[0428] ##STR00099##

[0429] The title compound (118 mg, 0.253 mmol, 90%) was obtained as a white solid from ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoate (139 mg, 0.281 mmol) in the same way as in step 4 of Example 26.

[0430] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 2.98-3.05 (1H, m), 3.45-3.52 (1H, m), 3.55 and 3.74 (total 6H, each s), 4.37-4.43 (1H, m), 5.93-5.96 (1H, m), 6.14 (1H, d, J=3.0 Hz), 6.61-6.70 (2H, m), 7.16-7.28 (5H, m), 7.48 (1H, t, J=8.5 Hz). MS (APCI): m/z 466 [M+H].sup.+.

Example 40

3-(Benzylsulfanyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0431] ##STR00100##

[0432] The title compound (32 mg, 0.0793 mmol, 39%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (64 mg, 0.202 mmol) and benzyl bromide (29 μL, 0.243 mmol) in the same way as in step 1 of Example 35.

[0433] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.66 (6H, s), 4.41 (2H, s), 5.87-5.90 (2H, m), 6.65 (2H, d, J=8.5 Hz), 7.19-7.32 (5H, m), 7.43 (1H, t, J=8.5 Hz). MS (APCI): m/z 408 [M+H].sup.+.

Example 41

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoic acid

Step 1

Ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoate

[0434] ##STR00101##

[0435] The title compound (119 mg, 0.285 mmol, 95%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and ethyl 2-bromopropionate (65 mg, 0.360 mmol) in the same way as in step 1 of Example 35.

[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.23 (3H, t, J=7.3 Hz), 1.56 (3H, d, J=7.3 Hz), 2.28 (3H, s), 3.72 and 3.72 (total 6H, each s), 4.15 (2H, q, J=7.3 Hz), 4.39 (1H, q, J=7.3 Hz), 5.88-5.91 (1H, m), 5.92 (1H, d, J=3.6 Hz), 6.68 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 418 [M+H].sup.+.

Step 2

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoic acid

[0437] ##STR00102##

[0438] The title compound (84 mg, 0.215 mmol, 79%) was obtained as a white solid from ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoate (114 mg, 0.273 mmol) in the same way as in step 4 of Example 26.

[0439] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.56 (3H, d, J=7.3 Hz), 2.28 (3H, s), 3.74 and 3.75 (total 6H, each s), 4.19 (1H, q, J=7.3 Hz), 5.92-5.95 (1H, m), 6.01 (1H, d, J=3.6 Hz), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z=390 [M+H].sup.+.

Example 42

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid

Step 1

Ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoate

[0440] ##STR00103##

[0441] The title compound (121 mg, 0.272 mmol, 91%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and ethyl 2-bromovalerate (0.360 mmol) in the same way as in step 1 of Example 35.

[0442] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.87 (3H, t, J=7.3 Hz), 1.23 (3H, t, J=7.0 Hz), 1.29-1.42 (2H, m), 1.77-1.95 (2H, m), 2.27 (3H, s), 3.71 and 3.72 (total 6H, each s), 4.15 (2H, q, J=7.3 Hz), 4.28 and 4.30 (total 1H, each d, J=6.1 Hz), 5.88-5.90 (1H, m), 5.92 (1H, d, J=3.0 Hz), 6.67 (2H, dd, J=8.5, 1.2 Hz), 7.45 (1H, t, J=8.5 Hz). MS (APCI): m/z 446 [M+H].sup.+.

Step 2

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid

[0443] ##STR00104##

[0444] The title compound (103 mg, 0.248 mmol, 95%) was obtained as a white solid from ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoate (116 mg, 0.261 mmol) in the same way as in step 4 of Example 26.

[0445] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.90 (3H, t, J=7.3 Hz), 1.36-1.53 (2H, m), 1.69-1.79 (1H, m), 2.02-2.13 (1H, m), 2.28 (3H, s), 3.74 and 3.75 (total 6H, each s), 4.00-4.06 (1H, m), 5.92-5.95 (1H, m), 5.99-6.02 (1H, m), 6.6 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z=418 [M+H].sup.+.

Example 43

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoic acid

Step 1

Ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoate

[0446] ##STR00105##

[0447] The title compound (130 mg, 0.292 mmol, 97%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and ethyl 2-bromo-3-methyl-butanoate (77 mg, 0.360 mmol) in the same way as in step 1 of Example 35.

[0448] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 6: 0.98 and 1.01 (total 6H, each d, J=6.7 Hz), 1.24 (3H, t, J=7.3 Hz), 2.17-2.26 (1H, m), 2.27 (3H, s), 3.72 and 3.72 (total 6H, each s), 4.15 (2H, q, J=7.3 Hz), 4.29 (1H, d, J=6.1 Hz), 5.87-5.90 (1H, m), 5.91 (1H, d, J=3.6 Hz), 6.68 (2H, d, J=8.5 Hz), 7.45 (1H, t, J=8.5 Hz). MS (APCI): m/z=446 [M+H].sup.+.

Step 2

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoic acid

[0449] ##STR00106##

[0450] The title compound (84 mg, 0.200 mmol, 71%) was obtained as a white solid from ethyl 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoate (125 mg, 0.281 mmol) in the same way as in step 4 of Example 26.

[0451] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 0.98 and 1.11 (total 6H, each d, J=6.7 Hz), 2.29 (3H, s), 2.39-2.48 (1H, m), 3.61 (1H, d, J=8.5 Hz), 3.72 and 3.75 (total 6H, each s), 5.92-5.95 (1H, m), 6.00 (1H, d, J=3.0 Hz), 6.71 (2H, dd, J=8.5, 3.0 Hz), 7.51 (1H, t, J=8.5 Hz). MS (APCI): m/z 418 [M+H].sup.+.

Example 44

3-Bromo-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0452] ##STR00107##

[0453] To a solution of 4-(2,6-dimethoxyphenyl)-3-(5-methylfuran-2-yl)-4H-1,2,4-triazole (202 mg, 0.708 mmol) in tetrahydrofuran (3.5 mL), N-bromosuccinimide (151 mg, 0.850 mmol) was added at room temperature, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=60/40-30/70 (V/V)] to obtain the title compound (245 mg, 0.672 mmol, 95%) as a white solid.

[0454] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 6: 2.29 (3H, s), 3.74 (6H, s), 5.90-5.92 (1H, m), 5.93-5.95 (1H, m), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 364 [M+H].sup.+.

Example 45

Methyl 3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoate

[0455] ##STR00108##

[0456] To a mixed solution of 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole (120 mg, 0.330 mmol) in toluene (1.90 mL) and tetrahydrofuran (0.95 mL), 3-(methoxycarbonyl)phenylboronic acid (119 mg, 0.659 mmol), potassium phosphate tribasic (200 mg, 0.989 mmol), bis(dibenzylideneacetone)palladium(0) (9.5 mg, 0.0165 mmol), and 2-dicyclohexylphosphino-2,6′-dimethoxybiphenyl (27 mg, 0.0659 mmol) were added, and the mixture was heated and stirred at 130° C. for 1 hour in a microwave reaction apparatus. Potassium phosphate tribasic (210 mg, 0.989 mmol), bis(dibenzylideneacetone)palladium(0) (20 mg, 0.0330 mmol), 2-dicyclohexylphosphino-2,6′-dimethoxybiphenyl (54 mg, 0.132 mmol), and 3-(methoxycarbonyl)phenylboronic acid (237 mg, 1.32 mmol) were further added thereto, and the mixture was heated and stirred at 140° C. for 2 hours using a microwave reaction apparatus. Ethyl acetate was added to the reaction solution. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=20/80-0/100 (V/V)] to obtain the title compound (69 mg, 0.164 mmol, 50%) as a white solid.

[0457] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.31 (3H, s), 3.67 (6H, s), 3.86 (3H, s), 5.87-5.88 (1H, m), 5.91-5.92 (1H, m), 6.64 (2H, d, J=8.5 Hz), 7.37-7.45 (2H, m), 7.82-7.84 (1H, m), 7.98-8.00 (1H, m), 8.16-8.16 (1H, m). MS (APCI): m/z 420 [M+H].sup.+.

Example 46

3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid

[0458] ##STR00109##

[0459] To methyl 3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoate (61 mg, 0.145 mmol), tetrahydrofuran (2.0 mL), methanol (2.0 mL), and a 5 mol/L aqueous sodium hydroxide solution (0.145 mL, 0.726 mmol) were added, and the mixture was heated and stirred at 65° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and 5 mol/L hydrochloric acid (0.145 mL, 0.726 mmol) was added thereto. The reaction mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (54 mg, 0.133 mmol, 92%) as a white solid.

[0460] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.67 (6H, s), 5.86 (1H, d, J=3.0 Hz), 6.12-6.14 (1H, m), 6.88 (2H, d, J=8.5 Hz), 7.49-7.57 (2H, m), 7.65-7.69 (1H, m), 7.95 (1H, dt, J=7.9, 1.5 Hz), 8.04 (1H, t, J=1.5 Hz). MS (APCI): m/z 406 [M+H].sup.+.

Example 47

Methyl 4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoate

[0461] ##STR00110##

[0462] The title compound (79 mg, 0.189 mmol, 47%) was obtained as a faint yellow solid in the same way as in Example 45 by heating and stirring at 140° C. for 1 hour in a microwave reaction apparatus using 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole (146 mg, 0.40 mmol), 4-(methoxycarbonyl)phenylboronic acid (216 mg, 1.20 mmol), potassium phosphate tribasic (255 mg, 1.20 mmol), bis(dibenzylideneacetone)palladium(0) (9.5 mg, 0.040 mmol), and 2-dicyclohexylphosphino-2,6′-dimethoxybiphenyl (65.7 mg, 0.1600 mmol).

[0463] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.31 (3H, s), 3.64 (6H, s), 3.89 (3H, s), 5.89-5.94 (2H, m), 6.63 (2H, d, J=8.5 Hz), 7.44 (1H, t, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz), 7.95 (2H, d, J=8.5 Hz). MS (APCI): m/z=420 [M+H].sup.+.

Example 48

4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid

[0464] ##STR00111##

[0465] The title compound (58 mg, 0.144 mmol, 90%) was obtained as a white solid from methyl 4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoate (67 mg, 0.160 mmol) in the same way as in Example 46.

[0466] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 2.24 (3H, s), 3.63 (6H, s), 5.85 (1H, d, J=3.6 Hz), 6.10-6.13 (1H, m), 6.86 (2H, d, J=8.5 Hz), 7.49-7.57 (3H, m), 7.88 (2H, d, J=8.5 Hz), 13.09 (1H, s). MS (APCI): m/z 406 [M+H].sup.+.

