Indian Patents
Title of Invention

TRIAZOLONE DERIVATIVE
Abstract ABSTRACT TRIAZOLONE DERIVATIVE A Compound represented by the following general formula (1), salts thereof or hydrates of the foregoing is a novel compound useful for treatment and/or prevention of diseases associated with thrombus formation, and which is safer with suitable physicochemical stability. (1) [wherein RIa. R1b Rlc and Rld each independently represent hydrogen, etc.; R" represents optionally substituted phenyl, etc.; R1 represents optionally substituted C6-10 aryl, etc.; and Z and Z" each independently represent hydrogen]
Full Text DESCRIPTION
TRIAZOLONE DERIVATIVE Technical Field
[0001] The present invention relates to novel triazolone derivatives which are useful as medicaments, to their pharmacologically acceptable salts, or hydrates thereof, and to therapeutic or prophylactic agents for diseases associated with thrombus formation comprising the same as active ingredients. Background Art
[0002] Living organisms with damaged blood vessels avoid hemorrhage death by rapid production of thrombin. However, excess production of thrombin due to inflammatory reaction in damaged blood vessels causes thrombosis, which impairs the function of essential organs. Thrombin inhibitors such as heparin and warfarin, which inhibit thrombin production or directly block thrombin activity, have long been used as anticoagulants to treat or prevent thrombosis. Still, it cannot be said that such medicaments are very satisfactory from a medical standpoint, and efforts continue throughout the world toward research and development of new orally administrable anticoagulants with excellent dose response and low risk of bleeding.
[0003] The blood clotting mechanism has been classified into two pathways, the "intrinsic clotting pathway" which begins with activation of factor XII (FXII) upon contact with negative charged substances, and the "extrinsic clotting pathway" which is activated by tissue factor (TF) and factor VII (FVII). Since the pathology of thrombosis onset is associated with specific expression of TF, it has been suggested that extrinsic clotting is of major importance. Compounds that inhibit clotting factor Vila, which is furthest upstream in the extrinsic clotting pathway of the clotting cascade, are thought to have potential use as therapeutic and/or prophylactic agents for diseases associated with thrombus formation, such as thrombosis, in which the extrinsic clotting mechanism plays a part. [0004] As compounds that inhibit clotting factor Vila there are known

in the prior art amidinonaphthol derivatives (see Non-patent document 1),
amidino derivatives (see Patent document 1), N-sulfonyl dipeptide
derivatives (see Patent document 2),
6-[[(allyI)oxy]methyl]naphthalene-2-carboxyimidamide derivatives (see
Patent document 3) and phenylglycine derivatives (Patent documents 4
and 5).
[0005] However, these known compounds are inadequate from the
standpoint of inhibition activity against clotting factor Vila, blood
clotting effects and thrombosis-treating effects.
[0006] [Non-patent document 1] Tetrahedron, 55, p.6219, 1999
[Patent document 1] EP 1078917
[Patent document 2] WO 00/58346
[Patent document 3] WO 00/66545
[Patent document 4] WO 00/35858
[Patent document 5] WO 00/41531 Disclosure of the Invention
[0007] It is an object of the present invention, which has been accomplished in light of the aforementioned problems of the prior art, to provide novel triazolone derivatives having serine protease inhibitory activity, and particularly excellent inhibitory activity against clotting factor Vila, as well as their pharmacologically acceptable salts and hydrates thereof, and therapeutic and/or prophylactic agents for diseases associated with thrombus formation, that employ the foregoing. [0008] As a result of much diligent research in light of the circumstances described above, the present inventors have succeeded in synthesizing novel triazolone derivatives having a specific chemical structure, and have completed this invention upon discovering that these compounds have excellent inhibitory activity against clotting factor Vila, and particularly that they are useful as therapeutic and/or prophylactic agents for diseases associated with thrombus formation. In other words, the present invention provides the following [l]-[34]. [1] A compound represented by general formula (1), or a salt thereof or a hydrate of the foregoing:


(1)
wherein Rla, Rlb, Rlc and Rld each independently represent hydrogen, hydroxyl, CI-6 alkyl or halogen;
R2 represents C6-10 aryl optionally having 1-5 substituents selected from Group Al below, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Al below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-5 substituents selected from Group A1 below;
R3 represents a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Al below, C6-10 aryl optionally having 1-5 substituents selected from Group Al below or a 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Al below; and Z1 and Z2 represent hydrogen,
wherein Group Al consists of hydroxyl, halogen, cyano, nitro, oxo, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyl optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyloxy optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyloxy, C2-6 alkynyloxy, CI-6 alkylthio, CI-6 alkylsulfinyl, CI-6 alkylsulfonyl, CI-6 alkylsulfonyloxy, C6-10 aryl optionally having 1-5 substituents selected from Group Bl below, C6-10 aryloxy optionally having 1-5 substituents selected from Group Bl below, 5- to 10-membered heteroaryl optionally having 1-5 substituents

selected from Group Bl below, 5- to 10-membered heteroaryloxy optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-5 substituents selected from Group Bl below, a group represented by the formula -NRU-R2t and a group represented by the formula -CO-R3t,
where Ru and R2t each independently represent hydrogen, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group Bl below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkylsulfonyl optionally having 1-3 substituents selected from Group Bl below, carbamoyl, aminosulfonyl, C6-10 aryl optionally having 1-5 substituents selected from Group Bl below or 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Bl below, and R3t represents hydroxyl, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, amino, mono(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below or di(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below,
wherein Group Bl consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, C3-8 cycloalkyl, amino, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, carbamoyl, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl, C6-10 aryl optionally having 1-5 substituents selected from Group CI below and 5-to 10-membered heteroaryl optionally having 1-5 substituents selected from Group CI below,
wherein Group CI consists of halogen, CI-6 alkyl and CI-6 alkoxy.
[2] A compound represented by general formula (1-1), or a salt thereof or a hydrate of the foregoing:


(1-2)
wherein Rla, Rlb, Rlc, R,d, R2, R3, Z1 and Z2 have the same definitions as Rla, Rlb, Rlc, Rld, R2, R3, Z1 and Z2 in claim 1. [4] A compound according to any one of [1] to [3] above, or a salt thereof or a hydrate of the foregoing, wherein Rla, Rlb, Rlc and Rld are each independently hydrogen, fluorine or hydroxyl. [5] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is phenyl optionally having 1-4 substituents selected from Group Dl below, pyridyl optionally having 1-3 substituents selected from Group Dl below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-4 substituents selected from Group Dl below,

wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,
wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)am inocarbonyl.
[6] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is phenyl optionally having 1-4 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,
wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
[7] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is phenyl optionally having 2 or 3 substituents selected from Group D3 below,
wherein Group D3 consists of fluorine, chlorine, methyl optionally having 1 substituent selected from Group D4 below, ethyl optionally having 1 substituent selected from Group D4 below, vinyl, ethynyl, methoxy optionally having 1 or 2 substituents selected from Group D4 below, ethoxy optionally having 1 or 2 substituents selected

from Group D4 below, 1-propyloxy optionally having 1 or 2 substituents selected from Group D4 below, 2-propyloxy optionally having 1 or 2 substituents selected from Group D4 below, allyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy and acetyl,
wherein Group D4 consists of hydroxyl, fluorine, cyano, methoxy, methylamino, dimethylamino, methylaminocarbonyl and dimethylaminocarbonyl.
[8] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is a group represented by the formula:

wherein R represents hydrogen, fluorine or chlorine;
R22 represents hydrogen, hydroxyl, methyl optionally having 1 substituent selected from Group D5 below, ethyl optionally having 1 substituent selected from Group D5 below, methoxy optionally having 1 substituent selected from Group D5 below, ethoxy optionally having 1 or 2 substituents selected from Group D5 below, 1-propyloxy optionally having 1 substituent selected from Group D5 below, 2-propyloxy optionally having 1 substituent selected from Group D5 below, allyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy or acetyl;
R23 represents hydrogen, fluorine, hydroxyl, methoxy optionally having 1 substituent selected from Group D6 below, ethoxy optionally having 1 substituent selected from Group D6 below or 2-propyloxy optionally having 1 substituent selected from Group D6 below; and
R24 represents hydrogen, fluorine, hydroxyl, methyl optionally having 1 substituent selected from Group D7 below, ethyl, vinyl, ethynyl, methoxy optionally having 1 substituent selected from Group D7 below, ethoxy optionally having 1 substituent selected from Group D7 below,

2-propyloxy or allyloxy,
wherein Group D5 consists of hydroxyl, fluorine, cyano, methoxy, dimethylamino, dimethylaminocarbonyl, 2-fluoroethoxy and 2-hydroxyethoxy,
wherein Group D6 consists of fluorine, cyano, methoxy, dimethylamino, methylaminocarbonyl and dimethylaminocarbonyl,
wherein Group D7 consists of hydroxyl, fluorine, cyano and ethoxy having one methoxy.
[9] A compound according to [8], or a salt thereof or a hydrate of the foregoing, wherein R21 is hydrogen or fluorine.
[10] A compound according to [8] or [9], or a salt thereof or a hydrate of
the foregoing, wherein R22 is hydrogen, hydroxyl, cyanomethyl,
methoxymethyl, methoxy, dimethylaminocarbonylmethoxy, ethoxy,
2-fluoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy,
2-(dimethylamino)ethoxy, tetrahydrofuryloxy, tetrahydropyranyloxy, fluoromethoxy, 3-hydroxypropyloxy, 2-fluoroethoxymethyl or 2-hydroxyethoxymethyl.
[11] A compound according to any one of [8] to [10], or a salt thereof or a hydrate of the foregoing, wherein R23 is hydrogen, fluorine, methoxy, cyanomethoxy, ethoxy, 2-propyloxy or 2-methoxyethoxy. [12] A compound according to any one of [8] to [11], or a salt thereof or a hydrate of the foregoing, wherein R24 is hydrogen, hydroxyl, methyl, methoxymethyl, ethyl, vinyl, ethynyl, methoxy, ethoxy or 2-fluoroethoxy. [13] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is pyridyl optionally having 1-3 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,

wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(CT-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
[14] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is pyridyl having 2 substituents selected from the group consisting of CI-6 alkyl and CI-6 alkoxy. [15] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is pyridyl having 2 substituents selected from the group consisting of methyl, methoxy and ethoxy. [16] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is a group represented by the formula:

wherein R represents methyl or methoxy; and R represents methoxy or ethoxy.
[17] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is a 9- to 12-membered benzene-fused cyclic group optionally having 1-4 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,

wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyI)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
[18] A compound according to any one of [1] to [4], or a salt thereof or a hydrate of the foregoing, wherein R2 is a group represented by the formula:

wherein R27 represents hydrogen or halogen;
R28 represents hydrogen, hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or C2-7 alkylcarbonyl; R29 represents hydrogen, cyano, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or carbamoyl;
X represents carbon optionally having 1 or 2 substituents selected from Group D8 below, nitrogen optionally having 1 substituent selected from Group D8 below or oxygen;
m represents an integer of 0-3 and n represents an integer of 0-2, with the proviso that the sum of m and n is 1-4; and
Rings A and B optionally contain one double bond in the ring and optionally have an oxo group on the ring,
wherein Group D8 consists of hydrogen, hydroxyl, halogen, CI-6 alkoxy, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl and CI-6 alkyl

optionally having halogen.
[19] A compound according to [18], or a salt thereof or a hydrate of the
foregoing, wherein R2 is a group represented by the formula:

wherein R27 represents hydrogen or halogen;
R28 represents hydrogen, hydroxyl, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or C2-7 alkylcarbonyl;
R29 represents hydrogen, cyano, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or aminocarbonyl; and
Ring A optionally has an oxo group on the ring,
wherein Group D8 consists of hydrogen, hydroxyl, halogen, CI-6 alkoxy, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl, and CI-6 alkyl optionally having halogen.
[20] A compound according to [19], or a salt thereof or a hydrate of the foregoing, wherein R28 is methyl, ethyl, methoxy, ethoxy, vinyl or ethynyl.

[21] A compound according to [19] or [20], or a salt thereof or a hydrate of the foregoing, wherein R29 is hydrogen.
[22] A compound according to any one of [1] to [21], or a salt thereof or a hydrate of the foregoing, wherein R3 is phenyl optionally having 1 -3 substituents selected from Group El below, pyridyl optionally having 1-3 substituents selected from Group El below, N-oxypyridyl optionally having 1-3 substituents selected from Group El below, N-Cl-6 alkylpyridinium optionally having 1-3 substituents selected from Group El below, pyrazinyl optionally having 1-3 substituents selected from Group El below, pyridazinyl optionally having 1-3 substituents selected from Group El below, pyrimidinyl optionally having 1-3 substituents selected from Group El below, pyrazolyl optionally having 1-3 substituents selected from Group El below, imidazolyl optionally having 1-3 substituents selected from Group El below, thiazolyl optionally having 1-3 substituents selected from Group El below, thienyl optionally having 1-3 substituents selected from Group El below or dihydropyrazinyl having an oxo group, with the proviso that when R3 is N-Cl-6 alkylpyridinium, R3 forms an ion pair with an anion in the molecule,
wherein Group El consists of hydroxyl, halogen, cyano, CI-6 alkyl, CI-6 alkoxy, a group represented by the formula -NH-R21t and a group represented by the formula -CO-R3":
where R21t represents hydrogen, CI-6 alkyl, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group E2 below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group E2 below, CI-6 alkylsulfonyl, carbamoyl or aminosulfonyl, and R31t represents hydroxyl, Cl-6 alkyl, Cl-6 alkoxy, amino, mono(Cl-6 alkyl)amino or di(Cl-6 alkyI)amino),
wherein Group E2 consists of hydroxyl, Cl-6 alkoxy and C3-8 cycloalkyl.
[23] A compound according to any one of [1] to [21], or a salt thereof or a hydrate of the foregoing, wherein R3 is phenyl optionally having 1 or 2 substituents selected from Group E3 below, pyridyl optionally having 1

or 2 substituents selected from Group E3 below, N-oxypyridyl optionally having 1 or 2 substituents selected from Group E3 below, pyrazinyl optionally having 1 or 2 substituents selected from Group E3 below, pyridazinyl optionally having 1 or 2 substituents selected from Group E3 below, pyrimidinyl optionally having 1 or 2 substituents selected from Group E3 below, pyrazolyl optionally having 1 or 2 substituents selected from Group E3 below, imidazolyl optionally having 1 or 2 substituents selected from Group E3 below, thiazolyl optionally having 1 or 2 substituents selected from Group E3 below, thienyl optionally having 1 or 2 substituents selected from Group E3 below or dihydropyrazinyl having an oxo group,
wherein Group E3 consists of halogen, CI-6 alkyl, CI-6 alkoxy, a group represented by the formula -NH-R22t,
where R22t represents hydrogen or C2-7 alkoxycarbonyl, and a group represented by the formula -CO-R32t,
where R represents hydroxyl, CI-6 alkoxy or amino. [24] A compound according to any one of [1] to [21], or a salt thereof or a hydrate of the foregoing, wherein R3 is phenyl optionally having one group selected from Group E4 below, pyridyl optionally having one group selected from Group E5 below, N-oxypyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl optionally having one group selected from Group E4 below, imidazolyl optionally having one group selected from Group E4 below, thiazolyl optionally having one group selected from Group E4 below, thienyl optionally having one group selected from Group E4 below or dihydropyrazinyl having an oxo group,
wherein Group E4 consists of methoxy, carboxyl, carbamoyl, methoxycarbonyl and methoxycarbonylamino,
wherein Group E5 consists of fluorine, methyl, methoxy and amino.
[25] A medicament comprising a compound according to any one of [1] to [24], or a salt thereof or a hydrate of the foregoing. [26] A therapeutic and/or prophylactic agent for a disease associated with thrombus formation, comprising a compound according to any one of [1]

to [24], or a salt thereof or a hydrate of the foregoing.
[27] A therapeutic and/or prophylactic agent for a disease selected from
Group Fl below, comprising a compound according to any one of [1] to
[24], or a salt thereof or a hydrate of the foregoing.
wherein Group Fl consists of thrombosis, deep vein thrombosis,
pulmonary embolism, cerebral infarction, myocardial infarction, acute
coronary syndrome, vascular restenosis, disseminated intravascular
coagulation syndrome and malignant tumor.
[28] A therapeutic and/or prophylactic agent for a disease selected from
Group F2 below, comprising a compound according to any one of [1] to
[24], or a salt thereof or a hydrate of the foregoing,
wherein Group F2 consists of thrombosis, deep vein thrombosis,
pulmonary embolism, cerebral infarction, myocardial infarction, acute
coronary syndrome, vascular restenosis and disseminated intravascular
coagulation syndrome.
[29] A method for treatment and/or prevention of a disease associated
with thrombus formation, which involves administration of a
pharmacologically effective dose of a compound according to any one of
[]] to [24], or a salt thereof or a hydrate of the foregoing.
[30] A method for treatment and/or prevention of a disease selected from
Group Fl below, which involves administration of a pharmacologically
effective dose of a compound according to any one of [1] to [24], or a
salt thereof or a hydrate of the foregoing,
wherein Group Fl consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis, disseminated intravascular coagulation syndrome and malignant tumor.
[31] A method for treatment and/or prevention of a disease selected from Group F2 below, which involves administration of a pharmacologically effective dose of a compound according to any one of [1] to [24], or a salt thereof or a hydrate of the foregoing,
wherein Group F2 consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute

coronary syndrome, vascular restenosis and disseminated intravascular
coagulation syndrome.
[32] Use of a compound according to any one of [1] to [24], or a salt
thereof or a hydrate of the foregoing, for production of a therapeutic
and/or prophylactic agent for a disease associated with thrombus
formation.
[33] Use of a compound according to any one of [1] to [24], or a salt
thereof or a hydrate of the foregoing, for production of a therapeutic
and/or prophylactic agent for a disease selected from Group Fl below.
wherein Group Fl consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis, disseminated intravascular coagulation syndrome and malignant tumor.
[34] Use of a compound according to any one of [1] to [24], or a salt thereof or a hydrate of the foregoing, for production of a therapeutic and/or prophylactic agent for a disease selected from Group F2 below.
wherein Group F2 consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis and disseminated intravascular coagulation syndrome.
[0016] The compounds of the invention have excellent inhibiting effects against clotting factor Vila and excellent anticoagulant effects, and are therefore useful as therapeutic and/or prophylactic agents for diseases associated with thrombus formation (for example, thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis or disseminated intravascular coagulation syndrome) (Johannes Ruef & Hugo A Katus, New antithrombotic drugs on the horizon, Expert Opin. Investig. Drugs (2003) 12 (5): 781-797).
[0017] Substances with inhibiting effects against clotting factor Vila have also been reported to exhibit malignant tumor metastasis suppression and reduction. Thus, the compounds of the present invention that have excellent inhibiting effects against clotting factor

Vila are also useful as therapeutic and/or prophylactic agents for malignant tumors and the like (Mattias Belting et al., Regulation of angiogenesis by tissue factor cytoplasmic domain signaling, Nature Medicine (2004) 10 (5): 502-509; X Jiang et al., Formation of tissue factor-factor Vila-factor Xa complex promotes cellular signaling and migration of human breast cancer cells, J Thromb Haemost, (2004) 2: 93-101; Hembrough TA. Swartz GM. Papathanassiu A. Vlasuk GP. Rote WE. Green SJ. Pribluda VS., Tissue factor/factor Vila inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Research (2003) 63 (11): 2997-3000).
[0018] Since the compounds of the invention have excellent suppressing effects against blood clotting, and are safer with suitable physicochemical stability, they are useful as medicaments, and especially as therapeutic and/or prophylactic agents for diseases associated with thrombus formation.
Best Modes for Carrying Out the Invention [0019] The present invention will now be explained in detail. [0020] 1) The compound represented by general formula (1). Throughout the present specification, the structural formulas for the compounds will show only one specific isomer for convenience, but the invention includes all isomers such as geometric isomers, optical isomers, stereoisomers and tautomers implied by the compound structures, as well as their isomer mixtures, and the compounds may therefore be any of the isomers or their mixtures, without being limited to the formulas shown for convenience. The compounds of the invention may therefore be in optically active or racemic form, both of which are included without restrictions according to the invention. Polymorphic crystals also exist, and there may be used any crystal form or a mixture thereof without any restrictions, while the compounds of the invention include both anhydrous and hydrated forms. [0021] 2) The compound represented by general formula (1-1) and (1-2). Throughout the present specification, the structural formulas for the compounds will show only one specific isomer for convenience, but the

invention includes all isomers such as geometric isomers, stereoisomers and tautomers implied by the compound structures, as well as their isomer mixtures, and the compounds may therefore be any of the isomers or their mixtures, without being limited to the formulas shown for convenience. Polymorphic crystals also exist, and there may be used any crystal form or a mixture thereof without any restrictions, while the compounds of the invention include both anhydrous and hydrated forms. [0022] The tautomer represented by general formula (1) includes the compounds represented by general formula (la) and (lb);



[0026] The definitions of the terms and symbols used throughout the present specification will now be explained, prior to a more detailed description of the invention.
[0027] The term "disease associated with thrombus formation" is not particularly restricted so long as it is a disease with onset directly or indirectly caused by thrombus formation, and as specific examples there may be mentioned thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis, disseminated intravascular coagulation syndrome and malignant tumor, and preferably thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis and disseminated intravascular coagulation syndrome.
[0028] A "halogen" refers to fluorine, chlorine, bromine or iodine. As preferred examples of "halogen" there may be mentioned fluorine and chlorine.
[0029] The term "CI-6 alkyl" refers to a straight-chain or branched CI-6
alkyl group, and as specific examples there may be mentioned methyl,
ethyl, 1-propyl (n-propyl), 2-propyl (i-propyl), 2-methyl-l -propyl
(i-butyl), 2-methyl-2-propyl (t-butyl), 1-butyl (n-butyl), 2-butyl
(s-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-l-butyl,
3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl,
2,2-dimethyl-l-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl- 1-pentyl,
3-methyl-l-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl,
3-methyl-3-pentyl, 2,3-dimethyl-l-butyl, 3,3-dimethyl-l-butyl,

2,2-dimethyl-l -butyl, 2-ethyl-l -butyl, 3,3-dimethyl-2-butyl and
2,3-dimethyl-2-butyl.
[0030] The term "C2-6 alkenyl" refers to a straight-chain or branched
C2-6 alkenyl group containing one double bond, and as specific
examples there may be mentioned vinyl(ethenyl), allyl(2-propenyl),
1-propenyl, isopropenyl(l-methylvinyl), 1-butenyl, 2-butenyl, 3-butenyl,
pentenyl and hexenyl.
[0031] The term "C2-6 alkynyl" refers to a straight-chain or branched
alkynyl group containing one triple bond, and as specific examples there
may be mentioned ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl
and hexynyl.
[0032] The term "C3-8 cycloalkyl" refers to a C3-8 monocyclic
saturated aliphatic hydrocarbon group, and as specific examples there
may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl.
[0033] The term "C6-10 aryl" refers to a C6-10 aromatic hydrocarbon
cyclic group, and as specific examples there may be mentioned phenyl
and naphthyl.
[0034] The term "5- to 10-membered heteroaryl" refers to an aromatic
cyclic group having 5-10 atoms composing the ring and containing 1-5
hetero atoms among the atoms composing the ring, and as specific
examples there may be mentioned furyl, thienyl, pyrrolyl, imidazolyl,
triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isooxazolyl,
isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl,
pyridazinyl, pyrimidinyl, triazinyl, purinyl, pteridinyl, quinolyl,
isoquinolyl, naphthylidinyl, quinoxalinyl, cinnolinyl, quinazolinyl,
phthaladinyl, imidazopyridyl, imidazothiazolyl, imidazooxazolyl,
benzothiazolyl, benzooxazolyl, benzoimidazolyl, indolyl, isoindolyl,
indazolyl, pyrrolopyridyl, thienopyridyl, furopyridyl, benzothiadiazolyl,
benzooxadiazolyl, pyridopyrimidinyl, benzofuryl, benzothienyl,
benzo[l,3]dioxole, thienofuryl, N-oxypyridyl and N-Cl-6
alkylpyridinium.
[0035] The term "5- or 6-membered non-aromatic heterocyclic group"

refers to (5) a non-aromatic cyclic group (1) having 5 or 6 atoms
composing the ring, (2) containing 1 or 2 hetero atoms among the atoms
composing the ring, (3) optionally containing 1 or 2 double bonds in the
ring and (4) optionally containing 1 or 2 oxo (carbonyl) groups on the
ring, and as specific examples there may be mentioned pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl,
tetrahydropyranyl, pyridonyl and dihydropyrazinyl. [0036] The term "5- to 8-membered heterocycle" refers to a ring (1) having 5-8 atoms composing the ring, (2) containing 1 or 2 hetero atoms among the atoms composing the ring, (3) optionally containing 1 or 2 double bonds in the ring and (4) optionally containing 1 or 2 oxo (carbonyl) groups on the ring, and as specific examples there may be mentioned pyrrolidine ring, piperidine ring, azepane ring, azocane ring, piperazine ring, diazepane ring, diazocane ring, morpholine ring, thiomorpholine ring, tetrahydrofuran ring, tetrahydropyran ring, oxepane ring, dioxane ring, dioxepane ring, dihydrofuran ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, oxazolidine ring, thiazolidine ring, pyridone ring and dihydropyrazine ring. [0037] The term "9- to 12-membered benzene-fused cyclic group" refers to a cyclic group comprising a "5- to 8-membered heterocycle" as defined above fused with a phenyl group, and as specific preferred examples there may be mentioned groups represented by the formula:



[0040] The term "CI-6 alkoxy" refers to a group consisting of an oxy group bonded to "CI-6 alkyl" as defined above, and as specific examples there may be mentioned methoxy, ethoxy, 1-propyloxy, 2-propyloxy, 2-methyl-l-propyloxy, 2-methyl-2-propyloxy, 1-butyloxy, 2-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-l-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl- 1-propyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl- 1-pentyloxy, 3-methyl-1-pentyloxy, 4-methyl-1-pentyloxy, 2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2,3-dimethyl-1-butyloxy, 3,3-dimethyl- 1-butyloxy, 2,2-dimethyl-1-butyloxy, 2-ethyl-1-butyloxy, 3,3-dimethyl-2-butyloxy and 2,3-dimethyl-2-butyloxy. [0041] The term "C3-8 cycloalkyloxy" refers to a group consisting of an oxy group bonded to "C3-8 cycloalkyl" as defined above, and as specific examples there may be mentioned cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. [0042] The term "C2-6 alkenyloxy" refers to a group consisting of an oxy group bonded to "C2-6 alkenyl" as defined above, and as specific examples there may be mentioned vinyloxy (ethenyloxy), allyloxy (2-propenyloxy), 1-propenyloxy, isopropenyloxy (1-methylvinyloxy),

1-butenyloxy, 2-butenyloxy, 3-butenyloxy, pentenyloxy and hexenyloxy. [0043] The term "C2-6 alkynyloxy" refers to a group consisting of an oxy group bonded to "C2-6 alkynyl" as defined above, and as specific examples there may be mentioned ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy and hexynyloxy. [0044] The term "CI-6 alkylthio" refers to a group consisting of a thio group bonded to "CI-6 alkyl" as defined above, and as specific examples there may be mentioned methylthio, ethylthio, 1 -propylthio, 2-propylthio, butylthio and pentylthio.
[0045] The term "CI-6 alkylsulfinyl" refers to a group consisting of a sulfinyl group bonded to "CI-6 alkyl" as defined above, and as specific examples there may be mentioned methylsulfinyl, ethylsulfinyl, 1-propylsulfinyl, 2-propylsulfinyl, butylsulfinyl and pentylsulfinyl. [0046] The term "CI-6 alkylsulfonyl" refers to a group consisting of a sulfonyl group bonded to "CI-6 alkyl" as defined above, and as specific examples there may be mentioned methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, butylsulfonyl and pentylsulfonyl. [0047] The term "C2-7 alkylcarbonyl" refers to a group consisting of a carbonyl group bonded to "CI-6 alkyl" as defined above, and as specific examples there may be mentioned acetyl, propionyl, isopropionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl. [0048] The term "C2-7 alkoxycarbonyl" refers to a group consisting of a carbonyl group bonded to "CI-6 alkoxy" as defined above, and as specific examples there may be mentioned methoxycarbonyl, ethoxycarbonyl, 1-propyloxycarbonyl and 2-propyloxycarbonyl. [0049] The term "C6-10 aryloxy" refers to a group consisting of an oxy group bonded to "C6-10 aryl" as defined above, and as specific examples there may be mentioned phenyloxy, 1 -naphthyloxy and 2-naphthyloxy. [0050] The term "5- to 10-membered heteroaryloxy" refers to a group consisting of an oxy group bonded to "5- to 10-membered heteroaryl" as defined above, and as specific examples there may be mentioned furyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, pyridyloxy and pyrazinyloxy.