Example 49

5-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid

Step 1

Ethyl 5-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoate

[0467] ##STR00112##

[0468] The title compound (131 mg, 0.295 mmol, 98%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and ethyl 5-bromopentanoate (57 μL, 0.360 mmol) in the same way as in Example 4.

[0469] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.24 (3H, t, J=7.1 Hz), 1.60-1.77 (4H, m), 2.26-2.31 (5H, m), 3.13 (2H, t, J=7.0 Hz), 3.72 (6H, s), 4.10 (2H, q, J=7.1 Hz), 5.87-5.90 (2H, m), 6.68 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 446 [M+H].sup.+.

Step 2

5-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid

[0470] ##STR00113##

[0471] The title compound (109 mg, 0.262 mmol, 92%) was obtained as a white solid from ethyl 5-[[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-4H-1,2,4-triazol-3-yl]sulfanyl]pentanoate (126.8 mg, 0.2846 mmol) and tetrahydrofuran (1.50 mL) in the same way as in Example 5.

[0472] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.69-1.80 (4H, m), 2.26 (3H, s), 2.39 (2H, t, J=7.0 Hz), 3.13 (2H, t, J=7.0 Hz), 3.72 (6H, s), 5.88-5.90 (1H, m), 5.93 (1H, d, J=3.6 Hz), 6.69 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z 418 [M+H].sup.+.

Example 50

6-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}hexanoic acid

Step 1

Ethyl 6-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}hexanoate

[0473] ##STR00114##

[0474] The title compound (131 mg, 0.286 mmol, 95%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (95 mg, 0.300 mmol) and 6-bromohexanoic acid ethyl ester (64 μL, 0.360 mmol) in the same way as in Example 4.

[0475] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.24 (3H, t, J=7.3 Hz), 1.34-1.43 (2H, m), 1.55-1.74 (4H, m), 2.26 (2H, t, J=7.3 Hz), 2.28 (3H, s), 3.11 (2H, t, J=7.3 Hz), 3.72 (6H, s), 4.11 (2H, q, J=7.3 Hz), 5.87-5.90 (2H, m), 6.69 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (APCI): m/z 460 [M+H].sup.+.

Step 2

6-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}hexanoic acid

[0476] ##STR00115##

[0477] The title compound (91 mg, 0.210 mmol, 77%) was obtained as a white solid from ethyl 6-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}hexanoate (125 mg, 0.273 mmol) in the same way as in Example 5.

[0478] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.39-1.49 (2H, m), 1.60-1.74 (4H, m), 2.27 (3H, s), 2.36 (2H, t, J=7.3 Hz), 3.09 (2H, t, J=7.3 Hz), 3.72 (6H, s), 5.88-5.90 (1H, m), 5.92 (1H, d, J=3.0 Hz), 6.69 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (APCI): m/z=432 [M+H].sup.+.

Example 51

Ethyl (3E)-4-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]-2-oxobut-3-enoate

[0479] ##STR00116##

[0480] The title compound (277 mg, 0.672 mmol, 67%) was obtained as a yellow solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (313 mg, 1.000 mmol) and ethyl (triphenylphosphoranylidene)pyruvate (1.200 mmol) in the same way as in step 2 of Example 8.

[0481] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.37 (3H, t, J=7.1 Hz), 2.30 (3H, s), 3.70 (6H, s), 4.35 (2H, q, J=7.1 Hz), 5.91-5.96 (1H, m), 5.96-6.00 (1H, m), 6.73 (2H, d, J=8.5 Hz), 7.22 (1H, d, J=16.1 Hz), 7.52 (1H, t, J=8.5 Hz), 7.77 (1H, d, J=16.1 Hz). MS (APCI): m/z 412 [M+H].sup.+.

Example 52

2-{(E)-2-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]ethenyl}-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0482] ##STR00117##

[0483] To a solution of (7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)methyl-triphenyl-phosphonium chloride (reference: Journal of Heterocyclic Chemistry, 1983, vol. 20, #4, p. 1053-1057; 471 mg, 1.000 mmol) in dimethyl sulfoxide (2.50 mL), potassium tert-butoxide (112 mg, 1.000 mmol) was added in small portions at room temperature, and the mixture was stirred for 30 minutes. A solution of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (57 mg, 0.500 mmol) in dimethyl sulfoxide (2.5 mL) was added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride was added thereto, followed by the extraction of organic matter with dichloromethane. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (elution solvent: dichloromethane/methanol=100/0-90/10) to obtain the title compound (177 mg, 0.3768 mmol, 75%) as a pale yellow solid.

[0484] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 2.40 (3H, s), 3.71 (6H, s), 5.90-5.93 (2H, m), 6.37 (1H, s), 6.74 (2H, d, J=8.5 Hz), 7.28 (1H, d, J=15.8 Hz), 7.43 (1H, d, J=15.8 Hz), 7.47-7.56 (3H, m), 8.78 (1H, s). MS (APCI): m/z 470 [M+H].sup.+.

Example 53

(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enenitrile

[0485] ##STR00118##

[0486] The title compound (783 mg, 2.33 mmol, 93%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (783 mg, 2.50 mmol) and cyanomethylenetributylphosphorane (0.787 mL, 3.000 mmol) in the same way as in step 2 of Example 8.

[0487] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.72 (6H, s), 5.92-5.95 (1H, m), 6.00 (1H, d, J=3.0 Hz), 6.42 (1H, d, J=16.4 Hz), 6.73 (2H, d, J=8.5 Hz), 6.76 (1H, d, J=16.4 Hz), 7.53 (1H, t, J=8.5 Hz). MS (APCI): m/z 337 [M+H].sup.+.

Example 54

(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]-N-methoxy-N-methylprop-2-enamide

[0488] ##STR00119##

[0489] The title compound (107 mg, 0.268 mmol, 54%) was obtained as a white solid from 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (157 mg, 0.500 mmol) and N-methoxy-N-methyl-2-(triphenylphosphoranylidene)acetamide (218 mg, 0.600 mmol) in the same way as in step 2 of Example 8.

[0490] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.26 (3H, s), 3.69 (6H, s), 3.73 (3H, s), 5.87-5.92 (2H, m), 6.69 (2H, d, J=8.5 Hz), 7.08 (1H, d, J=15.8 Hz), 7.47 (1H, t, J=8.5 Hz), 7.58 (1H, d, J=15.8 Hz). MS (APCI): m/z=399 [M+H].sup.+.

Example 55

Methyl (2Z)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

Step 1

Methyl (2Z)-4-[(2,6-dimethoxyphenyl)amino]-4-oxobut-2-enoate

[0491] ##STR00120##

[0492] To a solution of 2,6-dimethoxyaniline (2.00 g, 13.1 mmol) and maleic acid monomethyl ester (1.87 g, 14.4 mmol) in dichloromethane (39 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.13 g, 16.3 mmol) and 4-dimethylaminopyridine (16 mg, 0.1306 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed with a 1 N aqueous hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=40/60-10/90 (V/V)] to obtain the title compound (897 mg, 3.38 mmol, 26%) as a white solid.

[0493] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.81 (3H, br s), 3.84 (6H, s), 6.10-6.31 (1H, br m), 6.37-6.53 (1H, br m), 6.60 (2H, d, J=8.5 Hz), 7.19 (1H, t, J=8.5 Hz), 9.43 (1H, br s). MS (APCI): m/z 266 [M+H].sup.+.

Step 2

Methyl (2Z)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

[0494] ##STR00121##

[0495] The title compound was obtained as follows according to the reference (Org. Lett., 2015, 17, 1184-1187). (2Z)-4-[(2,6-dimethoxyphenyl)amino]-4-oxobut-2-enoate (890.0 mg, 3.355 mmol) and a stirrer bar were placed in a 20 mL glass vial for microwave reaction (Biotage 10-20 mL), which was then capped. 1,2-Dichloroethane (10 mL) was added thereto using a syringe, and then 2-fluoropyridine (317 μL, 3.691 mmol) was added thereto using a syringe. Trifluoromethanesulfonic anhydride (621 μL, 3.69 mmol) was gradually added dropwise thereto using a syringe with stirring under ice cooling, and the mixture was stirred for 10 minutes. The cap was temporarily removed, 5-methylfuran-2-carbohydrazide (470 mg, 3.36 mmol) was quickly added thereto, and the mixture was then heated and stirred at 140° C. for 2 hours using a microwave reaction apparatus. The reaction solution was directly purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=60/40-35/65 (V/V)] to obtain the title compound (96 mg, 0.259 mmol, 7.7%) as a faint brown solid.

[0496] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.70 (6H, s), 3.75 (3H, s), 5.90-5.93 (2H, m), 6.71 (2H, d, J=8.5 Hz), 6.87 (1H, d, J=15.8 Hz), 7.10 (1H, d, J=15.8 Hz), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 370 [M+H].sup.+.

Example 56

(2Z)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid

[0497] ##STR00122##

[0498] The title compound (64 mg, 0.181 mmol, 78%) was obtained as a white solid from methyl (2Z)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate (85 mg, 0.231 mmol) in the same way as in Example 9.

[0499] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.71 (6H, s), 5.92-5.94 (1H, m), 5.98 (1H, d, J=3.0 Hz), 6.71 (2H, d, J=8.5 Hz), 7.15 (2H, br s), 7.50 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+.

Example 57

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-phenyl-4H-1,2,4-triazole

[0500] ##STR00123##

[0501] To 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole (0.080 g, 0.220 mmol), phenylboronic acid (0.120 g, 0.879 mmol), potassium phosphate tribasic (0.191 g, 0.879 mmol), bis(dibenzylideneacetone)palladium(0) (0.023 g, 0.0329 mmol), and 2-dicyclohexylphosphino-2,6′-dimethoxybiphenyl (0.0570 g, 0.132 mmol), toluene (1.50 mL) and tetrahydrofuran (0.75 mL) were added, and the mixture was heated and stirred at 140° C. for 1 hour under microwave. The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=50/50-30/70 (V/V)] to obtain the title compound (0.0600 g, 0.166 mmol, 76%) as a pale yellow solid.

[0502] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.63 (6H, s), 5.86-5.89 (1H, m), 5.89-5.91 (1H, m), 6.62 (2H, d, J=8.5 Hz), 7.25-7.33 (3H, m), 7.41 (1H, t, J=8.5 Hz), 7.49-7.54 (2H, m). MS (ESI): m/z 362 [M+H].sup.+.