[0051] The term "5- or 6-membered non-aromatic heterocyclooxy"
refers to a group consisting of an oxy group bonded to a "5- or
6-membered non-aromatic heterocyclic group" as defined above, and as
specific examples there may be mentioned pyrrolidinyloxy,
piperidinyloxy, morpholinyloxy, thiomorpholinyloxy, tetrahydrofuryloxy
and tetrahydropyranyloxy.
[0052] The term "CI-6 alkylsulfonyloxy" refers to a group consisting of
an oxy group bonded to "CI-6 alkylsulfonyl" as defined above, and as
specific examples there may be mentioned methylsulfonyloxy,
ethylsulfonyloxy, 1 -propylsulfonyloxy, 2-propylsulfonyloxy,
butylsulfonyloxy and pentylsulfonyloxy.
[0053] The term "C6-10 arylmethyl" refers to a group consisting of
methyl bonded to "C6-10 aryl" as defined above, and as specific
examples there may be mentioned benzyl, 1-naphthylmethyl and
2 -naphthylmethyl.
[0054] The term "C6-10 arylamino" refers to a group consisting of an
amino group bonded to "C6-10 aryl" as defined above, and as specific
examples there may be mentioned phenylamino, 1-naphthylamino and
2-naphthylamino.
[0055] The term "mono(Cl-6 alkyl)amino" refers to a group consisting
of an amino group bonded to one "CI-6 alky!" as defined above, and as
specific examples there may be mentioned methylamino and ethylamino.
[0056] The term "di(Cl-6 alkyl)amino" refers to a group consisting of
an amino group bonded to two "CI-6 alkyl" as defined above, and as
specific examples there may be mentioned dimethylamino and
methylethylamino.
[0057] The term "mono(Cl-6 alkyl)aminocarbonyl" refers to a group
consisting of a carbonyl group bonded to "mono(Cl-6 alkyl)amino" as
defined above, and as specific examples there may be mentioned
methylaminocarbonyl and ethylaminocarbonyl.
[0058] The term "di(Cl-6 alkyl)aminocarbonyl" refers to a group
consisting of a carbonyl group bonded to "di(Cl-6 alkyl)amino" as
defined above, and as specific examples there may be mentioned

dimethylaminocarbonyl and methylethylaminocarbonyl. [0059] The term "pyridyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a pyridine ring, and specifically there may be mentioned 2-pyridyl, 3-pyridyl and 4-pyridyl. [0060] The term "N-oxypyridyl" refers to the aforementioned "pyridyl" having the nitrogen in the ring oxidized, and specifically there may be mentioned N-oxy-2-pyridyl, N-oxy-3-pyridyl and N-oxy-4-pyridyl. [0061] The term "N-Cl-6 alkylpyridinium" refers to a cyclic group consisting of the aforementioned "CI-6 alkyl" bonded to the nitrogen on the ring of the aforementioned "pyridyl", and specifically there may be mentioned N-methyl-2-pyridinium, N-methyl-3-pyridinium and N-methyl-4-pyridinium. The aforementioned "N-Cl-6 alkylpyridinium" group forms an ion pair with anions in the molecule, and as examples of such anions there may be mentioned acetate ion and trifluoroacetate ion. [0062] The term "pyrazinyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a pyrazine ring. [0063] The term "pyridazinyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a pyridazine ring, and specifically there may be mentioned 2-pyridazinyl and 3-pyridazinyl. [0064] The term "pyrimidinyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a pyrimidine ring, and specifically there may be mentioned 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.
[0065] The term "pyrazolyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a pyrazole ring, and specifically there may be mentioned 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl.
[0066] The term "imidazolyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a imidazole ring, and specifically there may be mentioned 2-imidazolyl, 4-imidazolyl and 5-imidazolyl.
[0067] The term "thiazolyl" refers to a monovalent group derived by removing one hydrogen from any desired position of a thiazole ring, and

specifically there may be mentioned 2-thiazolyl, 4-thiazolyl and
5-thiazolyl.
[0068] The term "thienyl" refers to a monovalent group derived by
removing one hydrogen from any desired position of a thiophene ring,
and specifically there may be mentioned 2-fhienyl and 3-thienyl.
[0069] The term "pyridonyl" refers to a monovalent group derived by
removing one hydrogen from any desired position of a pyridone ring, and
specifically there may be mentioned groups represented by the formula:

[0073] The term "tetrahydrofuryloxy" refers to a group consisting of an oxy group bonded to "a monovalent group derived by removing one hydrogen from any desired position of a tetrahydrofuran ring", and

specifically there may be mentioned 2-tetrahydrofuryloxy and
3-tetrahydrofuryloxy.
[0074] The term "tetrahydropyranyloxy" refers to a group consisting of
an oxy group bonded to "a monovalent group derived by removing one
hydrogen from any desired position of a tetrahydropyran ring", and
specifically there may be mentioned 2-tetrahydropyranyloxy,
3-tetrahydropyranyloxy and 4-tetrahydropyranyloxy.
[0075] The term "optionally having substituents" means that the
compound may have one or more substituents in any desired combination
at substitutable positions.
[0076] A "salt" as referred to throughout the present specification is not
particularly restricted so long as it is formed with the compound of the
invention and is pharmacologically acceptable, and as examples there
may be mentioned inorganic acid salts, organic acid salts, inorganic base
salts, organic base salts and acidic or basic amino acid salts.
[0077] As preferred examples of inorganic acid salts there may be
mentioned hydrochloric acid salts, hydrobromic acid salts, sulfuric acid
salts, nitric acid salts and phosphoric acid salts, and as preferred
examples of organic acid salts there may be mentioned acetic acid salts,
succinic acid salts, fumaric acid salts, maleic acid salts, tartaric acid
salts, citric acid salts, lactic acid salts, stearic acid salts, benzoic acid
salts, methanesulfonic acid salts, ethanesulfonic acid salts,
p-toluenesulfonic acid salts and benzenesulfonic acid salts.
[0078] As preferred examples of inorganic base salts there may be
mentioned alkali metal salts such as sodium and potassium salts, alkaline
earth metal salts such as calcium and magnesium salts, and aluminum
and ammonium salts, and as preferred examples of organic base salts
there may be mentioned diethylamine salts, diethanolamine salts,
meglumine salts and N,N'-dibenzylethylenediamine salts.
[0079] As preferred examples of acidic amino acid salts there may be
mentioned aspartic acid salts and glutamic acid salts, and as examples of
basic amino acid salts there may be mentioned arginine salts, lysine salts
and ornithine salts.

[0080] Each substituent of the compounds of the present invention
represented by the above formulas (1), (1-1) and (1-2) is explained
below.
[0081] Rla, R1b, Rlc and Rld each independently represent hydrogen,
hydroxyl, CI-6 alkyl or halogen.
As preferable examples of Rla, RIb, Rlc and Rld, hydrogen, fluorine or hydroxyl is mentioned independently.
As more preferable examples of Rla, R,b, Rlc and Rld, hydrogen or fluorine is mentioned independently.
Rla, Rlb, Rlc and Rld may be either (1) all is hydrogen, (2) all is substituents other than hydrogen or (3) some are hydrogen and the others are substituents other than hydrogen, and preferably three or four of Rla, Rlb, Rlc and Rld are hydrogen.
[0082] R2 represents C6-10 aryl optionally having 1-5 substituents selected from Group Al below, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Al below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-5 substituents selected from Group Al below.
As preferable examples of R2, phenyl optionally having 1-4 substituents selected from Group Dl below, pyridyl optionally having 1-3 substituents selected from Group Dl below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-4 substituents selected from Group Dl below is mentioned.
[0083] As a preferable example that R2 is phenyl optionally having substituents, phenyl optionally having 2 or 3 substituents selected from Group D3 below is mentioned.
As another preferable example that R2 is phenyl optionally having substituents, a group represented by the following formula is mentioned: [0084] [Chemical Formula 15]


R22 represents hydrogen, hydroxyl, methyl optionally having 1 substituent selected from Group D5 below, ethyl optionally having 1 substituent selected from Group D5 below, methoxy optionally having 1 substituent selected from Group D5 below, ethoxy optionally having 1 or 2 substituents selected from Group D5 below, 1-propyloxy optionally having 1 substituent selected from Group D5 below, 2-propyloxy optionally having 1 substituent selected from Group D5 below, allyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy or acetyl;
R23 represents hydrogen, fluorine, hydroxyl, methoxy optionally having 1 substituent selected from Group D6 below, ethoxy optionally having 1 substituent selected from Group D6 below or 2-propyloxy optionally having 1 substituent selected from Group D6 below; and
R24 represents hydrogen, fluorine, hydroxyl, methyl optionally having 1 substituent selected from Group D7 below, ethyl, vinyl, ethynyl, methoxy optionally having 1 substituent selected from Group D7 below, ethoxy optionally having 1 substituent selected from Group D7 below, 2-propyloxy or allyloxy.
As preferable examples of R21, hydrogen or fluorine is mentioned; as preferable examples of R22, hydrogen, hydroxyl, cyanomethyl, methoxymethyl, methoxy, dimethylaminocarbonylmethoxy, ethoxy, 2-fluoroethoxy, 2-hydroxyethoxy, 2-methoxy ethoxy, 2-(dimethylamino)ethoxy, tetrahydrofuryloxy, tetrahydropyranyloxy, fluoromethoxy, 3-hydroxypropyloxy, 2-fluoroethoxymethyl or 2-hydroxyethoxymethyl is mentioned; as preferable examples of R23, hydrogen, fluorine, methoxy, cyanomethoxy, ethoxy, 2-propyloxy or 2-methoxyethoxy is mentioned; and as preferable examples of R24, hydrogen, hydroxyl, methyl, methoxymethyl, ethyl, vinyl, ethynyl,

methoxy, ethoxy or 2-fluoroethoxy is mentioned.
As specific preferable examples that R2 is phenyl optionally having substituents, a group represented by the following formula is mentioned:

[0086] As a preferable example that R2 is pyridyl optionally having substituents, pyridyl optionally having 2 substituents selected from the group consisting of CI-6 alkyl and CI-6 alkoxy is mentioned; a more preferable example is pyridyl having 2 substituents selected from the group consisting of methyl, methoxy and ethoxy; and still more preferable examples are a group represented by the following formula: [0087] [Chemical Formula 17]


wherein R27 represents hydrogen or halogen;
R28 represents hydrogen, hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or C2-7 alkylcarbonyl;

R29 represents hydrogen, cyano, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or carbamoyl;
X represents carbon optionally having 1 or 2 substituents selected from Group D8 below, nitrogen optionally having 1 substituent selected from Group D8 below or oxygen;
m represents an integer of 0-3 and n represents an integer of 0-2, with the proviso that the sum of m and n is 1-4; and
Rings A and B optionally contain one double bond in the ring and optionally have an oxo group on the ring, and more preferable examples are a group represented by the formula:

wherein R27, R28 and R29 have the same definitions as above; and Ring A optionally has an oxo group on the ring.
As preferable examples of R28, methyl, ethyl, methoxy, ethoxy, vinyl or ethynyl is mentioned; and as a preferable example of R29, hydrogen is mentioned.
As specific preferable examples that R2 is a 9- to 12-membered benzene-fused cyclic group optionally having substituents, a group represented by the following formula is mentioned: [0092] [Chemical Formula 21]


[0093] R3 represents a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Al below, C6-10 ary] optionally having 1-5 substituents selected from Group Al below or a 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group A1 below.
As preferable examples of R3, phenyl optionally having 1-3 substituents selected from Group El below, pyridyl optionally having 1-3 substituents selected from Group El below, N-oxypyridyl optionally having 1-3 substituents selected from Group El below, N-Cl-6 alkylpyridinium optionally having 1-3 substituents selected from Group El below, pyrazinyl optionally having 1-3 substituents selected from Group El below, pyridazinyl optionally having 1-3 substituents selected from Group El below, pyrimidinyl optionally having 1-3 substituents selected from Group El below, pyrazolyl optionally having 1 or 2 substituents selected from Group El below, imidazolyl optionally having 1 or 2 substituents selected from Group El below, thiazolyl optionally having 1 or 2 substituents selected from Group El below, thienyl optionally having 1-3 substituents selected from Group El below or dihydropyrazinyl having an oxo group, with the proviso that when R3 is N-CI-6 alkylpyridinium, R3 forms an ion pair with an anion in the molecule, is mentioned.
As more preferable examples of R3, phenyl optionally having 1 or 2 substituents selected from Group E3 below, pyridyl optionally having 1 or 2 substituents selected from Group E3 below, N-oxypyridyl optionally having 1 or 2 substituents selected from Group E3 below,

pyrazinyl optionally having 1 or 2 substituents selected from Group E3 below, pyridazinyl optionally having 1 or 2 substituents selected from Group E3 below, pyrimidinyl optionally having 1 or 2 substituents selected from Group E3 below, pyrazolyl optionally having 1 or 2 substituents selected from Group E3 below, imidazolyl optionally having 1 or 2 substituents selected from Group E3 below, thiazolyl optionally having 1 or 2 substituents selected from Group E3 below, thienyl optionally having 1 or 2 substituents selected from Group E3 below or dihydropyrazinyl having an oxo group is mentioned.
As still more preferable examples of R3, phenyl optionally having one group selected from Group E4 below, pyridyl optionally having one group selected from Group E5 below, N-oxypyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl optionally having one group selected from Group E4 below, imidazolyl optionally having one group selected from Group E4 below, thiazolyl optionally having one group selected from Group E4 below, thienyl optionally having one group selected from Group E4 below or dihydropyrazinyl having an oxo group is mentioned.
As specific preferable examples of R3, a group represented by the following formula is mentioned: [0094] [Chemical Formula 22]


[0095] Group Al consists of hydroxyl, halogen, cyano, nitro, oxo, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyl optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyloxy optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyloxy, C2-6 alkynyloxy, CI-6 alkylthio, CI-6 alkylsulfinyl, CI-6 alkylsulfonyl, CI-6 alkylsulfonyloxy, C6-10 aryl optionally having 1-5 substituents selected from Group Bl below, C6-10 aryloxy optionally having 1-5 substituents selected from Group Bl below, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Bl below, 5- to 10-membered heteroaryloxy optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-5 substituents selected from Group Bl below, a group represented by the formula -NR."-R2t and a

group represented by the formula -CO-R3t,
where R!t and R2t each independently represent hydrogen, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group Bl below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkylsulfonyl optionally having 1-3 substituents selected from Group Bl below, carbamoyl, aminosulfonyl, C6-10 aryl optionally having 1-5 substituents selected from Group Bl below or 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Bl below, and R3t represents hydroxyl, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, amino, mono(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below or di(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below.
[0096] Group Bl consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, C3-8 cycloalkyl, amino, mono(Cl-6 alkyI)amino, di(Cl-6 alkyl)amino, carbamoyl, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl )aminocarbonyl, C6-10 aryl optionally having 1-5 substituents selected from Group CI below and 5-to 10-membered heteroaryl optionally having 1-5 substituents selected from Group C1.
[0097] Group CI consists of halogen, CI-6 alkyl and CI-6 alkoxy. [0098] Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl. [0099] Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6

alkyl)aminocarbonyl.
[0100] Group D3 consists of fluorine, chlorine, methyl optionally
having 1 substituent selected from Group D4 below, ethyl optionally
having 1 substituent selected from Group D4 below, vinyl, ethynyl,
methoxy optionally having 1 or 2 substituents selected from Group D4
below, ethoxy optionally having 1 or 2 substituents selected from Group
D4 below, 1-propyloxy optionally having 1 or 2 substituents selected
from Group D4 below, 2-propyloxy optionally having 1 or 2 substituents
selected from Group D4 below, allyloxy, tetrahydrofuryloxy,
tetrahydropyranyloxy and acetyl.
[0101] Group D4 consists of hydroxyl, fluorine, cyano, methoxy,
methylamino, dimethylamino, methylaminocarbonyl and
dimethylaminocarbonyl.
[0102] Group D5 consists of hydroxyl, fluorine, cyano, methoxy,
dimethylamino, dimethylaminocarbonyl, 2-fluoroethoxy and
2-hydroxyethoxy.
[0103] Group D6 consists of fluorine, cyano, methoxy, dimethylamino,
methylaminocarbonyl and dimethylaminocarbonyl,
[0104] Group D7 consists of hydroxyl, fluorine, cyano and ethoxy
having one methoxy.
[0105] Group D8 consists of hydrogen, hydroxyl, halogen, CI-6 alkoxy,
mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6
alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl and CI-6 alkyl
optionally having halogen.
[0106] Group El consists of hydroxyl, halogen, cyano, CI-6 alkyl, CI-6
alkoxy, a group represented by the formula -NH-R21t and a group
represented by the formula -CO-R31t,
where R21t represents hydrogen, Cl-6 alkyl, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group E2 below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group E2 below, Cl-6 alkylsulfonyl, carbamoyl or aminosulfonyl, and R31t represents hydroxyl, Cl-6 alkyl, Cl-6 alkoxy, amino, mono(Cl-6 alkyl)amino or di(Cl-6 alkyl)amino).

[0107] Group E2 consists of hydroxyl, CI-6 alkoxy and C3-8
cycloalkyl.
[0108] Group E3 consists of halogen, CI-6 alkyl, CI-6 alkoxy, a group
represented by the formula -NH-R22t,
where R22t represents hydrogen or C2-7 alkoxycarbonyl, and a group represented by the formula -CO-R32',
where R32t represents hydroxyl, CI-6 alkoxy or amino. [0109] Group E4 consists of methoxy, carboxyl, carbamoyl, methoxycarbonyl and methoxycarbonylamino. [0110] Group E5 consists of fluorine, methyl, methoxy and amino. [0111] Preferable compounds of the formulas (1), (1-1) and (1-2) include the compounds obtainable by selecting and combining respective embodiments of Rla, R,b, Rlc, Rld, R2 and R3.
[0112] Specific compounds of the formulas (1), (1-1) and (1-2) include the compounds described in Examples 1 to 238 and Examples X-l to X-249, but it should not be understood that the present invention is limited to said compounds.
[0113] More preferable compounds of the formulas (1), (1-1) and (1-2) include the compounds described in Examples 1 to 238. [0114] Still more preferable compounds of the formulas (1), (1-1) and (1-2) include the compounds illustrated below;
1) 4-({[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
(ex.3),
2)
4-({[3-methoxy-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine (ex.6),
3)
4-({[3-(2-dimethylaminoethoxy)-5-methoxyphenyI]-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
(ex.8),
4)

4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yI]-( 2-methoxy-6-methylpyridin-4-yl)methyI}amino)benzamidine (ex.19), 5)
4-{[(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.21),
4-{[(3,4-dimethoxy-5-methoxymethyl-phenyl)-(5-oxo-l-pyriraidin-2-yl-4
,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.22),
7)
4-{[(3-hydroxy-5-vinylphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-
[l,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.47),
8)
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
(ex.153),
9)
5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic
acid (ex.157),
10)
5-{3-[(4-carbamlmidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic
acid ethyl ester (ex.l57d),
11)
4-( {[3-(3 -hydroxypropoxy)-5-methoxyphenyl]-(5-oxo-1 -pyrimidin-2-yl-4
,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}araino)benzamidine (ex.158),
12)
4-({[3-(2-hydroxyethoxy)-4,5-dimethoxyphenyl]-(5-oxo-l-pyrimidin-2-y
l-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
(ex.159),
13)
4- {[(5-ethoxy-6-methoxypyridin-3 -yl)-(5 -oxo-1 -pyrimidin-2-yl-4,5 -dihy
dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.160),
14)
4-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
(ex.162),
15)
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,
3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-c
arboxylic acid amide (ex.164),
16)
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,
3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI}thiazole-5-c
arboxylic acid (ex.165),
17)
4-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid (ex. 166),
18)
4-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-
methoxyphenyl]methyl}-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl)thiazole-5-
carboxylic acid (ex.167),
19)
3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob
enzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiop
hene-2-carboxylic acid (ex.168),
20)
3-{3-[(4-carbamimidoylphenylamino)-(5,6-dimethoxypyridin-3-yl)methy
l]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
(ex.169),
21)
3-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
(ex.171),
22)

4-{3-[(4-carbamimidoylphenylamino)-(9-methoxy-3,4-dihydro-2H-benzo
[b][l,4]dioxepin-7-yl)methyI]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yi}thia
zole-5-carboxylic acid (ex.180),
23)
4-{3-[(4-Carbamimidoylphenylamino)-(5-ethoxy-6-methoxypyridin-3-yl)
methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
(ex.185),
24)
5-{3-[(4-Carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)m
ethyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic
acid (ex.187),
25)
4-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydro-
benzo[l,4]dioxin-6-yl)-methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thi
azole-5-carboxylic acid (ex.188),
26)
5-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxyli
cacid (ex.189),
27)
4-({[l.(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-
[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyI]methyl}amino)benzami
dine (ex.200),
28)
2-{3-[(4-Carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}benzamide (ex.211),
29)
4-{[[3-Ethynyl-5-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5
-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.212),
30)
4-{[[2-Fluoro-3-(2-hydroxyethoxymethyl)-5-methoxyphenyl]-(5-oxo-l-p yrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzami dine (ex.216),

31)
2-Fluoro-4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l
-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benza
midine (ex.218),
32)
4-{[[3-Ethoxy-5-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyI]amino}benzamidine (ex.220),
33)
4-{[(3-Ethoxy-5-hydroxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l
H-[ 1,2,4]triazol-3-yl)methyl]amino}benzamidine (ex.221),
34)
3-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic
acid (ex.222),
35)
4-{[[4-(2-Fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxaz
in-6-yl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-y])met
hyl]amino}benzamidine (ex.223),
36)
3-{3-[(4-Carbamimidoyl-3-fluorophenylamino)-(5-fluoro-8-methoxy-2,3-
dihydrobenzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l
-yl}thiophene-2-carboxylic acid (ex.231),
37)
4- {[(5,6-Dimethoxypyridin-3-yl)-(5-oxo-1 -pyrimidin-2-yl-4,5-dihydro-1
H-[U2,4]triazol-3-yl)methyl]amino}benzamidine (ex.234),
38)
3-{3-[(4-Carbamimidoylphenylamino)-(5-ethoxy-6-methoxypyridin-3-yl)
methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic
acid (ex.235) and
39)
3-(3-{(4-Carbamimi'doylphenylamino)-[2-fluoro-4-(2-hydroxyethoxy)-5-
methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene
-2-carboxylic acid (ex.237).

[0115] [General production processes for compounds of the invention] The compounds of the invention may be produced by the
processes described below. However, processes for production of
compounds of the invention are not restricted to these alone. The processes will now be explained.
[0116] [Production Process A] Production process for invention
compound intermediate (14a)

Here, Rla, Rlb, Rlc, RId, R2 and R3 have the same definitions as above. R201 represents C6-10 aryl optionally having 1-5 substituents selected from Group Al above, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Al above or a 9- to 12-membered benzene-fused cyclic group optionally having 1-5 substituents selected from Group Al above. When the substituent selected from Group Al

above is hydroxyl, the hydroxyl may be protected. R5 represents CI-6 alkyl optionally substituted with C6-10 aryl. T is a cyano group or a group represented by the formula: [0118] [Chemical Formula 24]

(wherein R4 is CI-6 alkyl optionally substituted with halogen, CI-6
alkoxy optionally substituted with C6-10 aryl, C6-10 aryl or C6-10
aryloxy).
[0119] [StepAl]
This is a step of reacting compound (la), compound (2a) and a cyanating agent such as trimethylsilyl cyanide or hydrogen cyanide (3a) in a solvent, in the presence or in the absence of a suitable Lewis acid catalyst and in the presence or in the absence of a suitable dehydrating agent, to produce compound (4a).
This step may be carried out by a commonly employed protocol as described in SYNLETT, 1997, 115-116 and elsewhere.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
As compound (la) there may be used a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
As compound (2a) there may be used a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used

halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, ester-based solvents such as ethyl acetate, nitrile-based solvents such as acetonitrile, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, and solvent mixtures thereof, among which dichloromethane or tetrahydrofuran is preferred.
As examples of Lewis acids to be used for the reaction there may be mentioned ytterbium(III) trifluoromethanesulfonate hydrate, scandium(III) trifluoromethanesulfonate, bismuth(III) chloride, ruthenium(III) chloride, nickel(II) chloride and lithium perchlorate, among which ytterbium(III) trifluoromethanesulfonate hydrate is preferred.
As examples of dehydrating agents for the reaction there may be used Molecular Sieves 3A, Molecular Sieves 4A, anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, among which Molecular Sieves 3A is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between -20°C and 50°C, and more preferably between 10°C and30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-96 hours and more preferably 12-48 hours at the aforementioned reaction temperature after addition of the reagents.
Compound (la) may be used in a 1- to 2-fold molar amount with respect to compound (2a), but preferably it is used in a 1- to 1.2-fold molar amount and more preferably in a 1- to 1.05-fold molar amount.
The cyanating agent (3a) may be used in a 1- to 3-fold molar amount with respect to compound (2a), but preferably it is used in a 1- to 2-fold molar amount and more preferably in a 1.5- to 2-fold molar

amount.
The Lewis acid catalyst may be used in a 0.01- to 2-fold molar amount with respect to compound (2a), but preferably it is used in a 0.05- to 0.2-fold molar amount and more preferably in a 0.1-fold molar amount. [0120] [StepA2]
This is a step of reacting compound (4a) with a sulfurizing agent such as aqueous ammonium sulfide (5a) in a solvent to produce compound (6a).
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol or ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, or mixtures thereof, among which methanol and tetrahydrofuran mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 0°C and 80°C, and more preferably between 10°C and 50°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-48 hours and more preferably about 2-12 hours at the aforementioned reaction temperature after addition of the reagents.
The sulfurizing agent (5a) may be used in a 1- to 10-fold molar amount with respect to compound (4a), but preferably it is used in a 2- to 6-fold molar amount and more preferably in a 3- to 5-fold molar amount. [0121] [Step A3]
This is a step of reacting compound (6a) with a methylating agent such as trimethyloxonium tetrafluoroborate (7a) in a solvent to

produce compound (8a).
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, nitrile-based solvents such as acetonitrile, nitro-based solvents such as nitromethane, or mixtures thereof, among which dichloromethane or acetonitrile is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between -20°C and 50°C, and more preferably between 0°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for between 10 minutes and 14 hours and more preferably between 10 minutes and 2 hours at the aforementioned reaction temperature after addition of the reagents.
The methylating agent (7a) may be used in a 1- to 1.5-fold molar amount with respect to compound (6a), but preferably it is used in a 1- to 1.2-fold molar amount and more preferably in a 1.05-fold molar amount. [0122] [StepA4]
This is a step of converting compound (8a) to compound (9a) with an appropriate oxidizing agent in a solvent.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, ester-based solvents such as ethyl acetate, ether-based

solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, ketone-based solvents such as acetone, and mixtures thereof, among which dichloromethane or ethyl acetate is preferred.
As specific examples of oxidizing agents for the reaction there may be used manganese dioxide, m-chloroperbenzoic acid and 2,3-dichloro-5,6-dicyano-p-benzoquinone, among which manganese dioxide is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and oxidizing agent used in the reaction, but it is preferably between 0°C and 50°C, and more preferably between 10°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for between 10 minutes and 12 hours and more preferably between 10 minutes and 2 hours at the aforementioned reaction temperature after addition of the reagents.
The oxidizing agent may be used in a 1- to 20-fold molar amount with respect to compound (8a), but preferably it is used in a 5- to 15-fold molar amount. [0123] [StepA5]
This is a step of reacting compound (9a) with a chloroformic acid ester such as methyl chloroformate or ethyl chloroformate (10a) in a solvent, in the presence of a suitable base, to produce compound (11a).
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane,

t-butylmethyl ether, diethyl ether and 1,4-dioxane, halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon-based solvents such as benzene, toluene and xylene, aliphatic hydrocarbon-based solvents such as heptane and hexane, and mixtures thereof, among which toluene is preferred.
As specific bases for the reaction there may be used organic bases such as collidine, pyridine and lutidine, among which collidine is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 0°C and 120°C, and more preferably between 60°C and 100°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably 1-14 hours at the aforementioned reaction temperature after addition of the reagents.
The chloroformic acid ester (10a) may be used in a 1- to 3-fold molar amount with respect to compound (9a), but preferably it is used in a 1- to 2-fold molar amount and more preferably in a 1.2- to 1.6-fold molar amount.
The base may be used in a 1- to 5-fold molar amount with respect to compound (9a), but preferably it is used in a 1- to 3-fold molar amount and more preferably in a 1.5- to 2.5-fold molar amount. [0124] [StepA6]
This is a step of reacting compound (11a) with compound (12a) in a solvent, in the presence or in the absence of a suitable base, to produce compound (13a).
As compound (12a) there may be used a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below. Also, compound (12a) may be used in

free form or as a salt.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used amide-based solvents such as N,N-dimethylformamide and dimethylacetamide, sulfoxide-based solvents such as dimethylsulfoxide, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, alcohol-based solvents such as methanol, ethanol and 2-propanol, halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, or mixtures thereof, among which N,N-dimethylformamide is preferred.
As specific examples of bases for the reaction there may be used triethylamine, diisopropylethylamine, collidine and pyridine, among which triethylamine is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 100°C, and more preferably between 60°C and 90°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-48 hours and more preferably about 14 hours at the aforementioned reaction temperature after addition of the reagents.
Compound (12a) may be used in a 1- to 3-fold molar amount with respect to compound (11a), but preferably it is used in a 1- to 1.2-fold molar amount and more preferably in a 1- to 1.05-fold molar amount.
The base may be used in a 1- to 3-fold molar amount with respect to compound (12a), but preferably it is used in a 1- to 2-fold

molar amount.
When R201 is C6-10 aryl having a protected hydroxyl group, 5- to 10-membered heteroaryl having a protected hydroxyl group or a 9- to 12-membered benzene-fused cyclic group having a protected hydroxyl group, this step may be preceded by 1) removal of the hydroxyl-protecting group and 2) alkylation of the hydroxyl group.
Removal of the protecting group may be accomplished by a method that is generally known in the field of synthetic organic chemistry, and for example, by the methods described in T.W. Greene, (Protective Groups in Organic Synthesis), John Wiley & Sons.
For example, when the hydroxyl-protecting group is a silyl-based protecting group such as t-butyldimethylsilyl or triisopropylsilyl, the removal may be accomplished by reacting a deprotecting agent such as tetrabutylammonium fluoride with compound (11a) in a solvent such as tetrahydrofuran.
Alkylation of the hydroxyl group may be accomplished by a
method that is generally known in the field of synthetic organic
chemistry, and for example, it may be accomplished by reacting
compound (11a) deprotected at the hydroxyl-protecting group
(hereinafter referred to as "deprotected compound") with an alkylating
agent such as iodoethane or l-fluoro-2-iodoethane in a solvent such as
N,N-dimethylformamide, in the presence or in the absence of a base such
as potassium carbonate. It may also be accomplished by reacting the
deprotected compound with an alcohol such as
3-hydroxytetrahydrofuran, l-methylpiperidin-4-ol or
2-dimethylaminoethanol in a solvent such as tetrahydrofuran, in the presence of triphenylphosphine and in the presence of an azodicarboxylic acid diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. [0125] [StepA7]
This is a step of reacting compound (13a) with a suitable reducing agent in a solvent in the presence or in the absence of a suitable acid, for conversion to compound (14a).

This step may be carried out by a commonly employed method as described in Jikken Kagaku Koza 20 (4th Edition, The Chemical Society of Japan, Maruzen Publishing, pp.282-284) and elsewhere.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, amide-based solvents such as N,N-dimethylformamide and dimethylacetamide, sulfoxide-based solvents such as dimethylsulfoxide, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, or mixtures thereof, among which a methanol/tetrahydrofuran solvent mixture is preferred.
Examples of reducing agents to be used for the reaction include
metal-hydrogen complex compounds such as sodium
cyanotrihydroborate, diisobutylaluminum hydride, lithium aluminum
hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium
borohydride, sodium triacetoxyborohydride, lithium borohydride, lithium
triethylborohydride and lithium tri(s-butyl)borohydride,
borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, thexylborane, catecholborane, 9-borabicyclo[3,3,l]nonane and the like, among which sodium cyanotrihydroborate is preferred.
As examples of acids for the reaction there may be used acetic acid, formic acid, hydrochloric acid and the like, among which acetic acid is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between -20°C and 80°C, and more preferably between

10°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 3 hours at the aforementioned reaction temperature after addition of the reagents.
The reducing agent may be used in a 1 - to 10-fold molar amount with respect to compound (13a), but preferably it is used in a 3- to 6-fold molar amount and more preferably in a 5-fold molar amount.
Alternatively, compound (13a) may be converted to compound (14a) by catalytic hydrogenation in the presence of a suitable metal catalyst.
The metal catalyst used for the reaction may be palladium-carbon, platinum(IV) oxide or the like, with palladium-carbon being preferred.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, ester-based solvents such as ethyl acetate, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, organic acids such as acetic acid and formic acid, water, or mixtures thereof, among which ethanol and acetic acid mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 10°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 12 hours at the aforementioned reaction

temperature after addition of the reagents.
The metal catalyst may be used in a 0.01- to 2-fold molar amount with respect to compound (13a), but preferably it is used in a 0.05- to 1 -fold molar amount.

Here, R,a, Rlb, Rlc, Rld, R201, R5 and T have the same definitions as
above.
[Step A8]
This is a step of reacting compound (8a) with a chloroformic acid ester such as methyl chloroformate or ethyl chloroformate (10a) in a solvent, in the presence of a suitable base, to produce compound (11a).
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, and mixtures thereof, among which toluene is preferred.
As specific bases for the reaction there may be used collidine, pyridine and lutidine, among which collidine is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 0°C and 100°C, and more preferably between 60°C and 80°C.

The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably 1-14 hours at the aforementioned reaction temperature after addition of the reagents.
The chloroformic acid ester (10a) may be used in a 1- to 5-fold molar amount with respect to compound (8a), but preferably it is used in a 1.5- to 3.5-fold molar amount and more preferably in a 2- to 3-fold molar amount.
The base may be used in a 1- to 7-fold molar amount with respect to compound (8a), but preferably it is used in a 2- to 4-fold molar amount.
[0127] [Production Process B] Production process (1) for invention compounds

above.
[0129] [StepBl]
This is a step of converting compound (lb) (compound (14a) wherein T
is the formula:
[0130] [Chemical Formula 27]

(wherein R4 is as defined above)) to compound (2b) of the invention in a solvent, in the presence of a suitable metal reagent.
The step may be carried out by a commonly employed protocol

as described in Tetrahedron Letters 44, (2003) 8697-8700 and elsewhere.
As compound (lb) there may be used, instead of compound (14a) obtained by [Production Process A] described above, a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The metal reagent used for the reaction may be iron powder, zinc, Raney nickel or the like, with iron powder being preferred.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, organic acids such as acetic acid and formic acid, water, or mixtures thereof, among which methanol, acetic acid and water mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 50°C and 70°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 12 hours at the aforementioned reaction temperature after addition of the reagents.
The metal reagent may be used in a 1- to 30-fold molar amount with respect to compound (lb), but preferably it is used in a 5- to 20-fold molar amount.
Alternatively, compound (lb) may be converted to compound (2b) of the invention by catalytic hydrogenation in the presence of a suitable metal catalyst.
The step may be carried out by a commonly employed protocol

as described in Tetrahedron Letters 36, (1995) 4471-4474 and elsewhere.
The metal catalyst used for the reaction may be palladium-carbon, platinum(IV) oxide or the like, with palladium-carbon being preferred.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, acetic acid ester-based solvents such as ethyl acetate, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, organic acids such as acetic acid and formic acid, water, or mixtures thereof, among which ethanol/acetic acid mixed solvents are preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 10°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 12 hours at the aforementioned reaction temperature after addition of the reagents.
The metal catalyst may be used in a 0.01- to 2-fold molar amount with respect to compound (lb), but preferably it is used in a 0.05- to 1-fold molar amount.
Prior to this step, the substituent on R3 may also be appropriately converted by a method ordinarily employed by those skilled in the art.
For example, when the substituent is nitro it may be converted to an amino group, and when the substituent is carboxyl it may be converted to alkoxycarbonyl, aminocarbonyl, amino or the like. [0131] [Production Process C] Production process (2) for invention compounds [0132] [Chemical Formula 28]


[0133] [Step CI]
This is a step of reacting compound (lc) (compound (14a) wherein T is a cyano group) with a sulfurizing agent such as aqueous ammonium sulfide (2c) in a solvent, in the presence or in the absence of a suitable base, to produce compound (3c).
As compound (lc) there may be used, instead of compound (14a) obtained by [Production Process A] described above, a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, pyridine, and mixtures thereof, among which pyridine is preferred.
As specific examples of bases for the reaction there may be used

collidine, pyridine and triethylamine, among which triethylamine is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 0°C and 100°C, and more preferably between 10°C and 80°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 2-48 hours and more preferably about 12 hours at the aforementioned reaction temperature after addition of the reagents.
The sulfurizing agent (2c) may be used in a 1- to 20-fold molar amount with respect to compound (lc), but preferably it is used in a 5- to 10-fold molar amount. [0134] [StepC2]
This is a step of reacting compound (3c) with a methylating agent such as trim ethyl oxonium tetrafluoroborate (4c) in a solvent to produce compound (5c).
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used halogen-based solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, nitrile-based solvents such as acetonitrile, or mixtures thereof, among which acetonitrile is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between -20°C and 50°C, and more preferably between 10°Cand30°C.
The reaction time will generally differ depending on the starting

materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for between 10 minutes and 10 hours and more preferably for about 1 hour at the aforementioned reaction temperature after addition of the reagents.
The methylating agent (4c) may be used in a 1- to 1.5-fold molar amount with respect to compound (3c), but preferably it is used in a 1- to 1.2-fold molar amount and more preferably in a 1.05-fold molar amount. [0135] [StepC3]
This is a step of reacting compound (5c) with an ammonia equivalent (6c) such as 1,1,3,3-tetramethyldisilazane or ammonium acetate in a solvent to produce compound (7c) of the invention.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and 1,4-dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, aliphatic hydrocarbon-based solvents such as heptane and hexane, nitrile-based solvents such as acetonitrile, or mixtures thereof, among which 2-propanol and acetonitrile mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 20°C and 100°C, and more preferably between 50°C and 80°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 12 hours at the aforementioned reaction temperature after addition of the reagents.
The ammonia equivalent (6c) may be used in a 1- to 5-fold molar

amount with respect to compound (5c), but preferably it is used in a 1.1-
to 3-fold molar amount.
[0136] [Production Process D] Production process (3) for invention
compounds

[0138] [StepDl]
This is a step of reacting compound (Id) (compound (14a) wherein T is a cyano group) with hydroxylamine hydrochloride (2d) in a solvent in the presence of a suitable base to produce compound (3d).
As compound (Id) there may be used, instead of compound (14a) obtained by [Production Process A] described above, a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, diethylene glycol, glycerin and octanol,

amide-based solvents such as formamide, dimethylformamide and dimethylacetamide, ether-based solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane, sulfoxide-based solvents such as dimethylsulfoxide, or mixtures thereof, among which ethanol is preferred.
As specific examples of bases for the reaction there may be used tertiary amines such as triethylamine and N-methylmorpholine, with triethylamine being preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 0°C and 150°C, and more preferably between 50°C and 100°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-96 hours and more preferably 2-24 hours at the aforementioned reaction temperature after addition of the reagents.
The hydroxylamine hydrochloride (2d) may be used in a 1- to 10-fold molar amount with respect to compound (Id), but preferably it is used in a 3- to 7-fold molar amount.
The base may be used in a 2- to 15-fold molar amount with respect to compound (Id), but preferably it is used in a 3- to 10-fold molar amount. [0139] [StepD2]
This is a step of converting compound (3d) to compound (5d) by catalytic hydrogenation in a solvent, in the presence of a suitable metal catalyst and in the presence of an acid anhydride (4d).
The metal catalyst used for the reaction may be palladium-carbon or the like.
The acid anhydride used for the reaction may be acetic anhydride, trifluoroacetic acid anhydride or the like, with acetic anhydride being preferred.
The solvent used for the reaction is not particularly restricted so

long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether and dioxane, aromatic hydrocarbon-based solvents such as benzene and toluene, organic acids such as acetic acid and formic acid, water, or mixtures thereof, with acetic acid being preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 10°C and 30°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably 1-6 hours at the aforementioned reaction temperature after addition of the reagents.
The metal catalyst may be used in a 0.01- to 2-fold molar amount with respect to compound (3d), but preferably it is used in a 0.05- to 1-fold molar amount.
The acid anhydride (4d) may be used in a 1- to 50-fold molar amount with respect to compound (3d), but preferably it is used in a 3- to 10-fold molar amount.
[0140] Compound (3d) may also be converted to compound (5d) of the invention in the presence of a suitable metal reagent.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The metal reagent used for the reaction may be iron powder, zinc, Raney nickel or the like, with iron powder being preferred.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, organic

acids such as acetic acid and formic acid, water, or mixtures thereof, among which methanol, acetic acid and water mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 50°C and 70°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-24 hours and more preferably about 12 hours at the aforementioned reaction temperature after addition of the reagents.
The metal reagent may be used in a 1- to 30-fold molar amount with respect to compound (lb), but preferably it is used in a 5- to 20-fold molar amount.
[0141] [Production Process E] Production process (4) for invention compounds

above.
[0142] [Step El]
This is a step of converting compound (le) (compound (13a) wherein T
is the formula:
[0143] [Chemical Formula 31]

(wherein R4 is as defined above)) to compound (2e) of the invention in a solvent, in the presence of a suitable metal reagent.

As compound (le) there may be used, instead of compound (13a) obtained by [Production Process A] described above, a publicly known compound, a commercially available compound or a compound that can be produced from a commercially available compound by a process ordinarily carried out by those skilled in the art or by the processes described in the examples below.
The step may also be carried out under a stream or under an atmosphere of an inert gas such as nitrogen or argon.
The metal reagent used for the reaction may be iron powder, zinc, Raney nickel or the like, with iron powder being preferred.
The solvent used for the reaction is not particularly restricted so long as it dissolves the starting materials to some degree and does not interfere with the reaction, and for example, there may be used alcohol-based solvents such as methanol, ethanol and 2-propanol, organic acids such as acetic acid and formic acid, water, or mixtures thereof, among which methanol, acetic acid and water mixed solvent is preferred.
The reaction temperature will generally differ depending on the starting materials, solvent and other reagents used in the reaction, but it is preferably between 10°C and 80°C, and more preferably between 50°C and 70°C.
The reaction time will generally differ depending on the starting materials, solvent and other reagents used in the reaction, as well as on the reaction temperature, but preferably stirring is carried out for 1-48 hours and more preferably about 24 hours at the aforementioned reaction temperature after addition of the reagents.
The metal reagent may be used in a 2- to 50-fold molar amount with respect to compound (le), but preferably it is used in a 10- to 30-fold molar amount.
[0144] Upon completion of the reaction in each step of the processes described above, the target compound of each step may be recovered from the reaction mixture by an ordinary method.
[0145] For example, when the entire reaction mixture is a solution, the reaction mixture may be returned to room temperature or cooled on ice as

desired, and neutralized with an appropriate acid, alkali, oxidizing agent or reducing agent, prior to addition of water and an organic solvent that is immiscible therewith and does not react with the target compound, such as ethyl acetate, and separation of the layer containing the target compound. Next, a solvent that is immiscible with the recovered layer and does not react with the target compound may be added, and then the layer containing the target compound washed and separated. When the layer is an organic layer, it may be dried using a desiccating agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate, and the solvent distilled off to recover the target compound. When the layer is an aqueous layer, it may be electrically desalted and then lyophilized to recover the target compound.
[0146] When the entire reaction mixture is a solution, it may be possible to recover the target compound simply by distilling off the components other than the target compound (for example, solvent, reagents, etc.) at ordinary pressure or under reduced pressure.
[0147] When the target compound precipitates alone as a solid, or when the entire reaction mixture is a solution and the target compound precipitates alone as a solid during the recovery process, the target compound may be first filtered by a filtration method, the filtered target compound washed with a suitable organic or inorganic solvent and drying performed for treatment of the mother liquor in the same manner as if the entire reaction mixture were a solution, in order to obtain the target compound.
[0148] On the other hand, when the reagents or catalyst are the only solids present, or when the entire reaction mixture is a solution and the reagents or catalyst alone precipitate in solid form during the recovery process, with the target compound remaining dissolved in solution, the reagents or catalyst may be first filtered by a filtration method, the filtered reagents or catalyst washed with a suitable organic or inorganic solvent, and the obtained wash combined with the mother liquor to obtain a liquid mixture, which may then be treated in the same manner as if the entire reaction mixture were a solution, in order to obtain the target

compound.
[0149] The reaction mixture may be used directly for subsequent steps without isolation of the target compound in cases where components other than the target compound in the reaction mixture will not inhibit reaction in the subsequent steps.
[0150] Purity of the target compound recovered by such methods can be increased by appropriately carrying out recrystallization, various chromatography methods or distillation.
[0151] When the recovered target compound is a solid, purity of the target compound can usually be improved by recrystallization. For recrystallization there may be used a simple solvent or a multiple solvent mixture that does not react with the target compound. Specifically, the target compound may first be dissolved at room temperature or with heating in the simple solvent or solvent mixture that does not react with the target compound. The obtained mixture may then be cooled with ice water or the like or allowed to stand at room temperature to cause precipitation of the target compound from the mixture. [0152] When the recovered target compound is a liquid, purity of the target compound can be improved by various chromatography methods. In most cases a weakly acidic silica gel such as silica gel 60 (70-230 mesh or 340-400 mesh) by Merck, Ltd. or BW-300 (300 mesh) by Fuji Silysia Chemical, Ltd. may be used. If the target compound is basic and adsorption onto the aforementioned silica gel types is too strong, there may be used propylamine-coated silica gel (200-350 mesh) by Fuji Silysia Chemical, Ltd.. If the target compound is dipolar or requires elution with a highly polar solvent such as methanol, there may be used NAM-200H or NAM-300H by Nagara Science Co., Ltd. Using these silica gels, the target compound may be eluted in a simple solvent or solvent mixture that does not react with the target compound and the solvent distilled off to obtain the target compound with enhanced purity. [0153] When the recovered target compound is a liquid, purity of the target compound can also be improved by distillation. For distillation, the target compound may be placed under reduced pressure at room

temperature or with heating to achieve distillation of the target compound.
[0154] Representative examples of production processes for compounds according to the invention were described above, but the starting compounds and reagents for production of the invention compounds may form salts, hydrates or solvates, will differ depending on the starting materials and solvents used, and are not particularly restricted so long as they do not inhibit the reaction. The solvent used will also differ depending on the starting materials and reagents, and of course is not particularly restricted so long as it can dissolve the starting materials to some degree and does not inhibit the reaction. When a compound of the invention is obtained in free form, it may be converted to an acceptable salt or a hydrate of the compound by an ordinary method. [0155] Conversely, when a compound of the invention is obtained as a salt or hydrate, it may be converted to the free form of the compound by an ordinary method.
[0156] Various isomers (for example, geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers and the like) obtained for compounds of the invention may be purified and isolated using ordinary separation means such as, for example, recrystallization, a diastereomer salt method, enzymatic resolution or chromatography methods (for example, thin-layer chromatography, column chromatography, gas chromatography, etc.).
[0157] When a compound of the invention is to be used as a medicament, the compound of the invention will usually be used after mixture and formulation with appropriate additives. However, this does not negate the use of the compounds of the invention in simple forms as medicaments.
[0158] As additives there may be mentioned excipients, binders, lubricants, disintegrators, coloring agents, taste correctives, emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, buffering agents, antiseptic agents, antioxidants, stabilizers, absorption accelerators and the like which are commonly used in medicaments, and

these may also be used in appropriate combinations as desired.
As examples of excipients there may be mentioned lactose, saccharose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium metasilicate aluminate and calcium hydrogenphosphate.
As examples of binders there may be mentioned polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone and macrogol.
As examples of lubricants there may be mentioned magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol and colloidal silica.
As examples of disintegrators there may be mentioned crystalline cellulose, agar, gelatin, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch and carboxymethyl starch sodium.
As examples of coloring agents there may be mentioned those approved for addition to pharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, P-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake and the like.
As taste correctives there may be mentioned cocoa powder, menthol, aromatic powder, peppermint oil, camphor, cinnamon powder and the like.
As emulsifiers or surfactants there may be mentioned stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glycerin monostearate, sucrose fatty acid ester and glycerin fatty acid ester.
As dissolving aids there may be mentioned polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80 and nicotinic acid amide.