Example 58

Methyl 2-[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-4H-1,2,4-triazol-3-yl]benzoate

[0503] ##STR00124##

[0504] The title compound (0.0240 g, 0.0572 mmol, 26%) was obtained as a pale yellow solid using 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole (0.0800 g, 0.220 mmol) in the same way as in Example 57.

[0505] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.61 (6H, s), 3.72 (3H, s), 5.92-5.94 (1H, m), 5.95-5.98 (1H, m), 6.52 (2H, d, J=8.5 Hz), 7.31 (1H, t, J=8.5 Hz), 7.41-7.45 (3H, m), 7.84-7.86 (1H, m). MS (ESI): m/z 420 [M+H].sup.+.

Example 59

2-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid

[0506] ##STR00125##

[0507] The title compound (0.0130 g, 0.0321 mmol, 56%) was obtained as a pale yellow solid using methyl 2-[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-4H-1,2,4-triazol-3-yl]benzoate (0.0240 g, 0.0572 mmol) in the same way as in Example 5.

[0508] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 2.28 (3H, s), 3.65 (6H, s), 6.04-6.07 (1H, m), 6.08-6.10 (1H, m), 6.65 (2H, d, J=8.5 Hz), 7.38 (1H, t, J=8.5 Hz), 7.44-7.48 (1H, m), 7.52-7.60 (2H, m), 7.89-7.93 (1H, m). MS (ESI): m/z 406 [M+H].sup.+.

Example 60

{[1-(2,6-Dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazol-5-yl]sulfanyl}acetic acid

Step 1

tert-Butyl {2-[(2,6-dimethoxyphenyl)amino]-2-oxoethyl}carbamate

[0509] ##STR00126##

[0510] N-(tert-Butoxycarbonyl)glycine (6.29 g, 35.9 mmol) and 2,6-dimethoxyaniline (5.00 g, 32.6 mmol) were dissolved in methanol (100 mL). To the solution, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (9.93 g, 35.9 mmol) was added at room temperature, and the mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and water was then added to the residue, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained solid was collected by filtration using diisopropyl ether to obtain the partially purified title compound (8.25 g, 26.6 mmol, 81%) as a light gray solid.

[0511] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 1.46 (9H, s), 3.83 (6H, s), 4.05 (2H, s), 6.59 (2H, d, J=8.5 Hz), 7.22 (1H, t, J=8.5 Hz). MS (ESI): m/z 311 [M+H].sup.+.

Step 2

tert-Butyl {2-[(2,6-dimethoxyphenyl)amino]-2-thioxoethyl}carbamate

[0512] ##STR00127##

[0513] To a solution of tert-butyl {2-[(2,6-dimethoxyphenyl)amino]-2-oxoethyl}carbamate (1.12 g, 3.20 mmol) in tetrahydrofuran (45 mL), Lawesson's Reagent (0.820 g, 1.90 mmol) was added at room temperature, and the mixture was stirred for 2 hours. Lawesson's Reagent (0.820 g, 1.90 mmol) was further added thereto, and the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=75/25-30/70 (V/V)] to obtain the title compound (1.04 g, 3.10 mmol, 95%) as a pale yellow solid.

[0514] MS (ESI): m/z 327 [M+H].sup.+.

Step 3

2-Amino-N-(2,6-dimethoxyphenyl)ethanethioamide trifluoroacetic acid

[0515] ##STR00128##

[0516] To a solution of tert-butyl {2-[(2,6-dimethoxyphenyl)amino]-2-thioxoethyl}carbamate (0.352 g, 1.07 mmol) in dichloromethane (6.0 mL), trifluoroacetic acid (1 mL, 1.0 ml) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the partially purified title compound (0.340 g, 1.00 mmol, 93%) as a pale yellow oil. The obtained title compound was used in the next reaction without being purified.

[0517] MS (ESI): m/z 227 [M+H].sup.+ (free form).

Step 4

N-{2-[(2,6-Dimethoxyphenyl)amino]-2-thioxoethyl}-5-methylfuran-2-carboxamide

[0518] ##STR00129##

[0519] To 5-methyl-2-furancarboxylic acid (0.160 g, 1.20 mmol), thionyl chloride (4.2 mL) was added, and the mixture was stirred at 90° C. for 2 hours. Then, the reaction solution was concentrated under reduced pressure to prepare 5-methylfuran-2-carbonyl chloride. A solution of 2-amino-N-(2,6-dimethoxyphenyl)ethanethioamide trifluoroacetic acid (0.340 g, 1.00 mmol) in tetrahydrofuran (15 mL) was cooled to 0° C., a solution of N,N-diisopropylethylamine (0.870 ml, 5.00 mmol) and the preliminarily prepared solution of 5-methylfuran-2-carbonyl chloride in tetrahydrofuran (15 mL) were added dropwise thereto, and the mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=80/20-50/50 (V/V)] to obtain the title compound (0.230 g, 0.688 mmol, 69%) as a yellow oil.

[0520] MS (ESI): m/z 335 [M+H].sup.+.

Step 5

1-(2,6-Dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazole-5-thiol

[0521] ##STR00130##

[0522] To a solution of N-{2-[(2,6-dimethoxyphenyl)amino]-2-thioxoethyl}-5-methylfuran-2-carboxamide (0.180 g, 0.538 mmol) in toluene (2.0 mL), phosphoryl chloride (1.00 mL, 11.0 mmol) was added at room temperature, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted by the addition of ethyl acetate. Then, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=75/25-30/70 (V/V)] to obtain the title compound (0.0850 g, 0.269 mmol, 50%) as a pale yellow oil.

[0523] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 2.32 (3H, s), 3.82 (6H, s), 6.03-6.06 (1H, m), 6.58-6.61 (1H, m), 6.59 (2H, d, J=8.5 Hz), 7.03 (1H, t, J=8.5 Hz), 7.13 (1H, s). MS (ESI): m/z 317 [M+H].sup.+.

Step 6

Ethyl {[1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazol-5-yl]sulfanyl}acetate

[0524] ##STR00131##

[0525] A solution of 1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazole-5-thiol (0.0850 g, 0.269 mmol) and ethyl 2-chloroacetate (0.067 mL, 0.537 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., sodium hydride (60% in oil. 0.0260 g, 0.537 mmol) was added thereto, and the mixture was stirred at 0° C. for 10 minutes. After stirring at room temperature for 4 hours, sodium hydride (60% in oil, 0.0260 g, 0.537 mmol) and ethyl 2-chloroacetate (0.067 mL, 0.537 mmol) were added thereto again, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=80/20-0/100 (V/V)] to obtain the title compound (0.0240 g, 0.0596 mmol, 22%) as a brown oil.

[0526] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.3 Hz), 2.31 (3H, s), 3.82 (6H, s), 4.20 (2H, q, J=7.3 Hz), 4.25 (2H, s), 6.04-6.07 (1H, m), 6.62-6.64 (1H, m), 6.62 (2H, d, J=8.3 Hz), 6.82 (1H, s), 7.26 (1H, t, J=8.3 Hz). MS (ESI): m/z 403 [M+H].sup.+.

Step 7

{[1-(2,6-Dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazol-5-yl]sulfanyl}acetic acid

[0527] ##STR00132##

[0528] The title compound (0.0180 g, 0.0487 mmol, 82%) was obtained as a light brown solid from ethyl {[1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazol-5-yl]sulfanyl}acetate (0.0240 g, 0.0596 mmol) in the same way as in Example 5.

[0529] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 2.29 (3H, s), 3.82 (6H, s), 4.22 (2H, s), 6.10 (1H, d, J=3.4 Hz), 6.59 (1H, d, J=3.4 Hz), 6.70 (1H, s), 6.75 (2H, d, J=8.3 Hz), 7.32 (1H, t, J=8.3 Hz). MS (ESI): m/z 375 [M+H].sup.+.

Example 61

{[4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0530] ##STR00133##

[0531] To a solution of ethyl 2-[[5-(5-bromo-2-furyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl]acetate (0.0510 g, 0.107 mmol) in ethanol (2.0 mL), a 10% palladium carbon catalyst (0.0550 g) was added, and the mixture was stirred at room temperature for 3 hours under the hydrogen atmosphere. Insoluble matter was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=60/40-30/70 (V/V)] to obtain the title compound (0.0130 g, 0.0342 mmol, 32%) as a colorless oil.

[0532] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.26 (3H, t, J=7.2 Hz), 3.73 (6H, s), 4.06 (2H, s), 4.19 (2H, q, J=7.2 Hz), 6.17-6.18 (1H, m), 6.32-6.33 (1H, m), 6.68 (2H, d, J=8.6 Hz), 7.38-7.39 (1H, m), 7.46 (1H, t, J=8.6 Hz). MS (ESI): m/z 362 [M+H].sup.+.

Step 2

{[4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0533] ##STR00134##

[0534] The title compound (0.0097 g, 0.027 mmol, 79%) was obtained as a pale yellow solid using ethyl {[4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (0.0130 g, 0.0342 mmol) in the same way as in Example 5.

[0535] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 3.77 (6H, s), 3.97 (2H, s), 6.22 (1H, d, J=3.4 Hz), 6.44 (1H, dd, J=1.5 Hz, 3.4 Hz), 6.88 (2H, d, J=8.3 Hz), 7.57 (1H, d, J=1.5 Hz), 7.58 (1H, t, J=8.3 Hz). MS (ESI): m/z 362 [M+H].sup.+.

Example 62

{[4-(2,6-Dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

Furan-3-carbohydrazide

[0536] ##STR00135##

[0537] To a solution of furan-3-carboxylic acid (10.5 g, 89.2 mmol) in methanol (100 mL), sulfuric acid (0.500 mL, 8.92 mmol) was added, and the mixture was stirred at 60° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethanol (70 mL). Hydrazine monohydrate (21.5 mL, 446 mmol) was added thereto, and the mixture was stirred at 100° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the deposited solid was collected by filtration using diisopropyl ether. The obtained solid was dried under reduced pressure at 50° C. to obtain the title compound (5.95 g, 47.2 mmol, 52.9%) as a yellow solid.

[0538] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 4.06 (2H, s, NH.sub.2), 6.62 (1H, s), 7.21 (1H, s, NH), 7.46 (1H, s), 7.96 (1H, s). MS (ESI): m/z 127 [M+H].sup.+.