As suspending agents there may be mentioned the
aforementioned surfactants, as well as hydrophilic polymers such as
polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose and
hydroxypropylcellulose.
As isotonizing agents there may be mentioned glucose, sodium chloride, mannitol, sorbitol and the like.
As buffering agents there may be mentioned buffers of phosphate, acetate, carbonate, citrate and the like.
As antiseptic agents there may be mentioned methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
As antioxidants there may be mentioned sulfurous acid salts, ascorbic acid, a-tocopherol and the like.
As stabilizers there may be mentioned those commonly used in medicaments.
As absorption accelerators there may also be mentioned those commonly used in medicaments.
[0159] As formulations there may be mentioned oral forms such as tablets, powders, granules, capsules, syrups, lozenges and inhalants; external forms such as suppositories, ointments, eye salves, tapes, eye drops, nose drops, ear drops, poultices, lotions, and the like; and injections.
The aforementioned oral forms may be formulated with appropriate combinations of the additives mentioned above. Their surfaces may also be coated if necessary.
The aforementioned external forms may be formulated with appropriate combinations of the additives mentioned above, and especially excipients, binders, taste correctives, emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, antiseptic agents, antioxidants, stabilizers and absorption accelerators.
Injections may also be formulated with appropriate combinations of the additives mentioned above, and especially emulsifiers, surfactants,

dissolving aids, suspending agents, isotonizing agents, buffering agents, antiseptic agents, antioxidants, stabilizers and absorption accelerators. [0160] The dosage of a medicament according to the invention will differ depending on the severity of symptoms, patient age, gender and body weight, type of dosage form/salt, patient medicament sensitivity and specific nature of the disease, but the dosage per day for adults will generally be about 1 mg to about 1000 mg (preferably about 10 mg to about 300 mg) for oral administration, about 1 mg to about 1000 mg (preferably about 10 to about 300 mg) for external application, and in the case of an injection, about 1 fig to about 3000 (j.g (preferably about 3 ug to about 3000 p.g) per kilogram of body weight, either administered as a single time or divided into 2 to 6 times per day.
These values are the actual administered amounts in the case of oral formulations and injections, and are the amounts actually absorbed by the body in the case of external formulations. Examples
[0161] The compounds of the invention may be produced by the processes described in the following examples, and the effects of the compounds may be confirmed by the methods described in the following testing examples. However, these specific examples are merely illustrative and are not intended to restrict the invention in any way, and various modifications may be implemented such as are within the scope of the invention.
[0162] Compounds mentioned with reference to published documents are produced in the manner described in those documents. [0163] Unless otherwise specified, the "silica gel" in "silica gel column chromatography" mentioned throughout the examples is either silica gel 60 (70-230 mesh or 340-400 mesh) by Merck, Ltd. or FLASH+Cartridge (KP-SIL, 60 A, 32-63 urn) by Biotage.
[0164] Also unless otherwise specified, the "silica gel" in "silica gel column chromatography" mentioned throughout the examples may refer to Hi-Flash™ Column (40 urn 60 A) by Yamazen Corp. in addition to the two silica gels mentioned above.

[0165] Unless otherwise specified, the "reverse phase silica gel" in
"reverse phase silica gel column chromatography" mentioned throughout
the examples refers to YMC*GEL ODS-A (12 nm S-50 um) by YMC Co.,
Ltd.
[0166] Also unless otherwise specified, the "NH silica gel" in "NH silica
gel column chromatography" mentioned throughout the examples refers
to propylamine-coated silica gel (200-350 mesh) by Fuji Silysia
Chemical, Ltd.
[0167] The "NAM silica gel" in "NAM silica gel column
chromatography" mentioned throughout the examples refers to
NAM-200H or NAM-300H by Nagara Science Co., Ltd.
[0168] Unless specifically stated otherwise, the "reverse-phase high
performance liquid chromatography" mentioned throughout the examples
was carried out under the following conditions.
[0169] [Column]
One of the following columns was selected for use.
Company: SHISEIDO
Name: CAPCELL PAK CI 8
Size: 50 mm * 20 mm l.D.
Type: ACR 5 um
[0170] Company: YMC
Name: YMC CombiPrep ODS-A
Size: 50 mm * 20 mm l.D.
Type: S-5 u,m
[0171] Company: WAKO
Name: WAKOpak Combi ODS-A
Size: 50 mm x 20 mm l.D.
[0172] [Mobile phase]
A combination of (1) and (2) below or a combination of (3) and (4)
below was prepared with a gradient in a 100:0-0:100 proportion range for
use as the mobile layer for liquid chromatography.
(1) 99.9% water (0.1% trifluoroacetic acid)
(2) 99.9% acetonitrile(0.1% trifluoroacetic acid)

(3) 99.9% water (0.1% acetic acid)
(4) 99.9% acetonitrile(0.1% acetic acid)
[0173] Unless specifically stated otherwise, the optical resolution using
a SUMICHIRAL OA-2500 throughout the examples was carried out
under the following conditions.
[0174] [Column]
Name: SUMICHIRAL OA-2500, 20 mm«p x 25 cm
Manufacturer: Sumika Chemical Analysis Service, Ltd.
[0175] [Mobile phase and elution rate]
0.05 M ammonium acetate-methanol solution, 10 ml/min
[0176] Unless otherwise specified, the term "HPLC retention time" used
throughout the examples is the retention time for optical resolution under
the following conditions.
[0177] [Column]
Name: SUMICHIRAL OA-2500, 20 mmtp x 25 cm
Manufacturer: Sumika Chemical Analysis Service, Ltd.
[0178] [Mobile phase and elution rate]
0.05 M ammonium acetate-methanol solution, 10 ml/min
[0179] Unless otherwise specified, the term "manganese dioxide" used
throughout the examples refers to CMD-1 by Chuo Denki Kogyo Co.,
Ltd.
[0180] The term "room temperature" in the examples ordinarily refers to
a temperature between about 10°C and 35°C. The percentage values are
weight percentages, unless otherwise specified. The other symbols used
in the examples stand for the following.
'H-NMR: Proton nuclear magnetic resonance
8: Chemical shift
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad

sept: septet
J: coupling constant
Hz: Hertz
M: mol/L
n-: normal
s-: secondary
t-: tertiary
N: Normality
CDCI3: deutero chloroform
d6-DMSO: deutero dimethylsulfoxide
CD3OD: deutero methanol
CD3CO2D: deutero acetic acid
DMF: N,N-dimethylformamide
THF: tetrahydrofuran
DMSO: dimethylsulfoxide
DIAD: diisopropyl azodicarboxylate
DEAD: diethyl azodicarboxylate
MS3A: Molecular Sieves 3A
Yb(OTf)3: ytterbium(III) trifluoromethanesulfonate hydrate
Me30+BF4": trimethyloxonium tetrafluoroborate
TBAF: tetrabutylammonium fluoride
[0181] Example Li (R) and
(S)-2-{3-|"("4-carbamimidovlphenylamino)-(2-fluoro-4.5-dimethoxvphenvl
)methyl]-5-oxo-4.5-dihvdro-[l.2,4]triazol-l-vU benzoic acid acetate
[0182] (la)
(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen
ylamino]acetonitrile
[0183] [Chemical Formula 32]

After adding 4.41 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine

[CAS No. 10185-68-9], 4.64 g of 2-fluoro-4,5-dimethoxybenzaldehyde [CAS No.71924-62-4], 5 g of Molecular Sieves 3A (hereinafter, "MS3A") and 6.69 ml of trimethylsilyl cyanide to a solution of 1.56 g of ytterbium(III) trifluoromethanesulfonate hydrate (hereinafter, "Yb(OTf)3") in 100 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 22 hours. After then adding 500 ml of ethyl acetate to the reaction mixture, it was filtered through celite and the celite was washed with 1000 ml of ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (8.84 g) as a light yellow solid.
]H-NMR (CDC13) 5 2.64 (s, 3H) 3.90 (s, 3H) 3.92 (s, 3H) 4.31 (d, J=7.6Hz, 1H) 5.61 (d, J=7.6Hz, 1H) 6.73 (d, J=11.2Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.04 (d, J=7.2Hz, 1H) 7.98 (d, J=8.8Hz, 2H) [0184] (lb)
2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylamino]thioacetamide [0185] [Chemical Formula 33]

After adding 36.8 ml of a 20% aqueous solution of ammonium sulfide to
a solution of 7.97 g of
(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylamino]acetonitrile in 750 ml of a methanol :tetrahydrofuran (hereinafter, "THF") = 2:1 mixed solvent, the mixture was stirred at room temperature for 22 hours. Next, 1500 ml of ethyl acetate and 1000 ml of water were added to the reaction mixture, stirring was carried out at room temperature for 15 minutes, and the precipitate was filtered off.

The organic layer in the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure and combined with the previously obtained precipitate to give the title compound (8.59 g) as a light yellow solid.
'H-NMR (d6-DMSO) 5 2.60 (s, 3H) 3.73 (s, 3H) 3.77 (s, 3H) 5.41 (d, J=6.0Hz, 1H) 6.75 (d, J=8.8Hz, 2H) 6.79 (d, J=6.0Hz, 1H) 6.92 (d, J=l 1.6Hz, 1H) 7.14 (d, J=6.8Hz, 1H) 7.74 (d, J=8.8Hz, 2H) 9.54 (br.s, 1H) 9.80 (br.s, 1H) [0186] (lc)
2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylamino]thioacetimidic acid methyl ester [0187] [Chemical Formula 34]

phenylamino]thioacetamide in 400 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.89 g, crude product) as an oil. [0188] (Id)
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester [0189] [Chemical Formula 35]


phenylamino]thioacetimidic acid methyl ester in 300 ml of toluene, the
mixture was stirred at 80°C for 18 hours under a nitrogen atmosphere.
After cooling the reaction mixture, dilute hydrochloric acid was added
and extraction was performed with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over anhydrous
sodium sulfate. The desiccating agent was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give the title
compound (4.12 g, isomeric mixture) as a light yellow solid.
'H-NMR (CDC13) Two isomers:
5 2.32 (s, 3H) 2.65 (s, 3H) 3.62 (s, 3H) 3.82 (s, 3H) 3.93 (s, 3H) 6.61 (d,
J=12.4Hz, 1H) 7.10 (d, J=6.8Hz, 2H) 7.44 (d, J=6.8Hz, 1H) 8.01 (d,
J=6.8Hz, 2H)
5 2.48 (s, 3H) 2.62 (s, 3H) 3.59 (s, 3H) 3.64 (s, 3H) 3.93 (s, 3H) 6.47 (d,
J=l 0.4Hz, 1H) 6.49 (d, J=6.0Hz, 1H) 6.83 (d, J=8.4Hz, 2H) 7.89 (d,
J=8.4Hz, 2H)
[0190] (le)
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylimino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic
acid
[0191] [Chemical Formula 36]


phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of N,N-dimethylformamide (hereinafter, "DMF"), the mixture was stirred at 85°C for 21 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, dilute hydrochloric acid (pH 3-4) was added and extraction was performed with ethyl acetate. The organic layer was then washed with dilute hydrochloric acid (pH 3-4) and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (548 mg) as a light yellow solid.
'H-NMR (CD3OD) 5 2.62 (s, 3H) 3.71 (s, 3H) 3.75 (s, 3H) 6.65 (d, J=l0.8Hz, 1H) 6.93 (d, J=5.5Hz, 1H) 6.95 (d, J=8.7Hz, 2H) 7.53 (td, J=8.2,1.3Hz, 1H) 7.54 (dd, J=8.2,1.3Hz, 1H) 7.66 (td, J=8.2,1.3Hz, 1H) 7.88 (d, J=8.7Hz, 2H) 7.97 (dd, J=8.2,1.3Hz, 1H) [0192] (If)
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid [0193] [Chemical Formula 37]


l)phenylimino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid in 40 ml of a methanohTHF =1:1 mixed solvent, the mixture was stirred at room temperature for 48 hours. Next, 0.7 ml of 5N hydrochloric acid was added, the reaction mixture was stirred at room temperature for 10 minutes, ethyl acetate and water were added, and filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (504 mg) as a light yellow solid.
'H-NMR (CD3OD) 5 2.59 (s, 3H) 3.78 (s, 3H) 3.82 (s, 3H) 5.89 (s, 1H) 6.81 (d, J=8.8Hz, 2H) 6.84 (d, J=ll.lHz, 1H) 7.08 (d, J=6.7Hz, 1H) 7.44.7.49 (m, 2H) 7.60 (t, J=8.1Hz, 1H) 7.79 (d, J=8.8Hz, 2H) 7.92 (d, J=8.1Hz, 1H) [0194] (lg)
2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid trifluoroacetate [0195] [Chemical Formula 38]


acid in 9 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent, the
mixture was stirred at 55°C for 40 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 31 mg of the title compound.
'H-NMR (CD3OD) 8 3.80 (s, 3H) 3.84 (s, 3H) 5.95 (s, 1H) 6.86 (d,
J=l 1.2Hz, 1H) 6.87 (d, J=8.9Hz, 2H) 7.05 (d, J=6.6Hz, 1H) 7.48 (dd,
J=8.1,l.lHz, 1H) 7.50 (td, J=8.1,l.lHz, 1H) 7.64 (d, J=8.9Hz, 2H) 7.53
(td, J=8.1,1.5Hz, 1H) 7.97 (dd, J=8.1,1.5Hz, 1H)
Mass spectrum (ESI)m/z: 507 (M+H)+
[0196] (lh) (R) and
(S)-2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid acetate

Daicel Chemical Industries, Ltd., Mobile phase: 2-propanol/hexane=l/3,
0.1% trifluoroacetic acid, Elution rate: 9 ml/min) was used for optical
resolution of 26 mg of

2-{3[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyI)met hyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid trifluoroacetate (retention time for the first eluting enantiomer: 17 min, retention time for the second eluting enantiomer: 37 min). Triethylamine was added to the obtained second eluting enantiomer and the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the second eluting enantiomer (4.4 mg) of the title compound.
[0198] Example 2j (R) and
(S)-4-(((2-fluoro-3.5-dimethoxvphenvl)-[5-oxo-l-(l-oxvpvridin-2-yl)-4. 5-dihvdro-lH-[1.2.41triazol-3-vl]methvl)amino)benzamidine acetate [0199] (2a) 4-{[cyano-(2-fluoro-3,5-dimethoxyphenyl)methyl]amino}benzonitrile

After adding 1.23 g of 4-aminobenzonitrile [CAS No.873-74-5], 1.92 g of 2-fluoro-3,5-dimethoxybenzaldehyde [CAS No.l 13984-71-7], 1.0 g of MS3A and 2.77 ml of trimethylsilyl cyanide to a solution of 0.645 g of Yb(OTf>3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. After then adding 500 ml of ethyl acetate and 300 ml of water to the reaction mixture, it was filtered through celite and the celite was washed with 500 ml of ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.59 g) as a white solid.
'H-NMR (CDC13) 5 3.83 (s, 3H) 3.89 (s, 3H) 4.52 (d, J=7.5Hz, 1H) 5.61 (d, J=7.5Hz, 1H) 6.59-6.65 (m, 2H) 6.77 (d, J=9.0Hz, 2H) 7.54 (d, J=9.0Hz, 2H)

[0201] (2b) 2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetamide

After adding 14.2 ml of a 20% aqueous solution of ammonium sulfide to
a solution of 2.59 g of
4-{[cyano-(2-fluoro-3,5-dimethoxyphenyl)methyl]amino}benzonitrile in 300 ml of a methanokTHF = 2:1 mixed solvent, the mixture was stirred at room temperature for 16 hours. Then, a further 14.2 ml of a 20% aqueous solution of ammonium sulfide was added, and the mixture was stirred at room temperature for 24 hours. Next, 500 ml of ethyl acetate and 800 ml of water were added to the reaction mixture, and the organic layer was washed twice with 300 ml of water and then once with 300 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate (1:1)) to give the title compound (2.01 g) as a light yellow solid.
'H-NMR (d6-DMSO) 8 3.74 (s, 3H) 3.83 (s, 3H) 5.44 (d, J=5.9Hz, 1H) 6.63-6.71 (m, 2H) 6.70 (d, J=9.0Hz, 2H) 7.19 (d, J=5.9Hz, 1H) 7.52 (d, J=9.0Hz, 2H) 9.58 (br.s, 1H) 9.93 (br.s, 1H) [0203] (2c)
2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidi c acid methyl ester

After adding 0.904 g of Me30+BF4" to a solution of 2.01 g of

2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetamide in 150 ml of acetonitrile under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. Next, 400 ml of ethyl acetate and 300 ml of saturated aqueous sodium hydrogencarbonate were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The mixture was dried over anhydrous magnesium sulfate and the desiccating agent was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (2.05 g) as a light yellow solid.
'H-NMR (CDC13) 8 2.33 (s, 3H) 3.73 (s, 3H) 3.88 (s, 3H) 5.46 (d, J=5.4Hz, 1H) 5.91 (br.s, 1H) 6.41 (dd, J=3.9,3.2Hz, 1H) 6.50 (dd, J=6.8,3.2Hz, 1H) 6.60 (d, J=9.1Hz, 2H) 7.41 (d, J=9.1Hz, 2H) [0205] (2d)
2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidic acid methyl ester

After adding 4.95 g of manganese dioxide to a solution of 2.05 g of
2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidi
c acid methyl ester in 100 ml of ethyl acetate, the mixture was stirred at
room temperature for 3 hours. The reaction mixture was filtered
through celite, and the celite was washed with 500 ml of ethyl acetate.
The organic layers were combined and concentrated under reduced
pressure. The title compound (2.01 g) was obtained as a light yellow
solid.
'H-NMR (CDCI3) Main isomer:
5 2.49 (s, 3H) 3.68 (s, 3H) 3.82 (s, 3H) 6.01 (dd, J=3.5,3.1Hz, 1H) 6.51
(dd, J=7.0,3.1Hz, 1H) 6.85 (d, J=8.5Hz, 2H) 7.50 (d, J=8.5Hz, 2H)
[0207] (2e)
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf

anylethylidenejcarbamic acid methyl ester

After adding 2.97 ml of 2,4,6-collidine and 1.74 ml of methyl
chloro formate to a solution of 2.01 g of
2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidic acid methyl ester in 80 ml of toluene, the mixture was stirred at 85°C for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture, 400 ml of ethyl acetate and 200 ml of a 2% aqueous sulfuric acid solution were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate (3:2)) to give the title compound (1.89 g) as a light yellow solid. 'H-NMR (CDCI3) Two main isomers:
5 2.34 (s, 3H) 3.62 (s, 3H) 3.66 (s, 3H) 3.75 (s, 3H) 6.70 (dd, J=6.6,3.3Hz, 1H) 6.93 (dd, J=4.0,3.3Hz, 1H) 7.08 (d, J=8.9Hz, 2H) 7.62 (d, J=8.9Hz, 2H)
5 2.46 (s, 3H) 3.70 (s, 3H) 3.81 (s, 3H) 3.84 (s, 3H) 6.15 (t, J=3.3Hz, 1H) 6.51 (dd, J=7.2,3.3Hz, 1H) 6.82 (d, J=8.7Hz, 2H) 7.49 (d, J=8.7Hz, 2H) [0209] (2f)
4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4,5-di hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzonitrile [0210] [Chemical Formula 45]


anylethylidene]carbamic acid methyl ester in 6 ml of DMF, the mixture was stirred at 85°C for 20 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure, the residue was dissolved in 20 ml of a methanokTHF =1:1 mixed solvent, and then 184 mg of sodium cyanotrihydroborate and 0.063 ml of acetic acid were added prior to stirring at room temperature for 24 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added and filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate (1:9)) to give the title compound (41 mg) as a brown oil.
'H-NMR (CD3OD) 5 3.73 (s, 3H) 3.85 (s, 3H) 5.94 (s, 1H) 6.59 (dd, J=3.3,2.8Hz, 1H) 6.63 (dd, J=7.1,2.8Hz, 1H) 6.78 (d, J=9.0Hz, 2H) 7.45 (d, J=9.0Hz, 2H) 7.54-7.64 (m, 2H) 7.72 (dd, J=8.5,1.9Hz, 1H) 8.44 (d, J=6.6Hz, 1H) [0211] (2g)
4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4,5-di hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)thiobenzamide [0212] [Chemical Formula 46]


hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzonitrile in 1 ml of
pyridine, the mixture was stirred at 60°C for 16 hours under a nitrogen
atmosphere. After cooling the reaction mixture, the solvent was
removed under reduced pressure. The residue was dissolved in 3 ml of
methanol and 1 ml of dimethylsulfoxide (hereinafter "DMSO"), and the
solution was filtered through celite. The filtrate was purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (21 mg) as a light yellow solid.
'H-NMR (CD3OD) 8 3.73 (s, 3H) 3.85 (s, 3H) 5.95 (s, 1H) 6.61-6.64 (m, 2H) 6.69 (d, J=9.5Hz, 2H) 7.75-7.64 (m, 2H) 7.72 (dd, J=7.5,1.8Hz, 1H) 7.85 (d, J=9.5Hz, 2H) 8.45 (dd, J=5.5,1.0Hz, 1H) [0213] (2h)
4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4,5-di hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine trifluoroacetate
1

4-({(2-fIuoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4,5-di hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)thiobenzamide in 5 ml of acetonitrile under a nitrogen atmosphere, the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the residue was dissolved in 1.5 ml of acetonitrile and 1 ml of 2-propanol, and 18 \il of 1,1,3,3-tetramethyldisilazane was added. The reaction mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere and then cooled, and 20 uJ of trifluoroacetic acid was added. The solvent was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (2.9 mg) as a white solid.
'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.86 (s, 3H) 5.99 (s, 1H) 6.60 (dd, J=3.9,3.0Hz, 1H) 6.66 (dd, J=6.8,3.0Hz 1H) 6.86 (d, J=9.0Hz, 2H) 7.58-7.65 (m, 2H) 7.63 (d, J=9.0Hz, 2H) 7.74 (dd, J=8.0,2.4Hz, 1H) 8.47 (dd, J=5.2,1.5Hz, 1H) Mass spectrum (ESI)m/z: 480 (M+H)+
[0215] (2i) (R) and
(S)-4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4, 5-dihydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzarnidine acetate

mg of
4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(l-oxypyridin-2-yl)-4,5-di
hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine trifluoroacetate,
and the first eluting enantiomer (8.3 mg) of the title compound was
obtained as a white solid.

'H-NMR (CD3OD) 5 3.74 (s, 3H) 3.86 (s, 3H) 5.97 (s, 1H) 6.61 (dd,
J=3.9,3.0Hz, 1H) 6.63 (dd, J=6.8,3.0Hz 1H) 6.82 (d, J=9.0Hz, 2H) 7.54
(td, J=7.2,2.0Hz, 1H) 7.61 (d, J=9.0Hz, 2H) 7.61-7.63 (m, 1H) 7.69 (dd,
J=7.2,2.0Hz, 1H) 8.43 (d, J=6.8Hz, 1H)
HPLC retention time: 8 min
[0217] (2j) (l-oxypyridin-2-yl)hydrazine
[0218] [Chemical Formula 49]

After adding 6 ml of hydrazine monohydrate to 1.66 ml of 2-chloropyridine N-oxide hydrochloride, the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (888 mg) as a yellowish white solid.
'H-NMR (CD3OD) 8 6.70 (td, J=8.3,1.5Hz, 1H) 7.33 (ddd, J=8.3,1.2,0.6Hz, 1H) 7.46 (ddd, J=8.3,7.1,1.2Hz, 1H) 8.00 (ddd, J=7.1,1.5,0.6Hz, 1H)
[0219] Example 3j (R) and
(S)-4-({r2-fluoro-3-(2-fluoroethoxv>-5-methoxvphenvl1-(5-oxo-l-pvrimi
din-2-vl-4.5-dihvdro-lH41-2.41triazol-3-vBmethvnamino)beTizamidine
acetate
[0220] (3a) (2-fluoro-5-methoxyphenoxy)triisopropylsilane
[0221] [Chemical Formula 50]

To a 200 ml THF solution containing 50.1 g of
1 -fluoro-4-methoxybenzene and 70 g of
N,N,N',N',N"-pentamethyldiethylenetriarnine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) over a period of 30 minutes, at -74°C under a nitrogen atmosphere. After stirring for 3

hours at between -74°C and -70°C, 100 ml of trimethyl borate was added. The temperature of the reaction mixture was then slowly allowed to rise to room temperature. Next, 70 ml of acetic acid and 75 ml of 30% aqueous hydrogen peroxide were added, and the reaction mixture was stirred overnight at room temperature. Water was then added to the reaction mixture, and then it was extracted with a mixture of hexane and ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of l-fluoro-2-hydroxy-4-methoxybenzene (65.59 g) as a white solid. The compound was dissolved in 500 ml of DMF, and then 40 g of imidazole and 85 g of chlorotriisopropylsilane were added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with t-butylmethyl ether. The organic layers were combined and washed with 0.5 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (t-butyl methyl ether-heptane) to give the title compound (113.04 g) as an oil. 'H-NMR (CDC13) 8 1.11 (d, J=7.2Hz, 18H) 1.23-1.32 (m, 3H) 3.75 (s, 3H) 6.39 (dt, J=2.8, 8.8Hz, 1H) 6.50 (dd, J=3.2, 7.2Hz, 1H) 6.93 (dd, J=8.0, 10.4Hz, 1H) [0222] (3b) 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde

To a 240 ml THF solution containing 113 g of (2-fluoro-5-methoxyphenoxy)triisopropylsilane and 70 g of N,N,N',N',N"-pentamethyldiethyIenetriamine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) over a period of 50 minutes, at -74°C. After stirring for 3 hours at -60°C, 70 ml of
N-formylmorpholine was added. The temperature of the reaction mixture was slowly allowed to rise to 6°C. Next, IN hydrochloric acid was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (t-butyl methyl ether-heptane) to give the title compound (113.26 g) as an oil. 'H-NMR (CDCb) 8 1.11 (d, J=7.2Hz, 18H) 1.22-1.35 (m, 3H) 3.80 (s, 3H) 6.77 (dd, J=2.8, 7.2Hz, 1H) 6.87 (dd, J=3.2, 4.0Hz, 1H) 10.33 (s, 1H)
[0224] (3c)
(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyI)-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylamino]acetonitrile [0225] [Chemical Formula 52]

After adding 5.47 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 10.2 g of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde, 10 g of MS3A and 6.2 ml of trimethylsilyl cyanide to a solution of 1.94 g of Yb(OTf)3 in 100 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred for 3 days at room temperature. Ethyl acetate was added to the reaction mixture, and washing was performed with water. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (9.01 g) as a light yellow solid.
!H-NMR (CDCb) 5 1.10 (d, J=8.4Hz, 18H) 1.22-1.31 (m, 3H) 2.62 (s, 3H) 3.78 (s, 3H) 4.32 (br.d, J=6.8Hz, 1H) 5.62 (d, J=6.8Hz, 1H) 6.57 (dd, 3=3.2, 7.2Hz, 1H) 6.67 (dd, J=2.8, 4.4Hz, 1H) 6.82 (d, J=8.8Hz, 2H) 7.96