Step 2

N-(2,6-Dimethoxyphenyl)-2-(furan-3-ylcarbonyl)hydrazinecarbothioamide

[0539] ##STR00136##

[0540] The title compound (1.27 g, 3.96 mmol, quantitative) was obtained as a pale yellow solid using furan-3-carbohydrazide (0.510 g, 3.96 mmol) in the same way as in step 2 of Example 1. MS (ESI): m/z 322 [M+H].sup.+.

Step 3

4-(2,6-Dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazole-3-thiol

[0541] ##STR00137##

[0542] The title compound (1.01 g, 3.33 mmol, 84%) was obtained as a pale yellow solid using N-(2,6-dimethoxyphenyl)-2-(furan-3-ylcarbonyl)hydrazinecarbothioamide (1.27 g, 3.96 mmol) in the same way as in step 3 of Example 1.

[0543] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.74 (6H, s), 6.60-6.61 (1H, m), 6.74 (2H, d, J=8.6 Hz), 7.03 (1H, s), 7.36-7.37 (1H, m), 7.51 (1H, t, J=8.6 Hz), 10.28 (1H, s, SH). MS (ESI): m/z 304 [M+H].sup.+.

Step 4

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0544] ##STR00138##

[0545] The title compound (0.107 g, 0.276 mmol, 84%) was obtained as a colorless oil using 4-(2,6-dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazole-3-thiol (0.100 g, 0.330 mmol) in the same way as in Example 2.

[0546] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.23 (3H, t, J=7.2 Hz), 3.70 (6H, s), 4.00 (2H, s), 4.15 (2H, q, J=7.2 Hz), 6.63-6.64 (1H, m), 6.65 (2H, d, J=8.6 Hz), 7.11-7.12 (1H, m), 7.29-7.30 (1H, m), 7.43 (1H, t, J=8.6 Hz). MS (ESI): m/z 390 [M+H].sup.+.

Step 5

{[4-(2,6-Dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0547] ##STR00139##

[0548] The title compound (0.0902 g, 0.250 mmol, 91%) was obtained as a pale yellow solid using ethyl {[4-(2,6-dimethoxyphenyl)-5-(furan-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (0.107 g, 0.276 mmol) in the same way as in Example 5.

[0549] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 3.75 (6H, s), 3.91 (2H, s), 6.54-6.55 (1H, m), 6.86 (2H, d, J=8.5 Hz), 7.22-7.23 (1H, m), 7.48-7.49 (1H, m), 7.57 (1H, t, J=8.5 Hz). MS (ESI): m/z 362 [M+H].sup.+.

Example 63

{[4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Step 1

Methyl 4,5-dimethylfuran-2-carboxylate

[0550] ##STR00140##

[0551] To a solution of 4,5-dimethyl-2-furancarboxylic acid (5.01 g, 36.0 mmol) in dichloromethane (30 mL), N,N-dimethylformamide (0.0200 mL, 0.260 mmol) was added, the mixture was cooled to 0° C., and oxalyl chloride (6.10 mL, 71.0 mmol) was then added dropwise thereto. After the dropwise addition, the reaction solution was heated to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. Methanol (50 mL) was added to the obtained residue at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to the obtained residue followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound (5.41 g, 35.0 mmol, 97%) as a yellow oil.

[0552] MS (ESI): m/z 155 [M+H].sup.+.

Step 2

4,5-Dimethylfuran-2-carbohydrazide

[0553] ##STR00141##

[0554] To a solution of methyl 4,5-dimethylfuran-2-carboxylate (5.41 g, 35.0 mmol) in ethanol (100 mL), hydrazine monohydrate (3.40 mL, 70.0 mmol) was added, and the mixture was stirred at 110° C. for 4 hours. Hydrazine monohydrate (100 mL, 210 mmol) was further added to the reaction solution, and the mixture was stirred at 100° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the deposited solid was collected by filtration using diisopropyl ether. The obtained solid was dried under reduced pressure at 50° C. to obtain the title compound (5.0 g, 32.7 mmol, 94%) as a pale yellow solid.

[0555] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.97 (3H, s), 2.24 (3H, s), 3.98 (2H, s, NH.sub.2), 6.91 (1H, s), 7.41 (1H, s, NH). MS (ESI): m/z 155 [M+H].sup.+.

Step 3

N-(2,6-Dimethoxyphenyl)-2-[(4,5-dimethylfuran-2-yl)carbonyl]hydrazinecarbothioamide

[0556] ##STR00142##

[0557] The title compound (1.13 g, 3.24 mmol, quantitative) was obtained as a pale yellow solid from 4,5-dimethylfuran-2-carbohydrazide (0.505 g, 3.24 mmol) in the same way as in step 2 of Example 5.

[0558] MS (ESI): m/z 350 [M+H].sup.+.

Step 4

4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazole-3-thiol

[0559] ##STR00143##

[0560] The title compound (1.00 g, 3.00 mmol, 93%) was obtained as a pale yellow solid from N-(2,6-dimethoxyphenyl)-2-[(4,5-dimethylfuran-2-yl)carbonyl]hydrazinecarbothioamide (1.13 g, 3.24 mmol) in the same way as in step 3 of Example 1.

[0561] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.83 (3H, s), 2.23 (3H, s), 3.79 (6H, s), 5.67 (1H, s), 6.74 (2H, d, J=8.5 Hz), 7.51 (1H, t, J=8.5 Hz), 10.74 (1H, s). MS (ESI): m/z 350 [M+H].sup.+.

Step 5

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate

[0562] ##STR00144##

[0563] The title compound (0.0965 g, 0.231 mmol, 77%) was obtained as a colorless oil from 4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (0.100 g, 0.302 mmol) in the same way as in Example 4.

[0564] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.26 (3H, t, J=7.0 Hz), 1.83 (3H, s), 2.17 (3H, s), 3.74 (6H, s), 4.03 (2H, s), 4.18 (2H, q, J=7.0 Hz), 5.84 (1H, s), 6.69 (2H, d, J=8.6 Hz), 7.46 (1H, t, J=8.6 Hz). MS (ESI): m/z 418 [M+H].sup.+.

Step 6

{[4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

[0565] ##STR00145##

[0566] The title compound (0.0772 g, 0.198 mmol, 86%) was obtained as a colorless solid from ethyl {[4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (0.0965 g, 0.231 mmol) in the same way as in Example 5.

[0567] .sup.1H-NMR (500 MHz, CD.sub.3OD) δ (ppm): 1.84 (3H, s), 2.15 (3H, s), 3.77 (6H, s), 3.93 (2H, s), 5.93 (1H, s), 6.87 (2H, d, J=8.3 Hz), 7.58 (1H, t, J=8.3 Hz). MS (ESI): m/z 375 [M+H].sup.+.

Example 64

Ammonium (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

[0568] ##STR00146##

[0569] To a solution of (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (43.6 mg, 0.123 mmol) in methanol, ammonia (ca. 4% in methanol, ca. 2.0 mol/L) (0.61 mL, 1.23 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated to dryness under reduced pressure to obtain the title compound (43.4 mg, 0.117 mmol, 95%) as a white solid.

[0570] .sup.1H-NMR (400 MHz, CD.sub.3OD) δ (ppm): 2.26 (3H, s), 3.77 (6H, s), 6.05-6.08 (1H, m), 6.10 (1H, d, J=3.6 Hz), 6.67 (1H, d, J=15.8 Hz), 6.93 (2H, d, J=8.5 Hz), 6.99 (1H, d, J=15.8 Hz), 7.64 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+ (free form).

Example 65

Sodium (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoate

[0571] ##STR00147##

[0572] To a solution of (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (63.7 mg, 0.179 mmol) in ethanol (1.80 mL), a 1.00 mol/L aqueous sodium hydroxide solution (0.179 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the mixture was azeotropically dried to obtain the partially purified title compound (65.1 mg, 0.173 mmol, 96%) as a white solid.

[0573] .sup.1H-NMR (400 MHz, CD.sub.3OD) δ (ppm): 2.26 (3H, s), 3.75 (6H, s), 5.99-6.01 (1H, m), 6.02-6.04 (1H, m), 6.78 (1H, d, J=15.8 Hz), 6.83 (1H, d, J=15.8 Hz), 6.89 (2H, d, J=8.5 Hz), 7.60 (1H, t, J=8.5 Hz). MS (APCI): m/z 356 [M+H].sup.+.

Example 66

Ethyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methoxy}acetate

[0574] ##STR00148##

[0575] [4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanol (0.115 g, 0.317 mmol) was dissolved in N,N-dimethylformamide (4.0 mL). To the solution, sodium hydride in oil (35.0 mg, 0.634 mmol) was added at room temperature, and the mixture was stirred for 10 minutes. Chloroacetic acid ethyl ester (0.078 g, 0.634 mmol) was added to the reaction solution, and the mixture was stirred for 8 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution. Ethyl acetate was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=50/50-0/100 (V/V))] to obtain the title compound (0.118 g, 0.294 mmol, 93%) as a yellow oil.

[0576] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.21 (3H, t, J=7.1 Hz), 2.26 (3H, s), 3.67 (6H, s), 3.98 (2H, s), 4.13 (2H, q, J=7.1 Hz), 4.60 (2H, s), 5.83 (1H, d, J=3.4 Hz), 5.86-5.88 (1H, m), 6.65 (2H, d, J=8.8 Hz), 7.42 (1H, t, J=8.8 Hz). MS (ESI): m/z 402 [M+H].sup.+.

Example 67

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methoxy}acetic acid

[0577] ##STR00149##

[0578] The title compound (0.0215 g, 0.0576 mmol, 39%) was obtained as a white solid using ethyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methoxy}acetate (0.060 g, 0.149 mmol) in the same way as in Example 5.

[0579] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ (ppm): 2.24 (3H, s), 3.69 (6H, s), 3.82 (2H, s), 4.44 (2H, s), 5.86 (1H, d, J=3.4 Hz), 6.09-6.11 (1H, m), 6.89 (2H, d, J=8.8 Hz), 7.55 (1H, t, J=8.8 Hz). MS (ESI): m/z 374 [M+H].sup.+.

Example 68

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole

Step 1

[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl methanesulfonate

[0580] ##STR00150##

[0581] [4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazol-3-yl]methanol (0.750 g, 2.38 mmol) was dissolved in dichloromethane (25 mL), and the solution was cooled to 0° C. Then, triethylamine (0.66 mL, 4.76 mmol) and methanesulfonyl chloride (0.370 mL, 4.76 mmol) were added thereto, and the mixture was stirred at the same temperature as above for 1 hour. Ice water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure to obtain the title compound as a yellow oil. The obtained residue was directly used in the next reaction without being purified.

[0582] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ (ppm): 2.29 (3H, s), 2.93 (3H, s), 3.74 (6H, s), 5.18 (2H, s), 5.93-5.95 (1H, m), 5.99 (1H, d, J=3.4 Hz), 6.72 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz).

Step 2

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole

[0583] ##STR00151##

[0584] The title compound (60.0 mg, 0.151 mmol, 49%) was obtained as a yellow solid from [4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl methanesulfonate (0.122 g, 0.310 mmol) and 4H-1,2,4-triazole-3-thiol (50.0 mg, 0.465 mmol) in the same way as in Example 2.

[0585] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ (ppm): 2.29 (3H, s), 3.75 (6H, s), 4.14 (2H, s), 5.93-5.95 (1H, m), 5.98-6.00 (1H, m), 6.73 (2H, d, J=8.5 Hz), 7.52 (1H, t, J=8.5 Hz). MS (ESI): m/z 399 [M+H].sup.+.

Example 69

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole

[0586] ##STR00152##

[0587] 4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole (60.0 mg, 0.151 mmol) was dissolved in dichloromethane (10 mL). To the solution, 3-chloroperoxybenzoic acid (contains ca. 30% water) (82.0 mg, 0.301 mmol) was added at room temperature, and the mixture was stirred at room temperature for 12 hours. Dimethyl sulfoxide (0.10 mL) was added to the reaction solution, and then a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-75/25 (V/V))] to obtain the title compound (32.5 mg, 0.0743 mmol, 49%) as a yellow solid.

[0588] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.80 (6H, s), 4.78 (2H, s), 5.94-5.95 (1H, m), 5.99-6.01 (1H, m), 6.76 (2H, d, J=8.5 Hz), 7.55 (1H, t, J=8.5 Hz), 8.46 (1H, s). MS (ESI): m/z 431 [M+H].sup.+.

Example 70

1-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine

[0589] ##STR00153##

[0590] To a solution of [4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl methanesulfonate (350 mg, 0.890 mmol) in acetone (0.30 mL), 28% aqueous ammonia solution (0.50 mL, 30 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-50/50 (V/V))] to obtain the title compound (150 mg, 0.477 mmol, 54%) as a light brown oil.

[0591] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.69 (2H, s), 3.73 (6H, s), 5.82-5.85 (1H, m), 5.88-5.89 (1H, m), 6.71 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (ESI): m/z 315 [M+H].sup.+.

Example 71

N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}methanesulfonamide

[0592] ##STR00154##

[0593] To a solution of 1-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine (23.0 mg, 0.0732 mmol) in dichloromethane (5.0 mL), N,N-diisopropylethylamine (0.050 mL, 0.220 mmol) and methanesulfonyl chloride (0.020 mL, 0.220 mmol) were added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V))] to obtain the title compound (18.3 mg, 0.0466 mmol, 64%) as a pale yellow solid.

[0594] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ (ppm): 2.25 (3H, s), 2.81 (3H, s), 3.72 (6H, s), 4.02 (2H, d, J=6.3 Hz), 5.85-5.88 (1H, m), 6.11-6.13 (1H, m), 6.91 (2H, d, J=8.5 Hz), 7.57 (1H, t, J=8.5 Hz), 7.61 (1H, t, J=6.3 Hz). MS (ESI): m/z 393 [M+H].sup.+.

Example 72

N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}-4-methyl-N-(4-methylbenzoyl)benzamide

[0595] ##STR00155##

[0596] The title compound (18.0 mg, 0.0416 mmol, 40%) was obtained as a pale yellow solid using 1-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine (26.0 mg, 0.0827 mmol) and p-toluoyl chloride (0.022 mL, 0.165 mmol) in the same way as in Example 71.

[0597] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.23 (3H, s), 2.24 (3H, s), 3.70 (6H, s), 5.02 (2H, s), 5.87-5.90 (1H, m), 5.99-6.01 (1H, m), 6.67 (2H, d, J=8.5 Hz), 6.97 (2H, d, J=7.8 Hz), 7.44 (1H, t, J=8.5 Hz), 7.52 (2H, d, J=7.8 Hz). MS (ESI): m/z 433 [M+H].sup.+.

Example 73

[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]acetonitrile

[0598] ##STR00156##

[0599] To a solution of [4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl methanesulfonate (304 mg, 0.763 mmol) in dimethyl sulfoxide (5.5 mL), sodium cyanide (233 mg, 3.81 mmol) was added, and the mixture was stirred at 90° C. for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=30/70-0/100 (V/V))] to obtain the title compound (22 mg, 0.068 mmol, 8.9%) as a light brown oil.

[0600] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.31 (3H, s), 3.78 (2H, s), 3.79 (6H, s), 5.94-5.96 (1H, m), 5.99 (1H, d, J=3.4 Hz), 6.76 (2H, d, J=8.5 Hz), 7.55 (1H, t, J=8.5 Hz). MS (ESI): m/z 325 [M+H].sup.+.

Example 74

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1H-tetrazole

Step 1

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2-trityl-2H-tetrazole

[0601] ##STR00157##

[0602] To a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (172 mg, 0.473 mmol) in acetone (10.0 mL), 5-(chloromethyl)-2-trityl-2H-tetrazole (reference: U56046227; 376 mg, 0.945 mmol) and a fine potassium carbonate powder (230 mg, 1.42 mmol) were added, and the mixture was stirred at 60° C. for 1 hour. 3-Pentanone (5.0 mL) was further added to the reaction solution, and the mixture was stirred at 100° C. for 1 hour. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=50/50-0/100 (V/V)] to obtain the title compound (360 mg, 0.560 mmol, quantitative) as a colorless oil.

[0603] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.61 (6H, s), 4.60 (2H, s), 5.89-5.91 (1H, m), 5.93 (1H, d, J=3.4 Hz), 6.63 (2H, d, J=8.5 Hz), 7.04-7.06 (6H, m), 7.30-7.33 (9H, m), 7.42 (1H, t, J=8.5 Hz).

Step 2

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1H-tetrazole

[0604] ##STR00158##

[0605] 5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2-trityl-2H-tetrazole (120 mg, 0.189 mmol) was dissolved in dichloromethane (5.0 mL) and methanol (5.0 mL). To the solution, a 10% palladium carbon catalyst (M) wet (100 mg) was added, and the mixture was stirred at room temperature for 2 hours under the hydrogen atmosphere. Trifluoroacetic acid (2.0 mL, 26.14 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-75/25 (V/V)] to obtain the title compound (67.0 mg, 0.168 mmol, 90%) as a colorless oil.

[0606] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.72 (6H, s), 4.56 (2H, s), 5.94-5.96 (1H, m), 6.02 (1H, d, J=3.4 Hz), 6.70 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz). MS (ESI): m/z 400 [M+H].sup.+.

Example 75

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyridazine

[0607] ##STR00159##

[0608] The title compound (123 mg, 0.300 mmol, 95%) was obtained as a light brown solid using 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (100 mg, 0.315 mmol) and 3-(chloromethyl)pyridazine hydrochloride (110 mg, 0.630 mmol) in the same way as in Example 2.

[0609] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.66 (6H, s), 4.70 (2H, s), 5.88-5.92 (2H, m), 6.65 (2H, d, J=8.5 Hz), 7.40 (1H, dd, J=8.3, 4.9 Hz), 7.44 (1H, t, J=8.5 Hz), 7.88 (1H, dd, J=8.3, 1.5 Hz), 9.06 (1H, dd, J=4.9, 1.5 Hz). MS (ESI): m/z 410 [M+H].sup.+.

Example 76

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(1,3-thiazol-2-ylmethyl)sulfanyl]-4H-1,2,4-triazole

[0610] ##STR00160##

[0611] The title compound (240 mg, 0.579 mmol, 61%) was obtained as a yellow solid using 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (300 mg, 0.945 mmol) and 1,3-thiazol-2-ylmethyl methanesulfonate (reference: WO2007/34277; 376 mg, 0.945 mmol) in the same way as in Example 2.

[0612] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.69 (6H, s), 4.78 (2H, s), 5.90-5.91 (1H, m), 5.94 (1H, d, J=2.9 Hz), 6.66 (2H, d, J=8.5 Hz), 7.24 (1H, d, J=3.4 Hz), 7.45 (1H, t, J=8.5 Hz), 7.68 (1H, d, J=3.4 Hz). MS (ESI): m/z 415 [M+H].sup.+.

Example 77

Methyl 2-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate

[0613] ##STR00161##

[0614] The title compound (87.0 mg, 0.187 mmol, 40%) was obtained as a white solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (150 mg, 0.473 mmol) and methyl 2-bromomethylbenzoate (220 mg, 0.945 mmol) in the same way as in Example 2.

[0615] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.60 (6H, s), 3.84 (3H, s), 4.78 (2H, s), 5.86-5.88 (2H, m), 6.61 (2H, d, J=8.5 Hz), 7.29 (1H, td, J=7.6, 1.3 Hz), 7.40 (1H, t, J=8.5 Hz), 7.41 (1H, td, J=7.6, 1.3 Hz), 7.61 (1H, dd, J=7.6, 1.3 Hz), 7.91 (1H, dd, J=7.6, 1.3 Hz). MS (ESI): m/z 466 [M+H].sup.+.

Example 78

2-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoic acid

[0616] ##STR00162##

[0617] The title compound (65.0 mg, 0.144 mmol, 77%) was obtained as a white solid using methyl 2-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate (87.0 mg, 0.187 mmol) in the same way as in Example 5.

[0618] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.24 (3H, s), 3.70 (6H, s), 4.48 (2H, s), 5.85-5.86 (2H, m), 6.69 (2H, d, J=8.5 Hz), 7.28-7.31 (1H, m), 7.33-7.37 (1H, m), 7.47-7.52 (2H, m), 7.64-7.67 (1H, m). MS (ESI): m/z 452 [M+H].sup.+.

Example 79

Methyl 3-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate

[0619] ##STR00163##

[0620] The title compound (134 mg, 0.288 mmol, 61%) was obtained as a white solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (165 mg, 0.473 mmol) and methyl 2-bromomethylbenzoate (220 mg, 0.945 mmol) in the same way as in Example 2.