(d, J=8.8Hz, 2H)
[0226] (3d)
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl
ester
[0227] [Chemical Formula 53]

After adding 30 ml of a 20% aqueous solution of ammonium sulfide to a
solution of 9.01 g of
(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylamino]acetonitrile in 90 ml of an ethanol.THF =
2:1 mixed solvent, the mixture was stirred at room temperature for 3
hours. Water was added to the reaction mixture and extraction was
performed with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure.
The residue was dissolved in 50 ml of DMF, and then 5 g of imidazole
and 4 ml of chlorotriisopropylsilane were added and the mixture was
stirred at room temperature until completion of the reaction. Water was
added to the reaction mixture, extraction was performed with ethyl
acetate, and the organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure to give
2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (9.35 g, crude product). To a solution of 9.35 g of the crude product in 100 ml of dichloromethane there was added 2 g of Me30+BF4~, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with

saturated brine and dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give
2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenylamino]thioacetimide acid methyl ester (crude product).
The crude product was dissolved in 50 ml of dichloromethane, and then
30 g of manganese dioxide was added and the mixture was stirred at
room temperature for 3 hours. The reaction mixture was filtered and
the filtrate was concentrated under reduced pressure.
The residue was dissolved in 50 ml of toluene, and then 9 ml of
2,4,6-collidine and 4 ml of methyl chloroformate were added and the
mixture was stirred overnight at 85°C under a nitrogen atmosphere.
After cooling the reaction mixture, IN hydrochloric acid was added and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
{2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbami c acid methyl ester (6.33 g) as a yellow solid.
6.33 g this compound was dissolved in 100 ml of THF, and then 12 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.9 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDC13) Two main isomers: 5 2.34 (s, 3H) 2.66 (s, 3H) 3.61 (s, 3H) 3.81 (s, 3H) 6.74 (dd, J=3.6,

7.2Hz, 1H) 6.93 (t, J=3.2Hz, 1H) 7.13 (d, J=8.4Hz, 2H) 8.03 (d, J=8.4Hz,
2H)
5 2.47 (s, 3H) 2.63 (s, 3H)3.63 (s, 3H) 3.64 (s, 3H) 6.17 (t, J=3.2 Hz,
1H) 6.53 (dd, J=2.8, 6.8Hz, 1H) 6.84 (d, J=8.4Hz, 2H) 7.90 (d, J=8.4Hz,
2H)
[0228] (3e)
{2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyIidene}carbamic acid
methyl ester
[0229] [Chemical Formula 54]

After adding 3.32 g of potassium carbonate and 3.13 g of l-fluoro-2-iodoethane to a solution of 5.5 g of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 100 ml of DMF, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (5.88 g) as a yellow solid. 'H-NMR (CDC13) Two main isomers:
8 2.46 (s, 3H) 2.62 (s, 3H) 3.62 (s, 3H) 3.62 (s, 3H) 4.10-4.20 (m, 2H) 4.60-4.75 (m, 2H) 6.16-6.20 (m, 1H) 6.47-6.51 (m, 1H) 6.83 (d, J=8.8Hz, 2H) 7.88 (d, J=8.8Hz, 2H)
8 2.33 (s, 3H) 2.65 (s, 3H) 3.61 (s, 3H) 3.82 (s, 3H) 4.22-4.31 (m, 2H) 4.71-4.83 (m, 2H) 6.70-6.73 (m, 1H) 7.01-7.04 (m, 1H) 7.10 (d, J=8.8Hz, 2H) 8.02 (d, J=8.8Hz, 2H)

[0230] (3Q
5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2,4]o xadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4] triazol-3-one
[0231] [Chemical Formula 55]

After adding 1.09 g of 2-hydrazinopyrimidine [CAS No.7504-94-1] and 1.37 ml of triethylamine to a solution of 5.0 g of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of DMF, the mixture was stirred at 85°C for 20 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of methanol, 10 ml of THF and 3 ml of acetic acid. Next, 2.0 g of sodium cyanotrihydroborate was added to the solution, and after stirring at room temperature for 3 hours, 1.0 g of sodium cyanotrihydroborate was further added and stirring was continued for 2 hours and 30 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the insoluble portion was filtered off to give the title compound as a white solid. The filtrate was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (total: 4.88 g) as a white solid.
'H-NMR (de-DMSO) 5 2.57 (s, 3H) 3.69 (s, 3H) 4.24-4.38 (m, 2H) 4.66-4.82 (m, 2H) 5.86 (d, J=8.0Hz, 1H) 6.60-6.68 (m, 1H) 6.73-6.75 (m, 1H) 6.79 (d, J=8.4Hz, 2H) 7.27 (d, J=8.0Hz, 1H) 7.38 (t, J=4.8Hz, 1H) 7.72 (d, J=8.4Hz, 2H) 8.79 (d, J=4.8Hz, 2H) 12.24 (s, 1H)

[0232] (3g)
4-({[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[0233] [Chemical Formula 56]

After adding 1.2 g of iron powder to a solution of 1.2 g of
5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2,4]o
xadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[ 1,2,4]
triazol-3-one in 18 ml of a methanol:water:acetic acid = 1:1:1 mixed
solvent, the mixture was stirred at 65°C for 24 hours and 30 minutes
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give the title compound (750
mg) as a light yellow solid.
'H-NMR (CD3OD) 5 1.94 (s, 3H) 3.70 (s, 3H) 4.21-4.31 (m, 2H)
4.65-4.79 (m, 2H) 5.99 (s, 1H) 6.62-6.66 (m, 2H) 6.86 (d, J=8.8Hz, 2H)
7.32 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 497 (M+H)+
[0234] (3h) (R) and
(S)-4-({[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimi
din-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[0235] [Chemical Formula 57]


A SUMICHIRAL OA-2500 column was used for optical resolution of 750
mg of
4-({[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate, and the first eluting enantiomer (349.9 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.72 (s, 3H) 4.22-4.32 (m, 2H) 4.65-4.80 (m, 2H) 5.97 (s, 1H) 6.63-6.68 (m, 2H) 6.87 (d, J=8.8Hz, 2H) 7.31 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0236] Example 4j 4-U(R) and
(SM3-methoxv-5-[(S)-(tetrahvdrofuran-3-vl)oxy]phenvU-f5-oxo-l-pvri
midin-2-vl-4.5-dihvdro-lH-[1.2,4]triazol-3-yl)methyl]amino}benzamidin
e acetate
[0237] (4a) 3-methoxy-5-triisopropylsilanyloxybenzaldehyde
[0238] [Chemical Formula 58]

To a 50 ml DMF solution containing 2.8 g of 3-hydroxy-5-methoxybenzaldehyde [CAS No.57179-35-8] there were added 2.5 g of imidazole and 5.9 ml of chlorotriisopropylsilane. The mixture was stirred at room temperature for 14 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine and then dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give the title compound (5.7 g) as a light yellow oil.
'H-NMR (CDCb) 5 1.11 (d, J=7.2Hz, 18H) 1.29 (sept, J=7.2Hz, 3H) 3.83
(s, 3H) 6.67-6.70 (m, 1H) 6.97 (s, 1H) 6.99 (s, 1H) 9.87 (s, 1H)
[0239] (4b)
{2-(3-methoxy-5-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester
[0240] [Chemical Formula 59]

After adding 3.24 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine. 10 g of MS3A, 1.15 g of Yb(OTf)3 and 7.0 ml of trimethylsilyl cyanide to a solution of 5.7 g of 3-methoxy-5-triisopropylsilanyloxybenzaldehyde in 150 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a white solid (5.59 g).
To a solution of 5.59 g of the obtained white solid in 110 ml of a methanol:THF = 8:3 mixed solvent there was added 60 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 31 hours and 50 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a light yellow solid (2.90 g).

To a solution of 2.90 g of the obtained light yellow solid in 30 ml of acetonitrile there was added 896 mg of Me30+BF4", and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a yellow solid (3.25 g). To a solution of 3.25 g of the obtained yellow solid in ethyl acetate there was added 10 g of manganese dioxide, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil (2.80 g).
To a solution of 2.80 g of the obtained yellow oil in 50 ml of toluene
there was added 2.4 ml of 2,4,6-collidine and 1.2 ml of methyl
chloroformate, and the mixture was stirred at 80°C for 4 hours under a
nitrogen atmosphere. Water was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
washed with ice-cooled IN hydrochloric acid, water and saturated brine
and then dried over anhydrous magnesium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (1.8 g) as a yellow oil. 'H-NMR (CDC13) Main isomer:
8 1.10 (d, J=7.2Hz, 18H) 1.17-1.32 (m, 3H) 2.31 (s, 3H) 2.65 (s, 3H) 3.63 (s, 3H) 3.83 (s, 3H) 6.59 (dd, J=2.0, 2.4Hz, 1H) 6.86-6.91 (m, 1H) 7.09-7.13 (m, 1H) 7.16 (d, J=8.8Hz, 2H) 8.01 (d, J=8.8Hz, 2H) [0241] (4c)
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0242] [Chemical Formula 60]


After adding 3.3 ml of TBAF (1.0 M, THF solution) to a 15 ml THF
solution containing 1.8 g of
{2-(3-methoxy-5-triisopropylsilanyloxyphenyI)-2-[4-(5-methyl-[l,2,4]ox adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 0°C for 1 hour and 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.06 g) as a yellow solid. 'H-NMR (CDC13) Main isomer:
8 2.32 (s, 3H) 2.65 (s, 3H) 3.64 (s, 3H) 3.83 (s, 3H) 5.15 (br.s, 1H) 6.56 (dd, J=2.0, 2.4Hz, 1H) 6.91 (dd, J=2.0, 2.4Hz, 1H) 7.02 (dd, J=2.4, 2.4Hz, 1H) 7.15 (d, J=8.8Hz, 2H) 8.01 (d, J=8.8Hz, 2H) [0243] (4d)
4-[({3-methoxy-5-[(S)-(tetrahydrofuran-3-yI)oxy]phenyl}-(5-oxo-l-pyri midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidin e acetate [0244] [Chemical Formula 61]

After adding 0.022 ml of (R)-(-)-3-hydroxytetrahydrofuran, 89.3 mg of triphenylphosphine and 0.155 ml of diethyl azodicarboxylate

(hereinafter, "DEAD") (2.2 M toluene solution) to a 1 ml THF solution
containing 100 mg of
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester at 0°C, the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and the residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give 121 mg of a crude product.
Next, 22.5 mg of 2-hydrazinopyrimidine and 0.028 ml of triethylamine were added to a 1 ml DMF solution containing 121 mg of the obtained crude product, and the mixture was stirred at 85°C for 11 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.1 ml of acetic acid. Next, 100 mg of sodium cyanotrihydroborate was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 65°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (20.75 mg) as a light yellow solid.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 1.95-2.09 (m, 1H) 2.11-2.24 (m, 1H) 3.74 (s, 3H) 3.77-3.94 (m, 4H) 4.90-4.99 (m, 1H) 5.62 (s, 1H) 6.39 (t, J=2.0Hz, 1H) 6.68 (s, 1H) 6.74 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.32 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 503 (M+H)+
[0245] (4e) 4-[((R) and
(S)-{3-methoxy-5-[(S)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyri midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidin

e acetate
[0246] [Chemical Formula 62]

A SUMICHIRAL OA-2500 column was used for optical resolution of
20.75 mg of
4-[({3-methoxy-5-[(S)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidin
e acetate, and the first eluting enantiomer (8.35 mg) of the title
compound was obtained as a light yellow solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 1.97-2.07 (m, 1H) 2.11-2.23 (m, 1H)
3.70-3.98 (m, 7H) 4.89-5.01 (m, 1H) 5.59 (s, 1H) 6.37 (dd, J=2.0, 2.4Hz,
1H) 6.69 (s, 1H) 6.74 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.29 (t, J=4.8Hz, 1H)
7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 14 min
[0247] Example 5j 4-IYflO and
(SM3-methoxv-5-[fR)-(tetrahydrofuran-3-vl)oxy]phenyU-(5-oxo-l-pvri
midin-2-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-yQmethvl)amino]benzamidin
e acetate
[0248] (5a)
4-[({3-methoxy-5-[(R)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidin
e acetate
[0249] [Chemical Formula 63]


After adding 0.022 ml of (S)-(+)-3-hydroxytetrahydrofuran, 89.3 mg of
triphenylphosphine and 0.155 ml of DEAD (2.2 M, toluene solution) to a
1 ml THF solution containing 100 mg of
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (4c)) at 0°C, the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and the residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give 121 mg of a crude product. Next, 22.5 mg of 2-hydrazinopyrimidine and 0.028 ml of triethylamine were added to a 1 ml DMF solution containing 121 mg of the obtained crude product, and the mixture was stirred at 85°C for 11 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.1 ml of acetic acid. Next, 100 mg of sodium cyanotrihydroborate was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 65°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (21.38 mg) as a light yellow solid. ^-NMR (CD3OD) 5 1.80-2.27 (m, 5H) 3.65-3.96 (m, 7H) 4.94 (br.s, 1H)

5.64 (s, 1H) 6.39 (s, 1H) 6.68 (s, 1H) 6.74 (s, 1H) 6.87 (d, J=8.8Hz, 2H)
7.33 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 503 (M+H)+
[0250] (5b) 4-[((R) and
(S)-{3-methoxy-5-[(R)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazoI-3-yl)methyl)amino]benzamidin
e acetate
[0251] [Chemical Formula 64]

A SUMICHIRAL OA-2500 column was used for optical resolution of
21.38 mg of
4-[({3-methoxy-5-[(R)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidin
e acetate, to give the first eluting enantiomer (8.79 mg) of the title
compound as a light yellow solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 2.01-2.11 (m, 1H) 2.15-2.28 (m, 1H)
3.75 (s, 3H) 3.78-3.94 (m, 4H) 4.92-5.00 (m, 1H) 5.58 (s, 1H) 6.38 (dd,
J=2.0, 2.4Hz, 1H) 6.68 (s, 1H) 6.74 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.30 (t,
J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 14 min
[0252] Example 6j (R) and
(S')-4-((r3-methoxv-5-(2-methoxvethoxv')phenvl]-(5-oxo-l-pvrimidin-2-v l-4J-dihvdro-lH-n.2,4]triazol-3-yQmethvUamino')benzamidine acetate [0253] (6a)
4-({[3-methoxy-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate [0254] [Chemical Formula 65]


After adding 94 mg of potassium carbonate and 0.043 ml of 1 -bromo-2-methoxyethane to a 1 ml DMF solution containing 100 mg of {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (4c)), the mixture was stirred at room temperature for 24 hours and 50 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and then dried through PRESEP™. The filtrate was concentrated to give 114 mg of a crude product.
Next, 25 mg of 2-hydrazinopyrimidine and 0.031 ml of triethylamine were added to a 1 ml DMF solution containing 114 mg of the obtained crude product, and the mixture was stirred at 85°C for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.05 ml of acetic acid. Next, 100 mg of sodium cyanotrihydroborate was added to the solution and the mixture was stirred at room temperature for 6 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 60°C for 11 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (17.93 mg) as a white solid. 'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.38 (s, 3H) 3.64-3.72 (m, 2H) 3.75 (s,

3H) 4.01-4.12 (m, 2H) 5.61 (s, 1H) 6.45 (t, J=2.0Hz, 1H) 6.74 (d, J=2.0Hz, 2H) 6.86 (d, J=8.8Hz, 2H) 7.33 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 491 (M+H)+
[0255] (6b) (R) and
(S)-4-[([3-methoxy-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-y l-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzamidine acetate [0256] [Chemical Formula 66]

A SUMICHIRAL OA-2500 column was used for optical resolution of
17.93 mg of
4-({[3-methoxy-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate, to give the first eluting enantiomer (5.86 mg) of the title compound as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.38 (s, 3H) 3.64-3.72 (m, 2H) 3.75 (s, 3H) 4.02-4.12 (m, 2H) 5.59 (s, 1H) 6.44 (t, J=2.0Hz, 1H) 6.74 (d, J=2.0Hz, 2H) 6.86 (d, J=8.8Hz, 2H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 4.6 mmtp * 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 1 ml/min)
[0257] Example 1\ (R) and
(S)-4-({[3-methoxy-5-(2-methoxvethoxv)phenvn-(5-oxo-l-pvridazin-3-v l-4.5-dihvdro-lH-[1.2,4]triazol-3-yl)methvl}amino)benzarnidine acetate [0258] [Chemical Formula 67]


After adding 94 mg of potassium carbonate and 0.043 ml of l-bromo-2-methoxyethane to a 1 ml DMF solution containing 100 mg of {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (4c)), the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried through PRESEP™. The filtrate was concentrated to give 112 mg of a crude product.
To a 1 ml DMF solution of the obtained crude product there was added 33 mg of 3-hydrazinopyridazine hydrochloride [CAS No. 117043-87-5] and 0.063 ml of triethylamine, and the mixture was stirred at 85°C for 11 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was then concentrated.
The residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.1 ml of acetic acid. Next, 100 mg of sodium cyanotrihydroborate was added to the solution and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product. To a solution of the obtained crude product in 2.4 ml of a methanohwater.acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 65°C for 18 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-({[3-methoxy-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyridazin-3-yl-4,

5-dihydro-lH-[l,2,4]triazol-3-yl)methyI}amino)benzamidine acetate.
Mass spectrum (ESI)m/z: 491 (M+H)+
The compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (4.57 mg) of the title compound
was obtained as a light yellow solid.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.37 (s, 3H) 3.65-3.71 (m, 2H) 3.74 (s,
3H) 4.02-4.09 (m, 2H) 5.57 (s, 1H) 6.41 (t, J=2.4Hz, 1H) 6.75 (d,
J=2.4Hz, 2H) 6.85 (d, J=8.8Hz, 2H) 7.59 (d, J=8.8Hz, 2H) 7.74 (dd,
J=4.8, 9.2Hz, 1H) 8.56 (dd, J=1.6, 9.2Hz, 1H) 8.99 (dd, J=1.6, 4.8Hz,
1H)
HPLC retention time: 12 min
[0259] Example 8j (R) and
(S)-4-(([3-f2-dimethylaminoethoxy)-5-methoxvphenyl]-(5-oxo-l-pvrimi
din-2-yl-4.5-dihvdro-lH-fl,2.41triazol-3-yl)methvl)amino)benzamidine
diacetate
[0260] [Chemical Formula 68]

After adding 40 mg of 2-dimethylaminoethanol, 120 mg of
triphenylphosphine and 0.200 ml of DEAD (2.2 M, toluene solution) to a
1 ml THF solution containing 100 mg of
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester (Example (4c)) at 0°C, the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction mixture was concentrated, and the residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give 55 mg of a crude product. To a 1 ml DMF solution containing 55 mg of the obtained crude product there were added 12 mg of 2-hydrazinopyrimidine and 0.015 ml of

triethylamine, and the mixture was stirred at 85°C for 11 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.1 ml of acetic acid. Next, 100 mg of sodium cyanotrihydroborate was added to the solution and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 2.4 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 65°C for 18 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
The obtained crude product was optically resolved using a SUM1CHIRAL OA-2500 column, and the first eluting enantiomer (4.35 mg) of the title compound was obtained as a light yellow solid. 'H-NMR (CD3OD) 8 1.92 (s, 6H) 2.49 (s, 6H) 2.96 (dd, J=5.2, 5.6Hz, 2H) 3.76 (s, 3H) 4.14 (dd, J=5.2, 5.6Hz, 2H) 5.58 (s, 1H) 6.47 (t, J=2.0Hz, 1H) 6.77 (t, J=2.0Hz, 2H) 6.85 (d, J=8.8Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 11 min
[0261] Example 9j (R) and
fS)-4-{[(3.5-dimethoxvphenvD-(5-oxo-l-pyrimidin-2-yl-4.5-dihvdro-lH-[1.2,4]triazol-3-vDmethyl]amino)benzamidine acetate [0262] (9a)
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0263] [Chemical Formula 69]

filtrate, and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a yellow oil (2.22 g). To a 20 ml THF solution containing the obtained yellow oil there was added 4.1 ml of TBAF (1.0 M, THF solution), and the mixture was stirred at 0°C for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.15 g) as a yellow solid. 'H-NMR (CDC13) Main isomer:
5 2.32 (s, 3H) 2.65 (s, 3H) 3.64 (s, 3H) 3.83 (s, 3H) 5.15 (br.s, 1H) 6.56
(dd, J=2.0, 2.4Hz, 1H) 6.91 (dd, J=2.0, 2.4Hz, 1H) 7.02 (dd, J=2.4,
2.4Hz, 1H) 7.15 (d, J=8.8Hz, 2H) 8.01 (d, J=8.8Hz, 2H)
[0264] (9b) (R) and
(S)-4-{[(3,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazoI-3-yl)methyl]amino}benzamidine acetate [0265] [Chemical Formula 70]

After adding 63 mg of potassium carbonate and 0.017 ml of methyl iodide to a 1 ml DMF solution containing 100 mg of {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, the

mixture was stirred at room temperature for 40 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried through PRESEP™. The filtrate was concentrated to give 106 mg of a crude product. Next, 25 mg of 2-hydrazinopyrimidine and 0.031 ml of triethylamine were added to a 1 ml DMF solution containing 106 mg of the obtained crude product, and the mixture was stirred at 85°C for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.05 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
The obtained crude product was optically resolved using a CHIRALPAK™ AD-H (column size: 2 cmcp * 25 cmL, Manufacturer: Daicel Chemical Industries, Ltd., Mobile phase: 2-propanol/hexane=2/3, 0.1% trifluoroacetic acid, Elution rate: 9 ml/min) (retention time for the first eluting enantiomer: 17 min). Triethylamine was added to the obtained first eluting enantiomer and the mixture was concentrated under reduced pressure.
To a solution of the residue in 2.2 ml of a methanol:water:acetic acid = 0.6:0.6:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 60°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid), to give one optical isomer of the title compound (10.84 mg) as a white solid. *H-NMR (CD3OD) 8 1.94 (s, 3H) 3.75 (s, 6H) 5.62 (s, 1H) 6.43 (d,

J=1.6Hz, 1H) 6.72 (s, 2H) 6.86 (d, J=8.4Hz, 2H) 7.33 (t, J=4.8Hz, 1H) 7.60 (d, J=8.4Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 447 (M+H)+
[0266] Example LPj (R) and
(SV4-{[n-methoxy-5-methoxvmethvlphenvlW5-oxo-l-pvrimidin-2-vl-4. 5-dihvdro-lH-[1.2.4]triazol-3-yl)methvl]amino}benzamidine acetate [0267] (10a) (3-methoxy-5-methoxymethylphenyl)methanol

To a 50 ml THF solution containing 4 g of
5-methoxy-l,3-benzenedimethanol there was added 951 mg of sodium
hydride (60% oily suspension) at 0°C. After stirring at room
temperature for 1 hour, 3.58 g of t-butyldimethylsilyl chloride was added
and stirring was continued at room temperature for 70 minutes. Water
was added to the reaction mixture and extraction was performed with
ethyl acetate. The organic layer was washed with water and saturated
brine, and then dried over anhydrous sodium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give a light yellow oil (3.74
g)-
To a 10 ml THF solution containing 1 g of the obtained light yellow oil
there was added 212 mg of sodium hydride (60% oily suspension) at 0°C.
After stirring at room temperature for 30 minutes, 0.5 ml of methyl
iodide was added and the mixture was stirred at room temperature for 2
hours. Water was added to the reaction mixture and extraction was
performed with ethyl acetate. The organic layer was washed with water
and saturated brine, and then dried over anhydrous sodium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure.
To a solution of the residue in 10 ml of THF there was added 4.3 ml of

TBAF (1.0 M, THF solution) at 0°C, and the mixture was stirred at room temperature for 17 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (618 mg) as a light yellow oil. 'H-NMR (CDCI3) 5 3.39 (s, 3H) 3.82 (s, 3H) 4.43 (s, 2H) 4.67 (s, 2H) 6.81 (s, 1H) 6.85 (s, 1H) 6.91 (s, 1H) [0269] (10b)
(3-methoxy-5-methoxymethylphenyl)-[4-(5-methyI-[l,2,4]oxadiazoI-3-yl )phenylamino]acetonitrile

To a solution of 618 mg of
(3-methoxy-5-methoxymethylphenyl)methanol in 15 ml of dichloromethane there was added 4.5 g of manganese dioxide, and the mixture was stirred at room temperature for 23 hours and 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 10 ml of dichloromethane there was added 550 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 1 g of MS3A, 195 mg of Yb(OTf)3 and 0.79 ml of trimethylsilyl cyanide, and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.25 g) as a light yellow oil. 'H-NMR (CDCb) 8 2.63 (s, 3H) 3.42 (s, 3H) 3.84 (s, 3H) 4.46 (s, 2H)

5.44 (br.s, 1H) 6.82 (d, J=8.8Hz, 2H) 6.96 (s, 1H) 7.02-7.04 (m, 1H) 7.15 (s, 1H) 7.96 (d, J=8.8Hz, 2H) [0271] (10c)
{2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

To a solution of 1.25 g of
(3-methoxy-5-methoxymethylphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylamino]acetonitrile in 30 ml of a methanol:THF = 2:1 mixed solvent there was added 10 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 16 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After adding 550 mg of Me30+BF4~ to a solution of the residue in 15 ml of dichloromethane, the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 6.5 g of manganese dioxide to a solution of the residue in 20 ml of dichloromethane, the mixture was stirred at room temperature for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding 1.35 ml of 2,4,6-collidine and 0.67 ml of methyl

chloroformate to a solution of the residue in 20 ml of toluene, the mixture was stirred at 80°C for 5 hours and 20 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (400 mg) as a yellow oil. [0273] (lOd)
4-{[(3-methoxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