[0621] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.66 (6H, s), 3.89 (3H, s), 4.42 (2H, s), 5.87-5.92 (2H, m), 6.65 (2H, d, J=8.3 Hz), 7.33 (1H, t, J=7.8 Hz), 7.43 (1H, t, J=8.3 Hz), 7.56 (1H, dd, J=7.8, 1.7 Hz), 7.90 (1H, dd, J=7.8, 1.7 Hz), 7.95 (1H, t, J=1.7 Hz). MS (ESI): m/z 466 [M+H].sup.+.

Example 80

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoic acid

[0622] ##STR00164##

[0623] The title compound (100 mg, 0.222 mmol, 77%) was obtained as a white solid using methyl 3-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate (134 mg, 0.288 mmol) in the same way as in Example 5.

[0624] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.69 (6H, s), 4.45 (2H, s), 5.90-5.91 (1H, m), 5.96 (1H, d, J=3.4 Hz), 6.67 (2H, d, J=8.5 Hz), 7.38 (1H, t, J=7.8 Hz), 7.46 (1H, t, J=8.5 Hz), 7.61 (1H, d, J=7.8 Hz), 7.98 (1H, d, J=7.8 Hz), 8.05 (1H, s). MS (ESI): m/z 452 [M+H].sup.+.

Example 81

Methyl 4-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate

[0625] ##STR00165##

[0626] The title compound (115 mg, 0.247 mmol, 52%) was obtained as a white solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (150 mg, 0.473 mmol) and methyl 2-bromomethylbenzoate (220 mg, 0.945 mmol) in the same way as in Example 2.

[0627] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.64 (6H, s), 3.89 (3H, s), 4.42 (2H, s), 5.87-5.90 (1H, m), 5.91 (1H, d, J=3.4 Hz), 6.64 (2H, d, J=8.5 Hz), 7.37 (2H, d, J=8.3 Hz), 7.43 (1H, t, J=8.5 Hz), 7.91 (2H, d, J=8.3 Hz). MS (ESI): m/z 466 [M+H].sup.+.

Example 82

4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoic acid

[0628] ##STR00166##

[0629] The title compound (88.9 mg, 0.147 mmol, 80%) was obtained as a white solid using methyl 4-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoate (115 mg, 0.247 mmol) in the same way as in Example 5.

[0630] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.65 (6H, s), 4.43 (2H, s), 5.88-5.91 (1H, m), 5.92 (1H, d, J=3.4 Hz), 6.64 (2H, d, J=8.5 Hz), 7.40 (2H, d, J=8.3 Hz), 7.44 (1H, t, J=8.5 Hz), 7.97 (2H, d, J=8.3 Hz). MS (ESI): m/z 452 [M+H].sup.+.

Example 83

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetamide

[0631] ##STR00167##

[0632] The title compound (200 mg, 0.534 mmol, 57%) was obtained as a pale yellow solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (300 mg, 0.945 mmol) and 2-bromoacetamide (400 mg, 2.84 mmol) in the same way as in Example 2.

[0633] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.72 (2H, s), 3.74 (6H, s), 5.90-5.93 (1H, m), 5.96 (1H, d, J=3.4 Hz), 6.69 (2H, d, J=8.5 Hz), 7.48 (1H, t, J=8.5 Hz). MS (ESI): m/z 375 [M+H].sup.+.

Example 84

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetonitrile

[0634] ##STR00168##

[0635] The title compound (250 mg, 0.701 mmol, 74%) was obtained as a pale yellow solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (300 mg, 0.945 mmol) and bromoacetonitrile (227 mg, 1.89 mmol) in the same way as in Example 2.

[0636] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.74 (6H, s), 3.96 (2H, s), 5.91-5.93 (1H, m), 5.99 (1H, d, J=3.4 Hz), 6.70 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz). MS (ESI): m/z 357 [M+H].sup.+.

Example 85

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-(methylsulfanyl)-4H-1,2,4-triazole

[0637] ##STR00169##

[0638] 4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole-3-thiol (3.18 g, 10.0 mmol) was dissolved in tetrahydrofuran (100 mL). To the solution, a fine potassium carbonate powder (4.50 g, 30.1 mmol) and iodomethane (stabilized with copper chip) (0.60 ml, 15.0 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then concentrated under reduced pressure, and the deposited solid was washed with n-hexane and diisopropyl ether. The obtained solid was dried under reduced pressure to obtain the partially purified title compound (2.50 g, 7.54 mmol, 75%) as a light brown solid.

[0639] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 2.64 (3H, s), 3.73 (6H, s), 5.87-5.91 (2H, m), 6.69 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (ESI): m/z 332 [M+H].sup.+.

Example 86

4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-(methylsulfonyl)-4H-1,2,4-triazole

[0640] ##STR00170##

[0641] The title compound (1.60 g, 4.4 mmol, 70%) was obtained as a yellow solid using 4-(2,6-dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-(methylsulfanyl)-4H-1,2,4-triazole (2.10 g, 6.30 mmol) in the same way as in Example 69.

[0642] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 3.33 (3H, s), 3.75 (6H, s), 5.95 (1H, d, J=3.4 Hz), 6.02 (1H, d, J=3.4 Hz), 6.70 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz). MS (ESI): m/z 364 [M+H].sup.+.

Example 87

3-(2,2-Dimethoxyethoxy)-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole

[0643] ##STR00171##

[0644] Glycolaldehyde dimethyl acetal (253 mg, 2.20 mmol) was dissolved in N,N-dimethylformamide (5.0 mL). To the solution, sodium hydride in oil (101 mg, 2.20 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-(methylsulfonyl)-4H-1,2,4-triazole (393 mg, 1.10 mmol) was added to the reaction solution, and the mixture was stirred at 120° C. for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=70/30-0/100 (V/V)] to obtain the title compound (244 mg, 0.627 mmol, 57%) as a yellow oil.

[0645] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.36 (6H, s), 3.72 (6H, s), 4.46 (1H, d, J=5.4 Hz), 4.74 (1H, t, J=5.4 Hz), 5.84-5.88 (2H, m), 6.65 (2H, d, J=8.5 Hz), 7.41 (1H, t, J=8.5 Hz). MS (ESI): m/z 390 [M+H].sup.+.

Example 88

{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]oxy}acetic acid

[0646] ##STR00172##

[0647] 3-(2,2-Dimethoxyethoxy)-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole (200 mg, 0.582 mmol) was dissolved in formic acid (10 ml), and the solution was stirred at 50° C. for 48 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate and subsequently with dichloromethane/methanol. Then, the extracted organic layers were mixed and concentrated under reduced pressure. t-Butyl alcohol (5.0 mL), 2-methyl-2-butene (5.0 mL), and water (2.0 mL) were added to the obtained residue, sodium dihydrogen phosphate (212 mg, 1.75 mmol) and sodium chlorite (105 mg, 1.12 mmol) were added thereto at room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The aqueous layer was purified by ODS column chromatography [elution solvent: 0.1% formic acid water/0.1% formic acid acetonitrile=100/0-20/80 (V/V)] to obtain the title compound (6.5 mg, 0.0180 mmol, 3.1%) as a pale yellow solid.

[0648] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.74 (6H, s), 4.93 (2H, s), 5.88-5.97 (2H, m), 6.68 (2H, d, J=8.5 Hz), 7.44 (1H, t, J=8.5 Hz). MS (ESI): m/z 360 [M+H].sup.+.

Example 89

Methyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(pyridin-2-yl)acetate

[0649] ##STR00173##

[0650] The title compound (diastereomeric mixture, 200 mg, 0.429 mmol, 45%) was obtained as a yellow solid using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (300 mg, 0.945 mmol) and methyl 2-bromo-2-(2-pyridyl)acetate (reference: WO2006/44602; 435 mg, 1.89 mmol) in the same way as in Example 2.

[0651] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.29 (3H, s), 3.58 (3H, s), 3.77 (3H, s), 3.78 (3H, s), 5.90-5.93 (2H, m), 5.92 (1H, s), 6.61 (1H, d, J=8.5 Hz), 6.69 (1H, d, J=8.5 Hz), 7.20-7.22 (1H, m), 7.43 (1H, t, J=8.5 Hz), 7.57-7.60 (1H, m), 7.65-7.69 (1H, m), 8.53-8.56 (1H, m). MS (ESI): m/z 467 [M+H].sup.+.

Example 90

Methyl 1-{(2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-L-prolinate

[0652] ##STR00174##

[0653] The title compound (197 mg, 0.421 mmol, 83%) was obtained as a yellow solid using (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (161 mg, 0.453 mmol), triethylamine (0.199 mL, 1.43 mmol), isobutyl chloroformate (84 μL, 0.6374 mmol), and methyl L-prolinate hydrochloride (127 mg, 0.765 mmol) in the same way as in Example 19.

[0654] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.98-2.28 (4H, m), 2.30 (3H, s), 3.67-3.76 (1H, m), 3.68 (3H, s), 3.69 (3H, s), 3.72 (3H, s), 3.83-3.90 (1H, m), 4.52 (1H, dd, J=8.5, 4.3 Hz), 5.85-5.92 (2H, m), 6.65-6.69 (2H, m), 7.03 (1H, d, J=15.2 Hz), 7.42-7.49 (2H, m). MS (APCI): m/z 467 [M+H].sup.+.

Example 91

Methyl (4R)-1-{(2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-4-hydroxy-L-prolinate

[0655] ##STR00175##

[0656] The title compound (197 mg, 0.409 mmol, 90%) was obtained as a white solid using (2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid (161 mg, 0.453 mmol), triethylamine (0.177 mL, 1.27 mmol), isobutyl chloroformate (0.074 mL, 0.566 mmol), and methyl (4R)-4-hydroxy-L-prolinate hydrochloride (123 mg, 0.680 mmol) in the same way as in Example 19.

[0657] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 2.07-2.18 (1H, m), 2.29 (3H, s), 2.32-2.40 (1H, m), 3.67 (3H, s), 3.69 (3H, s), 3.73 (3H, s), 3.86-3.89 (1H, br m), 3.98 (2H, d, J=3.0 Hz), 4.65-4.67 (1H, m), 5.90-5.91 (2H, m), 6.66 (2H, dd, J=8.5, 3.0 Hz), 7.01 (1H, d, J=15.8 Hz), 7.42-7.52 (2H, m). MS (APCI): m/z 483 [M+H].sup.+.