After adding 49 mg of 2-hydrazinopyrimidine and 0.062 ml of triethylamine to a 1 ml DMF solution containing 210 mg of {2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-1 -methylsulfanylethylidene} carbamic acid methyl ester, the mixture was stirred at 85°C for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1 ml of methanol, 1 ml of THF and 0.1 ml of acetic acid. After adding 250 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product. To a solution of the obtained crude product in 3 ml of a

methanol:water:acetic acid = 1:1:1 mixed solvent there was added 200 mg of iron powder, and the mixture was stirred at 65°C for 13 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (58.4
mg)-
'H-NMR (CD3OD) 5 1.94 (s, 3H) 3.35 (s, 3H) 3.78 (s, 3H) 4.41 (s, 2H)
5.67 (s, 1H) 6.76-6.95 (m, 3H) 7.06 (s, 1H) 7.11 (s, 1H) 7.33 (br.s, 1H)
7.60 (d, J=8.0Hz, 2H) 8.78 (d, J=3.6Hz, 2H)
Mass spectrum (ESI)m/z: 461 (M+H)+
[0275] (lOe) (R) and
(S)-4-{[(3-methoxy-5-methoxymethyIphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

A SUM1CHIRAL OA-2500 column was used for optical resolution of
58.4 mg of
4-{[(3-methoxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first eluting enantiomer (24.57 mg) of the title compound was obtained as a white solid.
!H-NMR (CD3OD) 8 1.91 (s, 3H) 3.33 (s, 3H) 3.76 (s, 3H) 4.39 (s, 2H) 5.64 (s, 1H) 6.84 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.06 (s, 1H) 7.10 (s, 1H) 7.29 (t, J=5.2Hz, 1H) 7.58 (d, J=8.8Hz, 2H) 8.75 (d, J=5.2Hz, 2H) HPLC retention time: 12 min
[0277] Example LU
4-{f(3-fluoromethvl-5-methoxyphenyl)-(5-oxo-l-pvrimidin-2-yl-4.5-dihv dro-1 H-[ 1,2,4]triazol-3-yQmethvl]amino)benzamidine acetate

[0278] (11a) 5-triisopropylsilanyloxyisophthalic acid dimethyl ester

After adding 5.1 g of imidazole and 12.9 ml of chlorotriisopropylsilane to a 100 ml DMF solution containing 10.5 g of 5-hydroxyisophthalic acid dimethyl ester, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.53 g) as a colorless oil. 'H-NMR (CDC13) 6 1.10 (d, J=7.6Hz, 18H) 1.26 (sept, J=7.6Hz, 3H) 3.93 (s, 6H) 7.70 (d, J=1.2Hz, 2H) 8.25 (t, J=1.2Hz, 1H) [0280] (lib) (3-hydroxymethyl-5-triisopropylsilanyloxyphenyl)methanol

To a 100 ml THF solution containing 21.53 g of 5-triisopropylsilanyloxyisophthalic acid dimethyl ester there was added 7.1 g of lithium aluminum hydride at 0°C. After stirring at 0°C for 1 hour, the mixture was stirred at room temperature for 3 hours and 30 minutes. Water and IN aqueous sodium hydroxide were added to the reaction mixture which was then filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was then washed with saturated brine and dried over anhydrous sodium sulfate. The

desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound
(13.53 g) as a colorless solid.
'H-NMR (CDCb) 5 1.10 (d, J=7.2Hz, 18H) 1.29 (sept, J=7.2Hz, 3H) 4.63
(s, 4H) 6.80 (s, 2H) 6.93 (s, 1H)
[0282] (lie)
3-(t-butyldimethylsilanyloxymethyl)-5-triisopropylsilanyloxybenzaldehy
de

To a 50 ml THF solution containing the 13.53 g of (3-hydroxymethyl-5-triisopropylsilanyloxyphenyl)methanol there was added 1.57 g of sodium hydride (60% oily suspension) at 0°C. After stirring at room temperature for 15 minutes, 6.6 g of t-butyldimethylsilyl chloride was added and the mixture was stirred at room temperature for 3 hours and 15 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a colorless oil (9.74 g).
'H-NMR (CDCb) 5 0.09 (s, 6H) 0.94 (s, 9H) 1.10 (d, J=7.2Hz, 18H) 1.26 (sept, J=7.2Hz, 3H) 4.61 (s, 2H) 4.67 (s, 2H) 6.76 (s, 1H) 6.81 (s, 1H) 6.84 (s, 1H)
To a solution of 9.74 g of the obtained colorless oil in 200 ml of dichloromethane there was added 28 g of manganese dioxide, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced

pressure, to give the title compound (8.05 g) as a light yellow oil. 'H-NMR (CDCI3) 8 0.11 (s, 6H) 0.95 (s, 9H) 1.10 (d, J=7.6Hz, 18H) 1.28 (sept, J=7.6Hz, 3H) 4.74 (s, 2H) 7.16 (s, 1H) 7.23 (s, 1H) 7.36 (s, 1H) 9.91 (s, 1H) [0284] (lid)
{2-(3-hydroxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

After adding 3.34 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,
10 g of MS3A, 1.18 g of Yb(OTf)3 and 4.8 ml of trimethylsilyl cyanide
to a solution of 8.05 g of
3-(t-butyldimethylsilanyloxymethyl)-5-triisopropylsilanyloxybenzaldehy de in 100 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a light yellow solid (6.95
g)-
To a solution of 6.95 g of the obtained light yellow solid in 120 ml of a
methanol:THF = 2:1 mixed solvent there was added 60 ml of a 20%
aqueous solution of ammonium sulfide, and the mixture was stirred at
room temperature for 2 days. Water was added to the reaction mixture,
which was then filtered to give a white solid (7.02 g).
To a solution of 7.02 g of the obtained white solid in 100 ml of
dichloromethane there was added 1.86 g of Me30+BF4", and the mixture
was stirred at room temperature for 26 hours. Saturated aqueous
sodium hydrogencarbonate was added to the reaction mixture and
extraction was performed with ethyl acetate. After washing the organic

layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After adding 1.24 g of imidazole and 1.83 g of t-butyldimethylsilyl chloride to a solution of the residue in 50 ml of DMF, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 8 g of manganese dioxide to a solution of the residue in 100 ml of dichloromethane, the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
After adding 5 ml of 2,4,6-collidine and 2.5 ml of methyl chloroformate to a solution of the residue in 100 ml of toluene, the mixture was stirred at 80°C for 8 hours and 40 minutes under a nitrogen atmosphere. The reaction mixture was filtered, water was added to the filtrate, and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a yellow oil (6.16 g). To a 100 ml THF solution containing 6.16 g of the obtained yellow oil there was added 19 ml of TBAF (1.0 M, THF solution), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.48

g) as a yellow solid. [0286] (lie)
{2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

To a 3 ml DMF solution containing 700 mg of {2-(3 -hydroxy-5 -hydro xymethylpheny l)-2 - [4-(5 -methyl- [ 1,2,4] oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester there was added 440 mg of potassium carbonate and 0.15 ml of methyl iodide, and the mixture was stirred at room temperature for 17 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (544 mg) as a yellow solid. 'H-NMR (CDC13) Main isomer:
8 2.34 (s, 3H) 2.66 (s, 3H) 3.62 (s, 3H) 3.88 (s, 3H) 4.73 (d, J=4.4Hz, 2H) 7.12 (br.s, 1H) 7.17 (d, J=8.8Hz, 2H) 7.36-7.42 (m, 2H) 8.03 (d, J=8.8Hz, 2H) [0288] (llf)
{2-(3-fluoromethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0289] [Chemical Formula 81]


To a solution of 100 mg of
{2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 1.5 ml of dichloromethane there was added 0.057 ml of [bis(2-methoxyethyl)amino]sulfur trifluoride at -78°C. After stirring at -78°C for 5 minutes, the mixture was stirred at room temperature for 1 hour and 25 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (59 mg) as a yellow oil. [0290] (llg)
4-{[(3-fluoromethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

After adding 14 mg of 2-hydrazinopyrimidine and 0.015 ml of triethylamine to a 1 ml DMF solution containing 59 mg of {2-(3-fluoromethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yI)phenyIimino]-l-methylsulfanylethyIidene}carbamic acid methyl ester, the mixture was stirred at 85°C for 22 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.75 ml of methanol, 0.75 ml of THF and 0.05

ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours and 40 minutes. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product. To a solution of the obtained crude product in 2.4 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 65°C for 15 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (14.16 mg) as a light yellow solid.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.78 (s, 3H) 5.31 (d, J=47.6Hz, 2H) 5.68 (s, 1H) 6.86 (d, J=8.4Hz, 2H) 6.90 (s, 1H) 7.12 (s, 1H) 7.15 (s, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.4Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESl)m/z: 449 (M+H)+
[0292] Example \2\ (R) and
(S)-4-([(3-hvdroxvmethvl-5-methoxyphenvn-(5-oxo-l-pvrimidin-2-yl-4.
5-dihydro-lH-[1.2.4]triazol-3-yDmethvnamino}benzamidine
trifluoroacetate
[0293] (12a)
4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

After adding 24 mg of 2-hydrazinopyrimidine and 0.030 ml of triethylamine to a 1 ml DMF solution containing 100 mg of {2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol

-3-yI)phenylimino]-l-methyIsuIfanylethyIidene}carbamic acid methyl
ester (Example (lie)), the mixture was stirred at 85°C for 14 hours and
30 minutes under a nitrogen atmosphere. The reaction mixture was
concentrated, and the residue was dissolved in 1 ml of methanol, 1 ml of
THF and 0.050 ml of acetic acid. After adding 100 mg of sodium
cyanotrihydroborate to the reaction mixture, it was stirred at room
temperature for 21 hours and 30 minutes. The reaction mixture was
crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product.
To a solution of the obtained crude product in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 150
mg of iron powder, and the mixture was stirred at 60°C for 17 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give the title compound (28.50
mg).
'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.78 (s, 3H) 4.58 (s, 2H) 5.68 (s, 1H)
6.87 (d, J=8.8Hz, 2H) 6.91 (s, 1H) 7.03 (s,lH) 7.13 (s, 1H) 7.35 (t,
J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 447 (M+H)+
[0295] (12b) (R) and
(S)-4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine
trifluoroacetate

After adding trifluoroacetic acid to a suspension of 28.5 mg of 4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di

hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate in 2.85 ml of DMSO, the mixture was concentrated under reduced pressure. The residue was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer was obtained. This was dissolved in a trifluoroacetic acid:acetonitrile:water = 1:50:50 mixed solvent and concentrated, and the first eluting enantiomer (9.80 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 3.81 (s, 3H) 4.59 (s, 2H) 5.70 (s, 1H) 6.88 (d, J=9.2Hz, 2H) 6.93 (s, 1H) 7.03 (s,lH) 7.13 (s, 1H) 7.37 (t, J=4.8Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 8.79 (d, J=4.8Hz, 2H) HPLC retention time: 11 min
[0297] Example 13:
4-(([3-(2-dimethvlamino-l-methvlethoxv')-2-fluoro-5-methoxvphenvl1-(5 -oxo-1-pvridin-2-vl-4.5-dihvdro-lH-fl.2.4]triazol-3-vl')methvUamino')be
nzamidine bistrifluoroacetate and
4-(([3-f2-dimethvlaminopropoxv)-2-fluoro-5-methoxvphenvl]-(5-oxo-l-pyridin-2-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methyUamino)benzamidi ne bistrifluoroacetate

After adding 217 mg of potassium carbonate and 124 mg of

(2-chloropropyl)dimethylamine hydrochloride to a 3 ml DMF solution
containing 300 mg of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-1 -methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)), the mixture was stirred at an external temperature of 80°C for 20 hours and 30 minutes. Next, 20 mg of tetrabutylammonium iodide was added to the reaction mixture and stirring was continued at the same temperature for 5 hours and 30 minutes. The reaction mixture was concentrated, and the obtained residue was crudely purified by NAM silica gel column chromatography (chloroform-methanol) to give 210 mg of a crude product. After dissolving 50 mg of the 210 mg of obtained crude product in 2 ml of DMF, 15 mg of 2-hydrazinopyridine and 0.025 ml of triethylamine were added to the solution and the mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The reaction mixture was then concentrated.
Next, 1 ml of methanol and 0.014 ml of acetic acid were added to dissolve the obtained residue. To this solution there was added 30 mg of sodium cyanotrihydroborate, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated. Next, 1.5 ml of a methanolrwatenacetic acid = 1:1:1 mixed solvent was added to dissolve the obtained residue. After adding 50 mg of iron powder to the solution, the mixture was stirred at 60°C for 14 hours and 45 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid), to give a mixture of the two title compounds (3.98 mg) as a light brown oil. Mass spectrum (ESI)m/z: 535 (M+H)+
[0300] Example 14:
4-({(2-fluoro-3-methoxv-5-methvlphenvl)-ri-(2-methoxvphenvl')-5-oxo-4
.5-dihydro-lH-f 1.2.4") triazol-3-vl]methvl)amino)benzamidine
trifluoroacetate
[0301] (14a) 2-fluoro-5-methyl-3-triisopropylsilanyloxybenzaldehyde

[0302J [Chemical Formula 87]

After adding 10.4 g of imidazole to a 200 ml DMF solution containing 17.6 g of 2-fluoro-5-methylphenol [CAS No.63762-79-8], the reaction mixture was cooled to 0°C. Next, 33.5 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture and extraction was performed with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 30 ml of N,N,N',N',N"-pentamethyldiethylenetriamine and 300 ml of THF to the obtained residue, the solution was cooled to an external temperature of -78°C. Next, 100 ml of n-butyllithium (1.6 M, hexane solution) was added dropwise over a period of 20 minutes. After stirring for 2 hours at -78°C, 18.3 ml of N-formylmorpholine was added. The temperature of the reaction mixture was allowed to rise to room temperature, and stirring was continued for 13 hours and 20 minutes. Ice was added to the reaction mixture, which was then concentrated under reduced pressure. After adding ethyl acetate and water to the residue, extraction was performed twice with ethyl acetate and the combined organic layers were washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (36.1 g) as a colorless oil.
'H-NMR (CDC13) 5 1.12 (d, J=7.2Hz, 18H) 1.24-1.33 (m, 3H) 2.31 (s, 3H) 6.99 (dd, 3=2A, 8.0Hz, 1H) 7.20 (dd, J=1.6, 5.6Hz, 1H) 10.30 (s, 1H) [0303] (14b)

{2-(2-fluoro-3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol
-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[0304] [Chemical Formula 88]

After adding 5.8 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 10 g of 2-fluoro-5-methyl-3-triisopropylsilanyloxybenzaldehyde, 10 g of MS3A and 8.9 ml of trimethylsilyl cyanide to a solution of 2.0 g of Yb(OTf)3 in 200 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (ethyl acetate-heptane) to give a yellow oil (13.7 g).
To a 200 ml THF solution containing 13.7 g of the obtained yellow oil there was added 45 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 11 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
Next, 300 ml of acetonitrile was added to dissolve the obtained residue. After adding 4.3 g of Me30+BF4" to the solution, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium

hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After adding 200 ml of dichloromethane and 30 g of manganese dioxide to the obtained residue, the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
Next, 200 ml of toluene was added to dissolve the obtained residue. After adding 12.8 ml of 2,4,6-collidine and 6.4 ml of methyl chloroformate to the solution, the mixture was stirred at 85°C for 24 hours under a nitrogen atmosphere. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, ice-cooled saturated sodium hydrogen carbonate water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a yellow oil (12.2 g).
To a 200 ml THF solution containing 12.2 g of the obtained yellow oil there was added 16.3 ml of TBAF (1.0 M, THF solution), and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.59 g, isomeric mixture). 'H-NMR (CDC13) Two main isomers:
5 2.19 (s, 3H) 2.46 (s, 3H) 2.62 (s, 3H) 3.59 (s, 3H) 6.48 (dd, J=1.6, 5.2Hz, 1H) 6.77-6.80 (m, 1H) 6.81 (d, J=8.4Hz, 2H) 7.87 (d, J=8.4Hz,

2H)
8 2.32 (s, 6H) 2.65 (s, 3H) 3.57 (s, 3H) 6.96-6.99 (m, 1H) 7.12 (d,
J=8.8Hz, 2H) 7.18-7.19 (m, 1H) 8.02 (d, J=8.8Hz, 2H)
[0305] (14c)
4-({(2-fluoro-3-methoxy-5-methylphenyl)-[l-(2-methoxyphenyl)-5-oxo-4
,5-dihydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine
trifluoroacetate

After adding 140 mg of potassium carbonate and 140 mg of iodomethane to a 3 ml DMF solution containing 220 mg of {2-(2-fluoro-3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at room temperature for 17 hours and 15 minutes. Ethyl acetate and water were added to the reaction mixture, and extraction was performed twice with ethyl acetate. The combined organic layers were washed twice with water and dried using magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
Half of the obtained residue was dissolved in 1 ml of DMF, and after adding 38 mg of (2-methoxyphenyl)hydrazine hydrochloride and 0.070 ml of triethylamine to the solution, the mixture was stirred at 85°C for 7 hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was then concentrated.
Next, 1 ml of methanol and 0.090 ml of acetic acid were added to dissolve the obtained residue. To this solution there was added 100 mg of sodium cyanotrihydroborate, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated. Next, 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent was

added to dissolve the obtained residue. After adding 140 mg of iron powder to the solution, the mixture was stirred at 55°C for 17 hours and 15 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (4.15 mg) as a white solid.
'H-NMR (CD3OD) 5 2.31 (s, 3H) 3.82 (s, 3H) 3.87 (s, 3H) 5.95 (s, 1H) 6.83-6.86 (m, 3H) 6.94 (dd, J=2.0, 8.0Hz, 1H) 7.02 (dt, J=0.8, 8.0Hz, 1H) 7.14 (dd, J=1.2, 8.4Hz, 1H) 7.30 (dd, J=1.6, 7.6Hz, 1H) 7.43 (ddd, JM1.2, 7.2, 8.4Hz, 1H) 7.62-7.65 (m, 2H) Mass spectrum (ESI)m/z: 477 (M+H)+
[0307] Example 15: (R) and
(S)-2-(3-r(4-carbamimidovlphenvlamino)-(5-oxo-l-pvrimidin-2-vl-4.5-di hvdro-lH-n.2.41triazol-3-vl)methvl1-2-fluoro-5-methoxvphenoxv>-N.N-dimethvlacetamide acetate

After adding 53 mg of potassium carbonate, 10 mg of
tetrabutylammonium iodide and 53 mg of
2-chloro-N,N-dimethylacetamide to a 1 ml DMF solution containing 100
mg of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)), the mixture was stirred at room temperature for 26 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, PRESEP™ was used for filtration, and the filtrate was concentrated. The obtained residue was dissolved in 1 ml of DMF, and then 22 mg of 2-hydrazinopyrimidine and 0.046 ml of triethylamine were added to the

solution and the mixture was stirred at 85°C for 12 hours under a
nitrogen atmosphere. The reaction mixture was then concentrated.
Next, 1 ml of methanol and 0.070 ml of acetic acid were added to
dissolve the obtained residue. After then adding 100 mg of sodium
cyanotrihydroborate to the solution, it was stirred overnight at room
temperature. The reaction mixture was then concentrated.
Next, 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent was
added to dissolve the obtained residue. After then adding 121 mg of
iron powder to the solution, the mixture was stirred at 60°C for 13 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid).
The obtained crude product was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (7.60
mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 2.96 (s, 3H) 3.08 (s, 3H) 3.69 (s, 3H)
4.87 (s, 2H) 5.95 (s, 1H) 6.57 (dd, J=2.8, 6.8Hz, 1H) 6.67-6.69 (m, 1H)
6.85 (d J=8.8Hz, 2H) 7.28-7.30 (m, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75 (d,
J=4.4Hz, 2H)
HPLC retention time: 19 min
[0309] Example 16j (R) and
(SV4-{[(4-cyanomethoxv-3-methoxvphenvD-(5-oxo-l-pyrirnidin-2-yl-4.5 -dihvdro-lH-[1.2.41triazol-3-vl)methvl]amino)benzamidine acetate [0310] (16a)
{2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester


After dissolving 520 mg of
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (18d)) in 5 ml of DMF, 262 mg of potassium carbonate and 107 jil of bromoacetonitrile were added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (514 mg, isomeric mixture) as a light yellow solid.
'H-NMR (CDC13) Main isomer:
5 2.34 (s, 3H) 2.66 (s, 3H) 3.63 (s, 3H) 3.97 (s, 3H) 4.90 (s, 2H) 7.06 (d, J=8.4Hz, 1H) 7.18 (d, J=8.8Hz. 2H) 7.32 (dd, J=8.4,2.0Hz, 1H) 7.68 (d, J=2.0Hz, 1H) 8.03 (d, J=8.8Hz, 2H) [0312] (16b)
4-{[(4-cyanomethoxy-3-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dih ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

To a solution of 535 mg of
{2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 8 ml of DMF there were added 123 mg of 2-hydrazinopyrimidine and 312 ul of triethylamine, and the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was

concentrated, and the residue was dissolved in 6 ml of a methanol:THF =
1:1 mixed solvent. Next, 229 uJ of acetic acid and 357 mg of sodium
cyanotrihydroborate were added to the solution and the mixture was
stirred at room temperature for 3 hours and 30 minutes. After adding
ethyl acetate to the reaction mixture, it was filtered through a small
amount of NAM silica gel, and the silica gel was washed with ethyl
acetate-methanol. The filtrate was concentrated under reduced pressure,
and the residue was crudely purified by NAM silica gel column
chromatography (methanol-ethyl acetate), to give
(2-methoxy-4-{[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-
l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}phenoxy)ace
tonitrile.
To a solution of this compound in 9 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 300 mg of iron powder, and the
mixture was stirred at 60°C for 16 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give 150 mg of the title compound.
'H-NMR (CD3OD) 5 3.87 (s, 3H) 4.95 (s, 2H) 5.72 (s, 1H) 6.88 (d,
J=8.8Hz, 2H) 7.13 (m, 2H) 7.26 (br.s, 1H) 7.37 (t, J=4.8Hz, 1H) 7.62 (d,
J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 472 (M+H)+
[0314] (16c) (R) and
(S)-4-{[(4-cyanomethoxy-3-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5
-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate


mg of
4-{[(4-cyanomethoxy-3-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dih ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first eluting enantiomer (40.5 mg) of the title compound was obtained. HPLC retention time: 12 min
[0316] Example Vh (R) and
(S)-4-(f(3-ethoxv-4-methoxvphenvl)-(5-oxo-1-pvrimidin-2-yl-4,5-dihydr o-lH-[1.2.4]triazol-3-yl)methyl]amino}benzamidine acetate [0317] (17a)
(4-methoxy-3-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylamino]acetonitrile

After adding 3.19 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 10 g of MS3A, 1.56 g of Yb(OTf)3 and 4.84 ml of trimethylsilyl cyanide to a solution of 5.6 g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 98 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a white solid (5.59 g). [0319] (17b)
2-(4-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]oxa diazol-3-yl)phenylamino]thioacetamide

After adding 30.8 ml of a 20% aqueous solution of ammonium sulfide to

a solution of 8.92 g of
(4-methoxy-3-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylamino]acetonitrile in 300 ml of a methanol:THF = 2:1 mixed solvent, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.59 g) as a crude product. [0321] (17c)
{2-(4-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]ox adiazol-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
After adding 2.35 g of Me30+BFV to a solution of 7.26 g of 2-(4-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]oxa diazol-3-yl)phenylamino]thioacetamide in 179 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in 300 ml of toluene there were added 6.4 ml of 2,4,6-collidine and 3.2 ml of methyl chloroformate, and the mixture was stirred at 85 °C for 16 hours under a nitrogen atmosphere. After cooling the reaction mixture, dilute hydrochloric acid was added and extraction was performed with ethyl acetate. The

organic layer was washed with water and saturated brine, and then dried
over anhydrous sodium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give the title compound (3.52 g, isomeric mixture) as a light yellow
oil.
'H-NMR (CDCI3) Main isomer:
8 1.09 (d, J=7.2Hz, 18H) 1.24-1.27 (m, 3H) 2.30 (s, 3H) 2.65 (s, 3H)
3.60 (s, 3H) 3.87 (s, 3H) 6.87 (d, J=8.8Hz, 1H) 7.16 (d, J=8.8Hz, 2H)
7.41 (m, 2H) 7.99 (d, J=8.8Hz, 2H)
[0323] (17d)
{2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

After dissolving 3.52 g of
{2-(4-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4]ox adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of THF, 6.49 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.88 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDCI3) Main isomer: 8 2.32 (s, 3H) 2.65 (s, 3H) 3.64 (s, 3H) 3.96 (s, 3H) 5.67 (s, 1H) 6.90 (d,

J=8.4Hz, 1H) 7.16 (d, J=8.8Hz, 2H) 7.36 (dd, J=8.4,2.0Hz, 1H) 7.53 (d, J=2.0Hz, 1H) 8.01 (d, J=8.8Hz, 2H) [0325] (17e)
{2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

After dissolving 1.0 g of
{2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 473 mg of potassium carbonate and 219 ul of iodoethane were added and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (983 mg, isomeric mixture) as a light yellow solid. 'H-NMR (CDC13) Main isomer:
5 1.50 (t, J=6.8Hz, 3H) 2.32 (s, 3H) 2.65 (s, 3H) 3.62 (s, 3H) 3.94 (s, 3H) 4.19 (q, J=6.8Hz, 2H) 6.89 (d, J=8.4Hz, 1H) 7.19 (d, J=8.8Hz, 2H) 7.30 (dd, J=8.4,2.4Hz, 1H) 7.58 (d, J=2.4Hz, 1H) 8.02 (d, J=8.8Hz, 2H) [0327] (17f)
5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one [0328] [Chemical Formula 99]


After adding 230 mg of 2-hydrazinopyrimidine and 293 u.1 of triethylamine to a 50 ml DMF solution containing 983 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 85°C for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of a methanohTHF = 1:1 mixed solvent. After adding 420 p.1 of acetic acid and 657 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture which was then filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (400 mg) as a light yellow solid.
'H-NMR (CDC13) 5 1.32 (t, J=7.2Hz, 3H) 2.58 (s, 3H) 3.80 (s, 3H) 3.90 (q, J=7.2Hz, 2H) 5.77 (d, J=7.2Hz, 1H) 6.77 (d, J=8.8Hz, 1H) 6.83 (d, J=8.8Hz, 2H) 7.12-7.17 (m, 3H) 7.81 (d, J=8.8Hz, 2H) 8.69 (d, J=4.8Hz, 2H)
[0329] (17g)
4-{[(3-ethoxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l H-[l,2,4]triazoI-3-yI)methyl]amino}benzamidine acetate [0330] [Chemical Formula 100]


To a solution of 70 mg of
5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen
ylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one in 3
ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was
added 70 mg of iron powder, and the mixture was stirred at 60°C for 14
hours under a nitrogen atmosphere. After filtering the reaction mixture,
it was purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid), to give 41 mg of the title
compound.
'H-NMR (CD3OD) 5 1.36 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 3.81 (s, 3H) 4.05
(q, J=7.2Hz, 2H) 5.57 (s, JH) 6.85 (d, J=8.8Hz, 2H) 6.95 (d, J=8.0Hz,
1H) 7.10 (dd, J=8.0,2.0Hz, 1H) 7.14 (d, J=2.0Hz, 1H) 7.30 (t, J=4.8Hz,
1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 461 (M+H)+
[0331] (17h) (R) and
(S)-4-{[(3-ethoxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydr
o-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0332] [Chemical Formula 101]

A SUMICHIRAL OA-2500 column was used for optical resolution of 250
mg of
4-{[(3-ethoxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l
H-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first eluting enantiomer (103 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.33 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 3.80 (s, 3H) 4.00 (q, J=7.2Hz, 2H) 5.60 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.95 (d, J=8.0Hz, 1H) 7.10 (dd, J=8.0,2.0Hz, 1H) 7.14 (d, J=2.0Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0333] Example 18j £R) and
(SV4-{[(4-ethoxv-3-methoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdr o-lH-[1.2.41triazol-3-vl)methyl]amino}benzamidine acetate [0334] (18a)
(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxa diazol-3-yl)phenylamino]acetonitrile

After adding 3.12 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,
3.3 g of MS3A, 1.11 g of Yb(OTf)3 and 4.75 ml of trimethylsilyl cyanide
to a solution of 5.0 g of
4-t-butyldimethylsilanyloxy-3-methoxybenzaldehyde [CAS
No.69404-94-0] in 98 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 23 hours. Next, 500 ml of ethyl acetate was added to the reaction mixture, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.45 g) as a crude product.