Example 92

(4R)-1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-4-hydroxy-L-proline

[0658] ##STR00176##

[0659] The title compound (56.2 mg, 0.120 mmol, 76%) was obtained as a white solid using methyl (4R)-1-{(2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-4-hydroxy-L-prolinate (76.1 mg, 0.158 mmol) in the same way as in Example 5.

[0660] .sup.1H-NMR (400 MHz, CD.sub.3OD) δ (ppm): 2.04-2.12 (1H, m), 2.27 (3H, s), 2.28-2.44 (1H, m), 3.62-3.68 (1H, m), 3.76 (6H, s), 3.81 (1H, dd, J=10.6, 3.9 Hz), 4.36-4.69 (2H, m), 6.04-6.10 (2H, m), 6.89-7.29 (4H, m), 7.63 (1H, t, J=8.5 Hz). MS (APCI): m/z 469 [M+H].sup.+.

Example 93

1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-L-proline

[0661] ##STR00177##

[0662] The title compound (57.3 mg, 0.127 mmol, 83%) was obtained as a yellow solid using 1-{(2E)-3-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-L-prolinate (71.0 mg, 0.152 mmol) in the same way as in Example 5.

[0663] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ (ppm): 1.90-2.13 (3H, m), 2.27 and 2.30 (total 3H, each s), 2.41-2.56 (1H, m), 3.50-3.74 (1H, m), 3.67 and 3.69 (total 3H, each s), 3.70 and 3.71 (total 3H, each s), 3.74-3.83 (1H, m), 4.66-4.70 and 4.89-4.94 (total 1H, each m), 5.86-5.94 (2H, m), 6.64-6.74 (2H, m), 6.98 and 7.08 (total 1H, each d, J=15.2 Hz), 7.41-7.63 (2H, m). MS (APCI): m/z 453 [M+H].sup.+.

Example 94

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2,4-oxadiazol-5(2H)-one

[0664] ##STR00178##

[0665] {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetonitrile (120 mg, 0.337 mmol) was dissolved in ethanol (5.4 ml). To the solution, 50% aqueous hydroxylamine solution (45 mg, 0.673 mmol) was added, and the mixture was stirred at 90° C. for 5 hours. Then, the solvent was distilled off under reduced pressure to obtain partially purified 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-N-hydroxyethanimidamide as a colorless amorphous form.

[0666] Then, obtained 2-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-N-hydroxyethanimidamide was dissolved in 1,4-dioxane (5.5 mL). To the solution, 1,1′-carbonyldiimidazole (65.2 mg, 0.403 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.062 mL, 0.403 mmol) were added, and the mixture was stirred at 90° C. for 5 hours. Then, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-67/33 (V/V)], and washed with 1 mol/L hydrochloric acid to obtain the title compound (123 mg, 0.296 mmol, 88%) as a white solid.

[0667] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.25 (3H, s), 3.72 (6H, s), 4.02 (2H, s), 5.90-5.93 (1H, m), 5.99-6.02 (1H, m), 6.68 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz), 11.48 (1H, br s). MS (ESI): m/z 416 [M+H].sup.+.

Example 95

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-N-(phenylsulfonyl)acetamide

[0668] ##STR00179##

[0669] To a solution of {[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid (38 mg, 0.101 mmol) in dichloromethane (10 mL), benzenesulfonamide (17 mg, 0.111 mmol), 4-dimethylaminopyridine (15 mg, 0.121 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added at room temperature, and the mixture was stirred for 10 hours. Water was added to the reaction solution, followed by extraction with dichloromethane and ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-70/30 (V/V)] to obtain the title compound (21 mg, 0.041 mmol, 40%) as a pale yellow solid.

[0670] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.64 (2H, s), 3.66 (6H, s), 5.90-5.92 (1H, m), 5.99-6.01 (1H, m), 6.66 (2H, d, J=8.5 Hz), 7.21-7.32 (3H, m), 7.45 (1H, t, J=8.5 Hz), 7.89-7.96 (2H, m). MS (ESI): m/z 515 [M+H].sup.+.

Example 96

Dipropan-2-yl ({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)phosphonate

[0671] ##STR00180##

[0672] The title compound (230 mg, 0.464 mmol, 98%) was obtained as a pale yellow oil using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (150 mg, 0.473 mmol) and diisopropyl bromomethylphosphonate (245 mg, 0.945 mmol) in the same way as in Example 2.

[0673] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.28 (6H, d, J=5.9 Hz), 1.31 (6H, d, J=5.9 Hz), 2.28 (3H, s), 3.60 (2H, d, J=14.6 Hz), 3.72 (6H, s), 4.67-4.76 (2H, m), 5.89-5.92 (2H, m), 6.68 (2H, d, J=8.5 Hz), 7.46 (1H, t, J=8.5 Hz). MS (ESI): m/z 496 [M+H].sup.+.

Example 97

Ethyl ({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}amino)(oxo)acetate

[0674] ##STR00181##

[0675] To a solution of 1-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine (100 mg, 0.318 mmol) in tetrahydrofuran (10 mL), triethylamine (0.100 mL, 0.636 mmol) and ethyl chloroglyoxylate (0.053 mL, 0.477 mmol) were added at room temperature, and the mixture was stirred for 3 hours. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V)] to obtain the title compound (46 mg, 0.111 mmol, 35%) as a yellow oil.

[0676] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.37 (3H, t, J=7.1 Hz), 2.29 (3H, s), 3.73 (6H, s), 4.33 (2H, q, J=7.1 Hz), 4.48 (2H, d, J=5.4 Hz), 5.88-5.93 (2H, m), 6.68 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz), 7.63-7.70 (1H, m). MS (ESI): m/z 415 [M+H].sup.+.

Example 98

({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}amino) (oxo)acetic acid

[0677] ##STR00182##

[0678] To a solution of Ethyl ({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}amino) (oxo)acetate (40 mg, 0.0965 mmol) in ethanol (5.0 mL), 1 mol/L aqueous sodium hydroxide solution (1.0 mL) was added at room temperature, and the mixture was stirred for 4 hours. Then, 1 mol/L hydrochloric acid (1.0 mL) was added, and the resulting precipitate was removed by filtration. The solvent was concentrated under reduced pressure, and the obtained residue was purified by ODS column chromatography [elution solvent: 0.1% formic acid water/0.1% formic acid acetonitrile=100/0-30/70 (V/V)], and lyophilized to obtain the title compound (20 mg, 0.0518 mmol, 54%) as a white solid.

[0679] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.74 (6H, s), 4.52 (2H, s), 5.89-5.92 (2H, m), 6.69 (2H, d, J=8.3 Hz), 7.48 (1H, t, J=8.3 Hz), 7.76 (1H, br s). MS (ESI): m/z 469 [M+H].sup.+.

Example 99

N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}-4-methylbenzamide

[0680] ##STR00183##

[0681] The title compound (78.0 mg, 0.180 mmol, 34%) was obtained as a white solid using 1-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine (166 mg, 0.528 mmol) and p-toluoyl chloride (0.070 mL, 0.528 mmol) in the same way as in Example 71.

[0682] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.30 (3H, s), 2.40 (3H, s), 3.67 (6H, s), 4.56 (2H, d, J=4.4 Hz), 5.88-5.92 (2H, m), 6.65 (2H, d, J=8.5 Hz), 6.91 (1H, br s), 7.23 (2H, d, J=8.3 Hz), 7.45 (1H, t, J=8.5 Hz), 7.65 (2H, d, J=8.3 Hz). MS (ESI): m/z 433 [M+H].sup.+.

Example 100

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step 1

Ethyl 2-(2-chloroethanimidoyl)hydrazinecarboxylate

[0683] ##STR00184##

[0684] A solution of Chloroacetonitrile (1.26 mL, 19.9 mmol) in methanol (15 mL) was cooled to 0° C. To the solution, 1 mol/L sodium methoxide methanol solution (0.72 mL, 0.72 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, acetic acid (0.034 mL) was added, and ethyl carbazate (2.00 g, 19.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the partially purified title compound (3.58 g, 20 mmol, quantitative) as a pale yellow solid.

[0685] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.34 (3H, t, J=7.1 Hz), 3.51 (2H, s), 4.29 (2H, q, J=7.1 Hz), 5.07 (2H, br s). MS (ESI): m/z 180 [M+H].sup.+.

Step 2

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0686] ##STR00185##

[0687] To a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (200 mg, 0.630 mmol) in acetone (15 mL), potassium carbonate (400 mg, 1.89 mmol) and ethyl 2-(2-chloroethanimidoyl)hydrazinecarboxylate (220 mg, 1.26 mmol) were added, and the mixture was stirred at 60° C. for 5 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was added N,N-dimethylformamide (15 mL), and the mixture was stirred at 140° C. for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate/methanol=50/50/0-0/100/0-0/80/20 (V/V/V)] and ODS column chromatography [elution solvent: 0.1% formic acid water/0.1% formic acid acetonitrile=100/0-30/70 (V/V)] to obtain the title compound (35 mg, 0.0845 mmol, 13%) as a white solid.

[0688] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.34 (3H, s), 3.79 (6H, s), 5.40 (2H, s), 5.83-5.86 (1H, m), 5.93-5.96 (1H, m), 6.75 (2H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 8.61 (1H, br s), 9.67 (1H, br s). MS (ESI): m/z 415 [M+H].sup.+.

Example 101

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3,4-oxadiazol-2(3H)-one

Step 1

2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetohydrazide

[0689] ##STR00186##

[0690] To a solution of Ethyl {[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (250 mg, 0.620 mmol) in ethanol (5.0 mL), hydrazine monohydrate (150 mg, 3.10 mmol) was added, and the mixture was stirred at 70° C. for 5 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V)] to obtain the title compound (288 mg, 0.740 mmol, quantitative) as a white solid.

[0691] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.75 (6H, s), 3.78 (2H, s), 3.91 (2H, br s), 5.91-5.93 (1H, m), 5.97 (1H, d, J=3.4 Hz), 6.70 (2H, d, J=8.5 Hz), 7.48 (1H, d, J=8.5 Hz), 9.16 (1H, br s). MS (ESI): m/z 390 [M+H].sup.+.

Step 2

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3,4-oxadiazol-2(3H)-one

[0692] ##STR00187##

[0693] To a solution of 2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetohydrazide (230 mg, 0.591 mmol) in tetrahydrofuran (20 mL), 1,1-carbonyldiimidazole (145 mg, 0.886 mmol) was added at room temperature, and the mixture was stirred for 6 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane/ethyl acetate=30/70-0/100 (V/V)] to obtain the title compound (142 mg, 0.342 mmol, 58%) as a white solid.

[0694] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.74 (6H, s), 4.16 (2H, s), 5.89-5.93 (1H, m), 5.99 (1H, d, J=3.4 Hz), 6.71 (2H, d, J=8.5 Hz), 7.49 (1H, d, J=8.5 Hz). MS (ESI): m/z 416 [M+H].sup.+.

Example 102

({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)phosphonic acid

[0695] ##STR00188##

[0696] Dipropan-2-yl ({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)phosphonate (270 mg, 0.545 mmol) was dissolved in acetonitrile (15 mL). To the solution, bromotrimethylsilane (1.5 mL, 11 mmol) was added at room temperature, and the mixture was stirred for 12 hours. Then, the solvent was added a small amount of methanol, and concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography [elution solvent: 0.1% formic acid water/0.1% formic acid acetonitrile=100/0-30/70 (V/V)], and lyophilized to obtain the title compound (80 mg, 0.194 mmol, 36%) as a white solid.

[0697] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.26 (3H, s), 3.26 (2H, d, J=12.2 Hz), 3.73 (6H, s), 5.92-5.94 (1H, m), 6.01-6.04 (1H, m), 6.69 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz). MS (ESI): m/z 412 [M+H].sup.+.

Example 103

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2-oxazol-5(4H)-one

Step 1

Ethyl 4-{[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-oxobutanoate

[0698] ##STR00189##

[0699] The title compound (398 mg, 0.893 mmol, 71%) was obtained as a pale yellow oil using 4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazole-3-thiol (400 mg, 1.26 mmol) and 4-chloroacetoacetic acid ethyl ester (0.240 mL, 1.89 mmol) in the same way as in Example 2.

[0700] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 1.27 (3H, t, J=7.3 Hz), 2.27 (3H, s), 3.72 (2H, s), 3.73 (6H, s), 4.18 (2H, q, J=7.3 Hz), 4.19 (2H, s), 5.87-5.92 (1H, m), 5.94 (1H, d, J=3.4 Hz), 6.68 (2H, d, J=8.5 Hz), 7.47 (1H, t, J=8.5 Hz). MS (ESI): m/z 446 [M+H].sup.+.

Step 2

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2-oxazol-5(4H)-one

[0701] ##STR00190##

[0702] To a solution of Ethyl 4-[[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazol-3-yl]sulfanyl]-3-oxo-butanoate (105 mg, 0.236 mmol) in ethanol (3.0 mL), potassium carbonate (37 mg, 0.236 mmol) and hydroxylammonium chloride (25 mg, 0.260 mmol) were added, and the mixture was stirred at room temperature for 10 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V)] and ODS column chromatography [elution solvent: 0.1% formic acid water/0.1% formic acid acetonitrile=100/0-30/70 (V/V)], and lyophilized to obtain the title compound (35 mg, 0.084 mmol, 36%) as a white solid.

[0703] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.51 (2H, s), 3.73 (6H, s), 4.15 (2H, s), 5.91-5.94 (1H, m), 5.96-5.99 (1H, m), 6.70 (2H, d, J=8.5 Hz), 7.49 (1H, t, J=8.5 Hz). MS (ESI): m/z 415 [M+H].sup.+.

Example 104

5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2-dihydro-3H-pyrazol-3-one

[0704] ##STR00191##

[0705] To a solution of Ethyl 4-[[4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furyl)-1,2,4-triazol-3-yl]sulfanyl]-3-oxo-butanoate (146 mg, 0.328 mmol) in ethanol (3.0 mL), hydrazine monohydrate (0.020 mL, 0.393 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V)] to obtain the title compound (55 mg, 0.133 mmol, 41%) as a white solid.

[0706] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ (ppm): 2.24 (3H, s), 3.69 (6H, s), 4.20 (2H, s), 5.32 (1H, s), 5.87-5.89 (1H, m), 6.09-6.12 (1H, m), 6.89 (2H, d, J=8.5 Hz), 7.56 (1H, t, J=8.5 Hz). MS (ESI): m/z 414 [M+H].sup.+.

Example 105

4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzamide

[0707] ##STR00192##

[0708] To 4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoic acid (30 mg, 0.0664 mmol), 28% aqueous ammonia solution (0.20 mL, 0.133 mmol) and methanol (3.0 mL) were added, and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (38 mg, 0.133 mmol) was added at room temperature, and the mixture was stirred for 12 hours. Further, 28% aqueous ammonia solution (0.20 mL, 0.133 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (38 mg, 0.133 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Then, the solvent was concentrated under reduced pressure, the obtained residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate/methanol=100/0-80/20 (V/V)] to obtain the title compound (12 mg, 0.0266 mmol, 40%) as a pale yellow solid.

[0709] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.28 (3H, s), 3.65 (6H, s), 4.41 (2H, s), 5.89-5.92 (2H, m), 6.66 (2H, d, J=8.5 Hz), 7.40 (2H, d, J=8.3 Hz), 7.45 (1H, t, J=8.5 Hz), 7.71 (2H, d, J=8.3 Hz). MS (ESI): m/z 451 [M+H].sup.+.

Example 106

3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzamide

[0710] ##STR00193##

[0711] The title compound (25.0 mg, 0.055 mmol, 83%) was obtained as a pale yellow solid using 3-({[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)benzoic acid (30 mg, 0.0664 mmol) in the same way as in Example 105.

[0712] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 3.64 (6H, s), 4.36 (2H, s), 5.87-5.90 (2H, m), 6.65 (2H, d, J=8.5 Hz), 7.34 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=8.5 Hz), 7.47 (1H, d, J=7.8 Hz), 7.72 (1H, d, J=7.8 Hz), 7.75 (1H, s). MS (ESI): m/z 451 [M+H].sup.+.

Example 107

N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}-4-methylbenzenesulfonamide

[0713] ##STR00194##

[0714] The title compound (14.0 mg, 0.0388 mmol, 36%) was obtained as a pale yellow solid using 1-[4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methanamine (26.0 mg, 0.083 mmol) and p-toluenesulfonyl chloride (31.0 mg, 0.165 mmol) in the same way as in Example 71.

[0715] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ (ppm): 2.27 (3H, s), 2.41 (3H, s), 3.71 (6H, s), 4.06 (2H, d, J=5.4 Hz), 5.09 (1H, t, J=5.4 Hz), 5.86-5.88 (1H, m), 5.89-5.91 (1H, m), 6.61 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 7.50 (1H, t, J=8.5 Hz), 7.67 (2H, d, J=8.5 Hz). MS (ESI): m/z 469 [M+H].sup.+.

Test Example 1

[0716] Measurement of Apelin Receptor Agonist Activity

[0717] The apelin receptor agonist activity of the compound represented by formula (I) or (II) of the present invention was measured by cell-based assay for determining the amount of intracellular cAMP.

[0718] CHO cells (DiscoveRx Corp.) stably expressing the human apelin receptor were inoculated to wells of a microtiter plate and cultured overnight at 37° C. under conditions of 5% CO.sub.2.

[0719] Each test compound and Forskolin were added to the wells at the same time. Specifically, the test compound dissolved in DMSO was diluted with a Forskolin-containing buffer [DMEM/F-12, HEPES, no phenol red (#11039, GIBCO)] to prepare a mixed solution containing the test compound at a final concentration of 0 to 10 μM (common ratio: 3, serial dilution: 11), Forskolin at a final concentration of 10 μM, and DMSO at a final concentration of 0.3% v/v, which was then added to the wells (N=4).

[0720] After 30 minutes, the cells were lysed, and HitHunter cAMP XS+ Assay #90-0075L (DiscoveRx Corp.) was added to the cell lysate. The mixture was left overnight, and the resulting chemiluminescence signals were then detected using Analyst GT (Molecular Devices LLC.) to determine the amount of cAMP.

[0721] The amount of cAMP determined by the addition of a positive control [Pyr1]-apelin-13 (final concentration: 0.300 μM) and Forskolin (final concentration: 10 μM) at the same time was used as an index to define 100% efficacy. The amount of cAMP determined by the addition of Forskolin (final concentration: 10 μM) alone was used as an index to define 0% efficacy.

[0722] A dose response curve was prepared from the final concentration of the test compound and the determined amount of cAMP using Sigmaplot 12.0. The concentration at which the test compound exhibited 50% efficacy was calculated as an EC.sub.50 value (μm).

[0723] The test results of the compound represented by formula (I) or (II) of the present invention are shown in Table 1.

TABLE-US-00001 TABLE 1 Example No. EC.sub.50 value (μM)  1 0.031  2 0.001  3 0.002  4 0.122  5 0.026  6 0.703  7 0.815  8 1.57  9 0.018  10 0.192  11 0.005  12 0.701  13 0.159  14 0.424  15 0.164  16 0.314  17 1.41  18 0.561  19 0.171  20 0.729  21 0.539  22 0.087  23 0.271  24 0.751  25 1.72  26 0.057  27 2.87  28 1.42  29 0.812  30 0.332  31 0.174  32 3.98  33 2.44  34 0.152  35 0.010  36 0.108  37 0.825  38 0.009  39 0.011  40 1.11  41 0.045  42 0.012  43 0.039  44 1.21  45 1.32  46 0.096  47 0.419  48 0.022  49 0.393  50 1.32  51 0.111  52 0.217  53 2.65  54 1.20  55 1.92  56 0.048  57 1.21  58 2.80  59 0.349  60 1.30  61 0.412  62 0.808  63 0.716  64 0.052  65 0.075  66 0.817  67 0.774  68 1.33  69 0.696  70 0.384  71 1.07  72 0.095  73 1.02  74 0.098  75 0.128  76 0.158  77 0.557  78 0.034  79 0.208  80 1.53  81 0.071  82 5.46  83 0.219  84 0.267  85 0.253  86 2.02  87 0.744  88 0.035  89 0.261  90 0.503  91 0.351  92 0.166  93 0.364  94 0.071  95 0.006  96 0.605  97 0.273  98 1.17  99 0.338 100 0.957 101 0.587 102 0.103 103 0.046 104 0.048 105 1.20 106 0.793 107 0.668

[0724] The present invention has demonstrated a novel azole derivative as an apelin receptor agonist, and a method for treating cardiovascular disease, diabetic disease, renal disease, hypertension, and arteriosclerosis, etc., using the same. The present invention is useful in the treatment of cardiovascular disease, diabetic disease, renal disease, hypertension, and arteriosclerosis, etc.