'H-NMR (CDCI3) 5 0.19 (s, 6H) 1.01 (s, 9H) 2.64 (s, 3H) 3.85 (s, 3H) 4.30 (d, J=8.0Hz, 1H) 5.40 (d, J=8.0Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 6.91 (d, J=8.0Hz, 1H) 7.03-7.08 (m, 2H) 7.98 (d, J=8.8Hz, 2H) [0336] (18b)
2-(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylamino]thioacetamide

After adding 32 ml of a 20% aqueous solution of ammonium sulfide to a
solution of 8.45 g of
(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxa diazol-3-yl)phenylamino]acetonitrile in 300 ml of a methanol:THF = 2:1 mixed solvent, the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.26 g) as a crude product. 'H-NMR (CDCb) 5 0.16 (s, 6H) 0.99 (s, 9H) 2.62 (s, 3H) 3.80 (s, 3H) 4.94 (d, J=2.4Hz, 1H) 5.10 (d, J=2.4Hz, 1H) 6.72 (d, J=8.8Hz, 2H) 6.84 (d, J=8.0Hz, 1H) 6.90-6.93 (m, 2H) 7.90 (d, J=8.8Hz, 2H) [0338] (18c)
{2-(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0339] [Chemical Formula 104]


After adding 2.89 g of Me30+BF4" to a solution of 8.26 g of 2-(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylamino]thioacetamide in 400 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 300 ml of toluene there were added 8.28 ml of 2,4,6-collidine and 4.15 ml of methyl chloroformate, and the mixture was stirred at 80°C for 14 hours under a nitrogen atmosphere. After cooling the reaction mixture, dilute hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.11 g, isomeric mixture) as a light yellow oil. 'H-NMR (CDC13) Main isomer:
8 0.19 (s, 6H) 1.00 (s, 9H) 2.31 (s, 3H) 2.65 (s, 3H) 3.59 (s, 3H) 3.87 (s, 3H) 6.86 (d, J=8.4Hz, 2H) 7.18-7.20 (m, 2H) 7.54 (d, J=2.0Hz, 1H) 8.00 (d, J=8.4Hz, 2H) [0340] (18d)
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0341] [Chemical Formula 105]


After dissolving 2.62 g of
2-(4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 52 ml of THF, 4.96 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.87 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDC13) Main isomer:
5 2.31 (s, 3H) 2.65 (s, 3H) 3.62 (s, 3H) 3.97 (s, 3H) 6.93 (d, J=8.0Hz, 1H) 7.16 (d, J=8.4Hz, 2H) 7.23 (br.d, J=8.0Hz, 1H) 7.59 (br.s, 1H) 8.00 (d, J=8.4Hz, 2H) [0342] (18e)
{2-(4-ethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester [0343] [Chemical Formula 106]

After dissolving 500 mg of
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 314 mg of potassium carbonate and 118 ul of iodoethane

were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (435 mg, isomeric mixture) as a light yellow solid. 'H-NMR (CDCb) Main isomer:
8 1.51 (t, J=6.8Hz, 3H) 2.32 (s, 3H) 2.65 (s, 3H) 3.62 (s, 3H) 3.95 (s, 3H) 4.15 (q, J=6.8Hz, 2H) 6.88 (d, J=8.8Hz, 1H) 7.19 (d, J=8.8Hz, 2H) 7.30 (dd, J=8.8,2.0Hz, 1H) 7.59 (d, J=2.0Hz, 1H) 8.02 (d, J=8.8Hz, 2H) [0344] (18f)
5-{(4-ethoxy-3-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one [0345] [Chemical Formula 107]

After adding 102 mg of 2-hydrazinopyrimidine and 129 u,l of
triethylamine to a solution of 435 mg of
{2-(4-ethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the mixture was stirred at 85°C for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 20 ml of a methanolrTHF =1:1 mixed solvent. Next, 186 ul of acetic acid and 292 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 2 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and

the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (152 mg).
'H-NMR (CD3OD) 8 1.37 (t, J=7.2Hz, 3H) 2.57 (s, 3H) 3.83 (s, 3H) 4.03 (q, J=7.2Hz, 2H) 5.58 (s, 1H) 6.82 (d, J=8.8Hz, 2H) 6.93 (d, J=8.4Hz, 1H) 7.08 (dd, J=8.4,2.4Hz, 1H) 7.17 (d, J=2.4Hz, 1H) 7.34 (t, J=4.8Hz, 1H) 7.76 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) [0346] (18g)
4-{[(4-ethoxy-3-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l H-[l,2,4]triazol-3-yl)methyI]amino}benzamidine trifluoroacetate [0347] [Chemical Formula 108]

To a solution of 35 mg of
5-{(4-ethoxy-3-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen
ylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l ,2,4]triazol-3-one in 3
ml of a methanokwatenacetic acid = 1:1:1 mixed solvent there was
added 30 mg of iron powder, and the mixture was stirred at 55°C for 15
hours under a nitrogen atmosphere. After filtering the reaction mixture,
it was purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give 18.3 mg of the title
compound.
'H-NMR (CD3OD) 5 1.36 (t, J=7.2Hz, 3H) 3.81 (s, 3H) 4.02 (q, J=7.2Hz,
2H) 5.66 (s, 1H) 6.86 (d, J=7.6Hz, 1H) 6.93 (d, J=8.4Hz, 2H) 7.06 (br.d,
J=7.6Hz, 1H) 7.14 (br.s, 1H) 7.37 (br.s, 1H) 7.59 (d, J=8.4Hz, 2H) 8.77
(br.s, 2H)
Mass spectrum (ESI)m/z: 461 (M+H)+
[0348] (18h) (R) and

(S)-4-{[(4-ethoxy-3-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydr o-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0349] [Chemical Formula 109]

A SUMICHIRAL OA-2500 column was used for optical resolution of 75
mg of
4- {[(4-ethoxy-3 -methoxyphenyl)-(5-oxo-1 -pyrimidin-2-yl-4,5-dihydro-1 H-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (produced by the same procedure as in Example (18g), using 0.1% acetic acid instead of the 0.1% trifluoroacetic acid in Example (18g)), and the first eluting enantiomer (20 mg) of the title compound was obtained as a white solid. HPLC retention time: 12 min
[0350] Example L?J (R) and
rS't-dn-n-aminopvridin-vn-S-oxo.S-dihvdro-lH-riltriazol-S-vl]-(2-methoxy-6-methvlpvridin-4-vnmethvllamino)benzamidine acetate (19a) 2-methoxy-6-methylpyridine-4-carbaldehyde [0351] [Chemical Formula 110]
To a solution of 5.0 g of 2-chloro-6-methylisonicotinic acid [CAS No.25462-85-5] in 50 ml of toluene there was added 3.9 ml of thionyl chloride under a nitrogen atmosphere, and the mixture was stirred for 1 hour under reflux. After cooling the reaction mixture to 0°C, 30 ml of a methanoktoluene = 1:2 solvent mixture was added thereto at 0°C over a period of 10 minutes. The reaction mixture was then stirred for 1 hour under reflux under a nitrogen atmosphere. After cooling the reaction mixture to 0°C, saturated aqueous potassium carbonate was added thereto

and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in 10 ml of dioxane there was added
4.4 g of sodium methoxide, and the mixture was stirred for 2 hours under
reflux under a nitrogen atmosphere. The reaction mixture was cooled to
0°C, and then ethyl acetate and ice-cold water were added thereto and
extraction was performed with ethyl acetate. The organic layer was
washed with saturated brine and then dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give
2-methoxy-6-methylisonicotinic acid methyl ester (2.5 g) as a light
yellow oil.
To a solution of 2.5 g of this compound in 30 ml of THF there was added 0.53 g of lithium aluminum hydride at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 30 minutes. After adding 0.53 ml of water, 0.53 ml of 15% aqueous sodium hydroxide and an additional
1.5 ml of water to the reaction mixture, it was stirred at room
temperature for 30 minutes. The reaction mixture was filtered, and the
filtrate was concentrated under reduced pressure to give 2.4 g of a crude
product of (2-methoxy-6-methy]-pyridin-4-yl)methanol.
To 50 ml of dichloromethane containing 1.67 ml of oxalyl chloride there was added dropwise 1.36 ml of DMSO at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 30 minutes. Next, 10 ml of a dichloromethane solution containing (2-methoxy-6-methyl-pyridin-4-yl)methanol was added dropwise, and the mixture was stirred at -78°C for 30 minutes. After then adding 6.7 ml of triethylamine to the reaction mixture over a period of 10 minutes, the mixture was stirred for 30 minutes while raising the temperature from -78PC to room temperature. Water was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer

was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.9 g) as a light yellow oil. 'H-NMR (CDCI3) 8 2.53 (s, 3H) 3.97 (s, 3H) 6.93 (s, 1H) 7.13 (s, 1H) 9.96 (s, 1H) [0352] (19b)
{2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0353] [Chemical Formula 111]

After adding 1.08 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 2 g of MS3A, 1.15 g of Yb(OTf)3 and 1.65 ml of trimethylsilyl cyanide to a solution of 0.93 g of 2-methoxy-6-methylpyridine-4-carbaldehyde in 20 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture which was then filtered through celite, and the celite was washed with ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 20 ml of a methanohTHF =1:1 mixed solvent there was added 10.5 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 150 minutes. Water was added to the reaction mixture, and after stirring at room temperature for 15 minutes, the precipitate was filtered out. The filtered solid was washed with water and heptane to give 2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylimino]thioacetamide (2.3 g) as a white solid.

To a solution of 2.0 g of this compound in 40 ml of acetonitrile there was added 841 mg of Me30+BF4" under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the obtained residue in 70 ml of ethyl acetate there was added 7.95 g of manganese dioxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To a solution of the residue in 50 ml of toluene there were added 2.15 ml of 2,4,6-collidine and 0.84 ml of methyl chloroformate, and the mixture was stirred at 80°C for 8 hours under a nitrogen atmosphere. After cooling the reaction mixture, dilute hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.35 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDC13) Main isomer:
5 2.34 (s, 3H) 2.51 (s, 3H) 2.65 (s, 3H) 3.65 (s, 3H) 3.95 (s, 3H) 6.88 (d, J=0.8Hz, 1H) 7.13 (d, J=8.8Hz, 2H) 7.21 (d, J=0.8Hz, 1H) 8.02 (d, J=8.8Hz, 2H) [0354] (19c)
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-( 2-methoxy-6-methylpyridin-4-yI)methyl}amino)benzamidine acetate [0355] [Chemical Formula 112]


After adding 32 mg of (3-nitropyridin-2-yl)hydrazine [CAS
No.15367-16-5] and 29 ul of triethylamine to a solution of 90 mg of
{2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
in 3 ml of DMF, the mixture was stirred at 85°C for 16 hours under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 2 ml of a methanohTHF =1:1 mixed solvent.
After adding 42 ui of acetic acid and 64 mg of sodium
cyanotrihydroborate to the reaction mixture, it was stirred at room
temperature for 4 hours. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
2-(3-nitropyridin-2-yl)-5-{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[l,2,4]triazol -3-one (30 mg).
To a solution of this compound in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 80 mg of iron powder, and the mixture was stirred at 55°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid), to give 20 mg of the title compound.
'H-NMR (CD3OD) 8 1.95 (s, 3H) 2.42 (s, 3H) 3.87 (s, 3H) 5.69 (s, 1H) 6.77 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.98 (s, 1H) 7.23 (dd, J=8.O,4.0Hz, 1H) 7.33 (d, J=8.0Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 7.82 (d, J=4.0Hz, 1H) Mass spectrum (ESI)m/z: 446 (M+H)+
[0356] (19d) (R) and
(S)-4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(2-methoxy-6-methylpyridin-4-yl)methyl}amino)benzamidine acetate


A SUMICHIRAL OA-2500 column was used for optical resolution of 20
mg of
4-( {[ 1 -(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-l H-[ 1,2,4]triazol-3-yl]-( 2-methoxy-6-methylpyridin-4-yl)methyl} amino)benzamidine acetate, and the first eluting enantiomer (7.5 mg) of the title compound was obtained. HPLC retention time: 7 min
[0358] Example 20j (R) and
(S)-4-{[("8-methoxv-2.3-dihvdro-benzon.41dioxin-6-vn-(5-oxo-l-pyrimi
din-2-yl-4.5-dihydro-lH-[1.2.4]triazol-3-vOmethvl]amino}benzamidine
acetate
[0359] (20a)
2-(8-methoxy-2,3-dihydro-benzo[l,4]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]
oxadiazol-3-yl)phenylamino]thioacetamide

After adding 890 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 987 mg of 8-methoxy-2,3-dihydro-benzo[l,4]dioxine-6-carbaldehyde [CAS No.75889-54-2], 1 g of MS3A and 1.4 ml of trimethylsilyl cyanide to a solution of 315 mg of Yb(OTf)3 in 15 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure. After adding 3 ml of a 20% aqueous solution of ammonium sulfide to a

solution of the residue in 9 ml of an ethanol:THF = 2:1 mixed solvent, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.92 g). 'H-NMR (d6-DMSO) 8 2.59 (s, 3H) 3.28 (s, 3H) 3.73 (s, 2H) 4.18 (s, 2H) 5.09 (d, J=6.0Hz, 1H) 6.64 (d, J=6.0Hz, 1H) 6.67 (d, J=2.0Hz, 1H) 6.72 (d, J=8.8Hz, 2H) 6.80 (d, J=1.6Hz, 1H) 7.68 (d, J=8.4Hz, 2H) 9.49 (br.s, 1H) 9.75 (br.s, 1H)
[0361] (20b) (R) and
(S)-4-{[(8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-(5-oxo-l-pyrimid in-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate

After adding 750 mg of Me30+BF4" to a solution of 1.92 g of
2-(8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]o
xadiazol-3-yl)phenylamino]thioacetamide in 20 ml of acetonitrile, the
mixture was stirred overnight at room temperature. Saturated aqueous
sodium hydrogencarbonate was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off, and the filtrate was concentrated under reduced pressure to
give
2-(8-methoxy-2,3-dihydrobenzo[ 1,4]dioxin-6-yl)-2-[4-(5-methyl-[ 1,2,4]o
xadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
After adding 10 g of manganese dioxide to a solution of this compound

in 100 ml of ethyl acetate, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 40 ml of toluene there were added 2 ml of
2,4,6-collidine and 1 ml of methyl chloroformate, and the mixture was
stirred at 80°C for 2 hours under a nitrogen atmosphere. After cooling
the reaction mixture, IN hydrochloric acid was added and extraction was
performed with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give
{2-(8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yI)-2-[4-(5-methyl-[ 1,2,4] oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (343 mg) as a yellow solid.
To a solution of 343 mg of this compound in 4 ml of DMF there were
added 68 mg of 2-hydrazinopyrimidine and 0.1 ml of triethylamine, and
the mixture was stirred overnight at 85°C under a nitrogen atmosphere.
The reaction mixture was concentrated, and the residue was dissolved in
5 ml of methanol and 0.5 ml of acetic acid. After adding 0.5 g of
sodium cyanotrihydroborate to this solution, the mixture was stirred at
room temperature for 1 hour. Water was added to the reaction mixture
and extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{(8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-methyl-[l,2,4]ox adiazol-3-yl)phenylamino]methyl} -2-pyrimidin-2-yl-2,4-dihydro-[ 1,2,4]t riazol-3-one (91 mg) as a light yellow solid.
To a solution of 91 mg of this compound in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred overnight at 60°C under a

nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-(5-oxo-l-pyrimidin-2
-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine
acetate (50 mg).
Mass spectrum (ESI)m/z: 475 (M+H)+
50 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (21.4 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.75 (s, 3H) 4.16-4.20 (m, 4H) 5.54 (s,
1H) 6.68 (d, J=2.0Hz, 1H) 6.74 (d, J=2.0Hz, 1H) 6.83 (d, J=9.2Hz, 2H)
7.29 (t, J=4.4Hz, 1H) 7.58 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 26 min (Column name: SUMICHIRAL OA-2500,
30 mmq> x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 15 ml/min)
[0363] Example 2Jj (R) and
(S)-4-{[(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-vl-4.5-dihvdro-lH-|"1.2.41triazol-3-yl)methvnamino)benzamidine acetate [0364] (21a) 4-bromo-2-hydroxymethyl-6-methoxyphenol [0365] [Chemical Formula 116]

To a solution of 50 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde in 200 ml of an ethanol:THF = 1:1 mixed solvent there was added 16.4 g of sodium borohydride while cooling on ice. After stirring at room temperature for 2 hours, IN hydrochloric acid was added to the reaction mixture while cooling on ice. The organic layer was washed with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (50 g) as a crude product.

[0366] (21b) 6-bromo-8-methoxy-4H-benzo-[l,3]dioxine [0367] [Chemical Formula 117]

To a solution of the 50 g of 4-bromo-2-hydroxymethyl-6-methoxyphenol in 450 ml of DMF there was added 20 g of sodium hydride (60% oily suspension) while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 15 ml of bromochloromethane and 3.2 g of sodium iodide to the reaction mixture, it was stirred at 80°C for 6 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (31.2 g) as a white solid.
'H-NMR (CDC13) 5 3.87 (s, 3H) 4.85 (s, 2H) 5.28 (s, 2H) 6.73 (s, 1H) 6.88 (s, 1H)
[0368] (21c) 8-methoxy-4H-benzo[l,3]dioxine-6-carbaldehyde [0369] [Chemical Formula 118]

To a solution of 31.2 g of 6-bromo-8-methoxy-4H-benzo[l,3]dioxine in 500 ml of THF there was added dropwise 55 ml of n-butyllithium (2.55 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -72°C for 30 minutes, 20 ml of N-formylmorpholine was added and the temperature was raised from -78°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The

organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound
(21.28 g) as a white solid.
'H-NMR (CDCb) 5 3.95 (s, 3H) 4.95 (s, 2H) 5.37 (s, 2H) 7.13 (dd,
J=0.8,2.0Hz, 1H) 7.31 (d, J=2.0Hz, 1H) 9.82 (s, 1H)
[0370] (2Id)
(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylamino]acetonitrile
[0371] [Chemical Formula 119]

To a solution of 3.5 g of Yb(OTf)3 in 250 ml of THF there were added 9.8 g of 4-(5-methyl-[l,2,4]oxadiazo]-3-yI)phenylamine, 10.8 g of 8-methoxy-4H-benzo[l,3]dioxine-6-carbaldehyde, 10 g of MS3A and 15 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 1000 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (29.2 g, crude product) as a light yellow solid.
'H-NMR (CDCb) 5 2.64 (s, 3H) 3.92 (s, 3H) 4.28 (br.s, 1H) 4.92 (s, 2H) 5.34 (s, 2H) 5.40 (br.d, J=6.0 Hz, 1H) 6.80-6.90 (m, 3H) 6.94 (br.s, 1H) 7.98 (br.d, J=7.2Hz, 2H) [0372] (21e)
2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylamino]thioacetamide [0373] [Chemical Formula 120]


After adding 90 ml of a 20% aqueous solution of ammonium sulfide to a
solution of 29.2 g of a crude
(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 240 ml of an ethanohTHF = 2:1 mixed solvent, the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (28.2 g, crude product) as a light yellow solid.
-NMR (CDC13) 8 2.62 (s, 3H) 3.89 (s, 3H) 4.89 (s, 2H) 5.11 (s, 1H) 5.30 (s, 2H) 6.69 (d, J=2.0Hz, 1H) 6.74 (d, J=8.8Hz, 2H) 6.84 (d, J=1.6Hz, 1H) 7.58 (br.d, J=4.8Hz, 1H) 7.91 (d, J=8.4Hz, 2H) 8.13 (br.d, J=4.8Hz, 1H) [0374] (2If)
2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylamino]thioacetimidic acid methyl ester [0375] [Chemical Formula 121]

After adding 10.6 g of Me30+BF4~ to a solution of 28.2 g of a crude
product of
2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylamino]thioacetamide in 100 ml of acetonitrile, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate was added to the reaction

mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (27.2 g, crude product) as a light yellow solid.
'H-NMR (CDCb) 5 2.35 (s, 3H) 2.61 (s, 3H) 3.89 (s, 3H) 4.88 (s, 2H) 4.98 (br.s, 1H) 5.29 (s, 2H) 6.64 (d, J=8.8Hz, 2H) 6.69 (s, 1H) 6.86 (s, 1H) 7.85 (d, J=8.8Hz, 2H) [0376] (21g)
2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylimino]thioacetimidic acid methyl ester [0377] [Chemical Formula 122]

After adding 100 g of manganese dioxide to a solution of 27.2 g of the
crude product of
2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo
l-3-yl)phenylamino]thioacetimidic acid methyl ester in 100 ml of ethyl
acetate, the mixture was stirred at room temperature for 1 hour. The
reaction mixture was filtered through celite, and the filtrate was
concentrated under reduced pressure to give the title compound (23.8 g,
crude product) as a brown solid.
'H-NMR (CDCb) 5 2.26 (s, 3H) 2.65 (s, 3H) 3.96 (s, 3H) 4.92 (s, 2H)
5.36 (s, 2H) 6.45 (br.s, 1H) 7.02 (d, J=8.8Hz, 2H) 7.06 (br.s, 1H) 7.52 (d,
J=1.6Hz, 1H) 7.99 (d, J=8.8Hz, 2H)
[0378] (21h)
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-1 -methylsulfanylethylidene]carbamic acid methyl
ester
[0379] [Chemical Formula 123]


To a solution of 23.8 g of the crude product of 2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylimino]thioacetimidic acid methyl ester in 100 ml of toluene there were added 32 ml of 2,4,6-collidine and 15 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.98 g) as a yellow solid.
'H-NMR (CDC13) 5 2.33 (s, 3H) 2.65 (s, 3H) 3.65 (s, 3H) 3.95 (s, 3H) 4.91 (s, 2H) 5.36 (s, 2H) 7.00 (d, J=1.6Hz, 1H) 7.17 (d, J=8.4Hz, 2H) 7.46 (br.s, 1H) 8.01 (d, J=8.4Hz, 2H) [0380] (21 i)
5-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one

To a solution of 6.02 g of
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz

ol-3-yl)phenyIimino]-l -methylsulfanylethylidene]carbamic acid methyl ester in 50 ml of DMF there were added 1.24 g of 2-hydrazinopyrimidine and 1.9 ml of triethylamine, and the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 50 ml of methanol and 5 ml of acetic acid. After then adding 3.4 g of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (3.317 g) as a light yellow solid. 'H-NMR (CDC13) 5 2.59 (s, 3H) 3.72 (s, 3H) 4.69 (q, J=14.8Hz, 2H) 5.21 (s, 2H) 5.76 (br.d, J=7.6Hz, 1H) 6.37 (br.s, 1H) 6.79 (d, J=8.4Hz, 2H) 6.84 (s, 1H) 7.07 (s, 1H) 7.19 (t, J=4.8Hz, 1H) 7.79 (d, J=8.8Hz, 2H) 8.68 (d, J=4.8Hz, 2H) 11.17 (br.s, 1H) [0382] (21j)
4-{[(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0383] [Chemical Formula 125]

To a solution of 814 mg of
5-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one in 15 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 1 g of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After adding 7.5 ml of

a methanol:water:acetic acid = 1:1:1 mixed solvent to the reaction
mixture, the mixture was further stirred at 60°C for 5 hours. After
filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give the title compound (476 mg).
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.79 (s, 3H) 4.82 (m, 2H) 5.21 (s, 2H)
5.60 (s, 1H) 6.80 (s, 1H) 6.85 (d, J=8.4Hz, 2H) 7.04 (s, 1H) 7.32 (t,
J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 475 (M+H)+
[0384] (21k) (R) and
(S)-4-{[(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-
4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0385] [Chemical Formula 126]

A SUM1CHIRAL OA-2500 column was used for optical resolution of 120
mg of
4- {[(8-methoxy-4H-benzo[ 1,3]dioxin-6-yl)-(5-oxo-1 -pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and
the first eluting enantiomer (47 mg) of the title compound was obtained
as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.81 (s, 3H) 4.84 (m, 2H) 5.21 (s, 2H)
5.56 (s, 1H) 6.81 (d, J=1.6Hz, 1H) 6.84 (d, J=8.4Hz, 2H) 7.05 (d,
J=1.6Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d,
J=4.8Hz, 2H)
HPLC retention time: 17 min
[0386] Example 22j (R) and
(S)-4-{[(3,4-dimethoxv-5-methoxvmethvl-phenvl)-(5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH-[1.2.41triazol-3-vl)methvllamino}benzamidine acetate

[0387] (22a)
3,4-dimethoxy-5-triisopropylsilanyloxymethylbenzaldehyde [0388] [Chemical Formula 127]

To a solution of 2.3 g of 5-bromo-2,3-dimethoxybenzaldehyde [CAS
No.71295-21-1] in 40 ml of an ethanol:THF = 1:1 mixed solvent there
was added 1 g of sodium borohydride while cooling on ice, and the
mixture was stirred at room temperature for 3 hours. Next, IN
hydrochloric acid was added to the reaction mixture and extraction was
performed with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure.
The residue was dissolved in 20 ml of DMF, and then 1.5 g of imidazole
and 2.4 ml of chlorotriisopropylsilane were added and the mixture was
stirred overnight at room temperature. Next, IN hydrochloric acid was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give
(5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane (3.616 g) as an oil.
To a solution of the 3.616 g of
(5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at -78°C under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was

concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give the title
compound (2.605 g) as an oil.
'H-NMR (CDCb) 5 1.12 (d, J=6.8Hz, 18H) 1.17-1.26 (m, 3H) 3.91 (s,
3H) 3.92 (s, 3H) 4.88 (s, 2H) 7.37 (d, J=2.0Hz, 1H) 7.69 (d, J=2.0Hz,
1H) 9.89 (s, 1H)
[0389] (22b)
[2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadia
zol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl
ester
[0390] [Chemical Formula 128]

After adding 1.3 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 2.605 g of 3,4-dimethoxy-5-triisopropylsilanyloxymethylbenzaldehyde, 2.2 g of MS3A and 1.5 ml of trimethylsilyl cyanide to a solution of 460 mg of Yb(OTf)3 in 18 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (3,4-dimethoxy-5-triisopropylsilanyloxymethylphenyl)-[4-(5-methyl-[l,2 ,4]oxadiazol-3-yl)phenylamino]acetonitrile.
To a solution of this compound in 45 ml of an ethanohTHF = 2:1 mixed solvent there was added 15 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product

of
2-(3,4-dimethoxy-5-triisopropylsilanyloxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (3.79 g). To a solution of 2.605 g of this compound in 40 ml of dichloromethane there was added 1.3 g of Me30+BF4_, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 100 ml of dichloromethane there was
added 6 g of manganese dioxide, and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was filtered through
celite, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 50 ml of toluene there were added 5 ml of
2,4,6-collidine and 2.5 ml of methyl chloroformate, and the mixture was
stirred overnight at 85°C under a nitrogen atmosphere. After cooling
the reaction mixture, IN hydrochloric acid was added and extraction was
performed with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give
[2-(3,4-dimethoxy-5-triisopropylsilanyloxymethyl-phenyl)-2-[4-(5-methy l-[l,2,4]oxadiazol-3-yl)-phenylimino]-l-methylsulfanylethylidene]carba mic acid methyl ester (2.03 g, isomeric mixture) as a yellow solid. After dissolving 2.03 g of this compound in 50 ml of THF, 3.7 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by

silica gel column chromatography (ethyl acetate-heptane) to give the title
compound (1.41 g, isomeric mixture) as a light yellow solid.
Mass spectrum (ESI)m/z: 485 (M+H)+
[0391] (22c)
[2-(3,4-dimethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid
methyl ester
[0392] [Chemical Formula 129]

After dissolving 322 mg of
[2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenyIimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of dichloromethane, 364 mg of 1,8-bis (dimethylamino)naphthalene and 240 mg of Me30+BF4_ were added and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (169 mg, isomeric mixture) as a light yellow solid.
'H-NMR (CDC13) 8 2.33 (s, 3H) 2.65 (s, 3H) 3.40 (s, 3H) 3.62 (s, 3H)
3.91 (s, 3H) 3.93 (s, 3H) 4.51 (s, 2H) 7.17 (d, J=8.0Hz, 2H) 7.36 (br.d,
J=2.0Hz, 1H) 7.56 (d, J=2.4Hz, 1H) 8.10 (d, J=8.0Hz, 2H)
[0393] (22d) (R) and
(S)-4-{[(3,4-dimethoxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-y l-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0394] [Chemical Formula 130]


To a solution of 169 mg of
[2-(3,4-dimethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid
methyl ester in 2 ml of DMF there were added 40 mg of
2-hydrazinopyrimidine and 50 u,l of triethylamine, and the mixture was
stirred overnight at 85°C under a nitrogen atmosphere. The reaction
mixture was concentrated, and the residue was dissolved in 3 ml of
methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium
cyanotrihydroborate to the solution, the mixture was stirred at room
temperature for 1 hour. Water was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{(3,4-dimethoxy-5-methoxymethylphenyl)-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol -3-one (89 mg) as a light brown solid.
To a solution of 89 mg of this compound in 4.5 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After further adding 150 mg of iron powder, the mixture was stirred at 60°C for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{[(3,4-dimethoxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (38

mg).
Mass spectrum (ESI)m/z: 491 (M+H)+
38 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (16.9 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.35 (s, 3H) 3.77 (s, 3H) 3.84 (s, 3H)
4.45 (s, 2H) 5.62 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.16 (d, J=1.6Hz, 1H)
7.20 (d, J=1.6Hz, 1H) 7.30 (t, J=4.4Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.77
(d, J=5.2Hz, 2H)
HPLC retention time: 13 min
[0395] Example 23i
4-{rf5-hydroxymethvl-3.4-dimethoxvphenyl)-f5-oxo-l-pyrimidin-2-yl-4, 5-dihvdro-lH-[1.2.4]triazol-3-vl)methvnaminolbenzamidine acetate [0396] [Chemical Formula 131]

To a solution of 114 mg of
[2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenyIimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)) in 2 ml of DMF there were added 25 mg of 2-hydrazinopyrimidine and 35 ul of triethylamine, and the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.

The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{(5-hydroxymethyl-3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol
-3-one (51 mg) as a light brown solid.
To a solution of 51 mg of this compound in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 50 mg
of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give the title compound (13.5
mg).
'H-NMR (d6-DMSO) 5 1.82 (s, 3H) 3.65 (s, 3H) 3.76 (s, 3H) 4.45 (s, 2H)
5.15 (br.s, 1H) 5.36 (d, J=6.8Hz, 1H) 6.82 (d, J=8.4Hz, 2H) 7.10 (t,
J=4.8Hz, 1H) 7.15 (s, 1H) 7.26 (d, J=7.2Hz, 1H) 7.53 (d, J=8.8Hz, 2H)
8.62 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 477 (M+H)+
[0397] Example 24j (R) and
fS)-4-{[(8-methoxvchroman-6-yl)-(5-oxo-l-pyrimidin-2-vl-4.5-dihvdro-l H-[l .2.41triazol-3-vl)methvl]amino)benzamidine acetate [0398] (24a)
{2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0399] [Chemical Formula 132]

After adding 700 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 770 mg of 8-methoxychromane-6-carbaldehyde [CAS No.81258-23-3], 1 g of MS3A and 1.1 ml of trimethylsilyl cyanide to a solution of 250 mg of Yb(OTf>3 in 5 ml of dichloromethane under a nitrogen atmosphere, the

mixture was stirred overnight at room temperature. The reaction
mixture was filtered through celite, and the celite was washed with 100
ml of ethyl acetate. The organic layer was concentrated under reduced
pressure to give a crude product of
(8-methoxychroman-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylami nojacetonitrile.
To a solution of this compound in 12 ml of an ethanol:THF = 4:1 mixed
solvent there was added 6 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred at 50°C for 4 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give
2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyl amino]thioacetamide (1.91 g, crude product).
To a solution of 1.91 g of this compound in 10 ml of dichloromethane
there was added 719 mg of Me30+BF4~, and the mixture was stirred at
room temperature for 1 hour. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 10 g of manganese dioxide to a solution of the residue in 10 ml of ethyl acetate, the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 30 ml of toluene there were added 2.4 ml of 2,4,6-collidine and 1.2 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give the title compound (960 mg, isomeric mixture)
as a yellow solid.
Mass spectrum (ESI)m/z: 481 (M+H)+
[0400] (24b) (R) and
(S)-4-{[(8-methoxychroman-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l
H-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0401] [Chemical Formula 133]

To a solution of 281 mg of
{2-(8-methoxychroman-6-yI)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yI)phen
ylirnino]-l-rnethylsulfanyl-ethylidene}carbamic acid methyl ester in 2 ml
of DMF there were added 58 mg of 2-hydrazinopyrimidine and 130 ul of
triethylamine, and the mixture was stirred overnight at 85°C under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 8.75 ml of a methanohacetic acid =10:1 mixed
solvent. After adding 265 mg of sodium cyanotrihydroborate to the
reaction mixture, the mixture was stirred at room temperature for 1 hour.
Water was added to the reaction mixture and extraction was performed
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyla mino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one. To a solution of this compound in 8 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 265 mg of iron powder, and the

mixture was stirred overnight at 60°C under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{[(8-methoxychroman-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[
l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (88 mg).
Mass spectrum (ESI)m/z: 473 (M+H)+
88 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (44 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.90 (s, 3H) 1.95-1.99 (m, 2H) 2.75 (t, J=6.4Hz,
2H) 3.78 (s, 3H) 4.16 (t, J=5.2Hz, 2H) 5.46 (s, 1H) 6.83 (d, J=8.8Hz, 2H)
6.85 (d, J=1.2Hz, 1H) 6.97 (d, J=2.4Hz, 1H) 7.25 (t, J=5.2Hz, 1H) 7.57
(d, J=9.2Hz, 2H) 8.74 (d, J=5.2Hz, 2H)
HPLC retention time: 15 min
[0402] Example 25:
4-({[3-n-hvdroxvethvl)-4.5-dimethoxvphenyl1-f5-oxo-1-pvrimidin-2-yl-4.5-dihvdro-lH-|"1.2.41triazol-3-vl)methvUamino)benzamidine acetate [0403] (25a)
3,4-dimethoxy-5-(l-triisopropylsilanyloxyethyl)benzaldehyde [0404] [Chemical Formula 134]

To a solution of 4 g of 5-bromo-2,3-dimethoxybenzaldehyde in 75 ml of THF there was added dropwise 20 ml of methylmagnesium bromide (0.93 M, THF solution) under a nitrogen atmosphere. After stirring at room temperature for 1 hour, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.

The residue was dissolved in DMF, and then imidazole and chlorotriisopropylsilane were added and the mixture was stirred at room temperature overnight and at 60°C for 3 hours. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give [l-(5-bromo-2,3-dimethoxyphenyl)ethoxy]triisopropylsilane (5.423 g) as an oil.
To a solution of 5.423 g of this compound in 60 ml of THF there was added dropwise 5.3 ml of n-butyllithium (2.66 M, hexane solution) at -78°C under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.348 g) as an oil.
'H-NMR (CDC13) 5 1.01 (d, J=7.2Hz, 9H) 1.05 (d, J=6.4Hz, 9H) 1.06-1.16 (m, 3H) 1.41 (d, J=6.0Hz, 3H) 3.92 (s, 6H) 5.32 (dd, J=6.4, 12.4Hz, 1H) 7.34 (d, J=2.0Hz, 1H) 7.74 (d, J=2.0Hz, IH) 9.88 (s, 1H) [0405] (25b)
{2-[3-(l-hydroxyethyl)-4,5-dimethoxyphenyl]-2-[4-(5-methyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester [0406] [Chemical Formula 135]


After adding 0.99 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 2.607 g of 3,4-dimethoxy-5-(l-triisopropylsilanyloxyethyl)benzaldehyde, 1.7 g of MS3A and 1.6 ml of trimethylsilyl cyanide to a solution of 350 mg of Yb(OTf)3 in 14 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of [3,4-dimethoxy-5-(l-triisopropylsilanyloxyethyl)phenyl]-[4-(5-methyl-[l ,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
To a solution of this compound in 45 ml of an ethanol:THF = 2:1 mixed solvent there was added 15 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[3,4-dimethoxy-5-(l-triisopropylsilanyloxyethyl)phenyl]-2-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (4.8 g, crude product).
To a solution of 4.8 g of this compound in 40 ml of dichloromethane there was added 1 g of Me30+BF4-, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 154 ml of dichloromethane there was

added 7 g of manganese dioxide, and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was filtered through
celite, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 40 ml of toluene there were added 2.2 ml
of 2,4,6-collidine and 1.1 ml of methyl chloroformate, and the mixture
was stirred overnight at 85°C under a nitrogen atmosphere. After
cooling the reaction mixture, IN hydrochloric acid was added and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
{2-[3,4-dimethoxy-5-(l-triisopropylsilanyloxyethyl)phenyl]-2-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb amic acid methyl ester (336 mg, isomeric mixture) as a yellow solid. 336 mg of this compound was dissolved in 8 ml of THF, and then 0.65 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (132 mg, isomeric mixture) as a light yellow solid.
Mass spectrum (ESI)m/z: 499 (M+H)+ [0407] (25c)
4-({[3-(l-hydroxyethyl)-4,5-dimethoxyphenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate [0408] [Chemical Formula 136]


After adding 22 mg of 2-hydrazinopyrimidine and 50 u.1 of triethylamine
to a solution of 112 mg of
{2-[3-(l-hydroxyethyl)-4,5-dimethoxyphenyl]-2-[4-(5-methyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{[3-(l-hydroxyethyl)-4,5-dimethoxyphenyl]-[4-(5-methyl-[l,2,4]oxadi azol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-4,5-dihydro-lH-[ 1,2,4] triazol-3-one (93 mg) as a light brown solid.
To a solution of 93 mg of this compound in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (35.7
mg)-
'H-NMR (CD3OD) 5 1.35, 1.40 (each d, J=6.4Hz, total 3H) 1.94 (s, 3H)
3.80 (s, 3H) 3.84, 3.86 (each s, total 3H) 5.14, 5.14 (each q, J=6.4Hz,
total 1H) 5.64, 5.66 (each s, total 1H) 6.87, 6.88 (each d, J=9.2Hz, total

2H) 7.12, 7.13 (each d, J=4.8Hz, total 1H) 7.26, 7.26 (each d, J=4.4Hz, total 1H) 7.34 (t, J=4.8Hz, 1H) 7.60, 7.61 (each d, J=8.4Hz, total 2H) 8.77, 8.78 (each d, J=4.8Hz, total 2H) Mass spectrum (ESl)m/z: 491 (M+H)+
[0409] Example 26] (R) and
(S)-4- {[(3 -cvanomethvl-4.5 -dimethoxvphenyl)-(5 -oxo-1 -pyrimidin-2-vl -
4.5-dihvdro-1 H-f 1.2.4]triazol-3-vl)methyl]amino} benzamidine acetate
[0410] (26a)
{2-(3-cyanomethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[0411] [Chemical Formula 137]

After dissolving 194 mg of
[2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)), 315 mg of triphenylphosphine and 0.11 ml of acetone cyanohydrin in 4 ml of THF under a nitrogen atmosphere, the solution was cooled to -78°C. Next, 0.23 ml of diisopropyl azodicarboxylate (hereinafter, "DIAD") was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (197 mg, isomeric mixture) as a light yellow solid. Mass spectrum (ESI)m/z: 494 (M+H)+
[0412] (26b) (R) and
(S)-4-{[(3-cyanomethyl-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0413] [Chemical Formula 138]


After adding 30 mg of 2-hydrazinopyrimidine and 50 u.1 of triethylamine
to a solution of 152 mg of
{2-(cyanomethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester in 2 ml of DMF, the mixture was stirred overnight at 85°C under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid.
After adding 100 mg of sodium cyanotrihydroborate to the solution, the
mixture was stirred at room temperature for 1 hour. Water was added to
the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by NAM silica gel column
chromatography (methanol-ethyl acetate) to give
(2,3-dimethoxy-5-{[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}phenyl) acetonitrile (72 mg) as a light brown solid.
To a solution of 72 mg of this compound in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(3-cyanomethyI-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yI-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (48 mg). Mass spectrum (ESI)m/z: 486 (M+H)+

48 mg of this compound was optically resolved using a SUM1CHIRAL
OA-2500 column, and the first eluting enantiomer (19.3 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.77 (s, 2H) 3.86 (s, 6H) 5.60 (s, 1H)
6.85 (d, J=8.8Hz, 2H) 7.13 (d, J=2.0Hz, 1H) 7.24 (d, J=2.4Hz, 1H) 7.28
(t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.75 (d, J=4.4Hz, 2H)
HPLC retention time: 12 min
[0414] Example 27: (R) and
CS)-4-(rr8-ethvl-4H-benzon.31dioxin-6-vl)-r5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH41.2,4]triazol-3-vl)methvl]amino)benzamidine acetate [0415] (27a) 8-ethyl-4H-benzo[l,3]dioxine-6-carbaldehyde [0416] [Chemical Formula 139]

To a solution of 1.88 g of 5-bromo-3-ethyl-2-hydroxybenzaldehyde in 40 ml of an ethanolrTHF = 1:1 mixed solvent there was added 1 g of sodium borohydride while cooling on ice. After stirring at room temperature for 2 hours, IN hydrochloric acid was added to the reaction mixture while cooling on ice. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 4-bromo-8-ethyl-6-hydroxymethylphenol as a white solid.
After adding 0.83 g of sodium hydride (60% oily suspension) to a solution of 1.91 g of this compound in 30 ml of DMF while cooling on ice, the mixture was stirred at room temperature for 30 minutes. After then adding 0.67 ml of bromochloromethane and 0.25 g of sodium iodide to the reaction mixture, it was stirred at 80°C for 6 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The

desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
6-bromo-8-ethyl-4H-benzo[l,3]dioxine (1.50 g).
To a solution of 1.50 g of this compound in 30 ml of THF there was added dropwise 4.5 ml of n-butyllithium (1.58 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -70°C for 30 minutes, 1 ml of N-formylmorpholine was added and the temperature was raised from -70°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (871 mg). [0417] (27b)
[2-(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester [0418] [Chemical Formula 140]

After adding 794 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 871 mg of 8-ethyl-4H-benzo[l,3]dioxine-6-carbaldehyde, 1 g of MS3A and 1 ml of trimethylsilyl cyanide to a solution of 281 mg of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give (8-ethyl-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p

henylamino]acetonitrile(crude product) as a light yellow solid. To a solution of this compound in 45 ml of an ethanol:THF = 2:1 mixed solvent there was added 15 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of
2-(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide.
After adding 0.8 g of Me30+BF4_ to a solution of this compound in 30 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 4 g of manganese dioxide to a solution of the residue in ethyl acetate, the mixture was stirred at room temperature for 1 hour. Next, 8 g of manganese dioxide was further added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 30 ml of toluene there were added 2 ml of 2,4,6-collidine and 1 ml of methyl chloroformate, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (773 mg) as a yellow solid.

Mass spectrum (ESI)m/z: 481 (M+H)+
[0419] (27c) (R) and
(S)-4-{[(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0420] [Chemical Formula 141]

To a solution of 101 mg of
[2-(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 21 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine, and the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-on e.
To a solution of this compound in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 70 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)

to give
4-{[(8-ethyI-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dih ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (26 mg). Mass spectrum (ESI)m/z: 473 (M+H)+
26 mg of this compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (9.7 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.13 (t, J=7.6Hz, 3H) 1.89 (s, 3H) 2.57 (q, J=7.6Hz, 2H) 4.82-4.90 (m, 2H) 5.22 (s, 2H) 5.49 (s, 1H) 6.83 (d, J=8.8Hz, 2H) 7.03 (br.s, 1H) 7.21 (br.s, 1H) 7.25 (t, J=5.2Hz, 1H) 7.58 (d, J=9.2Hz, • 2H) 8.74 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0421] Example 28] (R) and
(S)-4-(r(8-ethoxv-4H-benzo[1.3]dioxin-6-vD-(5-oxo-l-pvrimidin-2-yl-4, 5-dihydro-lH-[1.2,4]triazol-3-vl)methvl]amino}benzamidine acetate [0422] (28a) 8-ethoxy-4H-benzo[l,3]dioxine-6-carbaldehyde [0423] [Chemical Formula 142]

After adding 5.59 g of N-bromosuccinimide to a solution of 5.11 g of 3-ethoxy-2-hydroxybenzaldehyde in 100 ml of acetonitrile, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized using t-butyl methyl ether-heptane to give 5-bromo-3-ethoxy-2-hydroxybenzaldehyde (2.53 g). 1 H-NMR (CDCI3) 5 1.49 (t, J=7.2Hz, 3H) 4.11 (q, J=7.2Hz, 2H) 7.16 (d, J=2.4Hz, 1H) 7.29 (d, J=2.0Hz, 1H) 9.84 (s, 1H) 10.91 (s, 1H) To a solution of 2.53 g of this compound in 40 ml of an ethanohTHF =

1:1 mixed solvent there was added 1 g of sodium borohydride while cooling on ice. After stirring at room temperature for 3 hours, IN hydrochloric acid was added to the reaction mixture while cooling on ice. The organic layer was washed with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 4-bromo-8-ethoxy-6-hydroxymethylphenol.
To a solution of this compound in 40 ml of DMF there was added 1 g of
sodium hydride (60% oily suspension) while cooling on ice, and the
mixture was stirred at room temperature for 30 minutes. After then
adding 1 ml of bromochloromethane and 0.25 g of sodium iodide to the
reaction mixture, it was stirred at 80°C for 6 hours under a nitrogen
atmosphere. Saturated aqueous ammonium chloride was added to the
reaction mixture, and extraction was performed with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
6-bromo-8-ethoxy-4H-benzo[l,3]dioxine (1.62 g).
To a solution of 1.62 g of this compound in 30 ml of THF there was added dropwise 2.8 ml of n-butyllithium (2.62 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -70°C for 30 minutes, 1 ml of N-formylmorpholine was added and the temperature was raised from -70°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (773 mg). [0424] (28b)
{2-(8-ethoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl

ester
[0425] [Chemical Formula 143]

To a solution of 230 mg of Yb(OTf)3 in 20 ml of dichloromethane there
were added 650 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,
773 mg of 8-ethyl-4H-benzo[l,3]dioxine-6-carbaldehyde, 1 g of MS3A
and 0.8 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the
mixture was stirred overnight at room temperature. The reaction
mixture was filtered through celite, and the celite was washed with 100
ml of ethyl acetate. The organic layer was concentrated under reduced
pressure to give
(8-ethoxy-4H-benzo[l,3]dioxin-6-yI)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylamino]acetonitrile (crude product).
To a solution of this compound in an ethanol:THF = 2:1 mixed solvent
there was added a 20% aqueous solution of ammonium sulfide, and the
mixture was stirred overnight at room temperature. Water was added to
the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give
2-(8-ethoxy-4H-benzo[l,3]dioxin-6-yI)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (1.74 g, crude product). After adding 650 mg of Me30+BF4~ to a solution of 1.7 g of this compound in 40 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.

After adding manganese dioxide to a solution of the residue in ethyl acetate, the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in toluene there were added 2,4,6-collidine and methyl chloroformate, and the mixture was stirred at 80°C under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.7 g) as a yellow solid. Mass spectrum (ESI)m/z: 497 (M+H)+
[0426] (28c) (R) and
(S)-4-{[(8-ethoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0427] [Chemical Formula 144]

To a solution of 105 mg of
{2-(8-ethoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF there were added 20.9 mg of 2-hydrazinopyrimidine and 50 \i\ of triethylamine, and the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room

temperature for 1 hour. Water was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{(8-ethoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3 -yI)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one (46 mg).
To a solution of 46 mg of this compound in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 65 mg
of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(8-ethoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (26
mg)-
Mass spectrum (ESI)m/z: 489 (M+H)+
26 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (9.7 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.34 (t, J=6.8Hz, 3H) 1.91 (s, 3H) 3.97-4.07 (m,
2H) 4.79-4.90 (m, 2H) 5.22 (s, 2H) 5.54 (s, 1H) 6.80 (s, 1H) 6.84 (d,
J=8.8Hz, 2H) 7.03 (s, 1H) 7.30 (t, J=5.2Hz, 1H) 7.59 (d, J=8.8Hz, 2H)
8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 16 min
[0428] Example 29: (R) and
fSV4-r(ri-r3-fluoropvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-(8-methoxvchroman-6-vDmethvnamino)benzamidine acetate [0429] (29a) (3-fluoropyridin-2-yl)hydrazine [0430] [Chemical Formula 145]


To a solution of 9.59 g of 2-chloro-3-fluoropyridine in 6 ml of ethanol there was added 6 ml of hydrazine monohydrate, and the mixture was stirred at 60°C for 3 days. The solution was adsorbed onto 50 g of NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (403 mg) as a yellow solid. 'H-NMR (DMSO-d6) 5 4.10 (s, 2H) 6.54-6.58 (m, 1H) 7.27-7.32 (m, 1H) 7.72 (s, 1H) 7.86 (d, J=5.2Hz, 1H)
[0431] (29b) (R) and
(S)-4-({[l-(3-fluoropyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(8-methoxychroman-6-yl)methyl} amino)benzamidine acetate [0432] [Chemical Formula 146]

After adding 25 mg of (3-fluoropyridin-2-yl)hydrazine and 50 u.1 of
triethylamine to a solution of 100 mg of
{2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylimino]-l-methylsulfanylethyIidene}carbamic acid methyl ester (Example (24a)) in 2 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was

purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
2-(3-fluoro-pyridin-2-yI)-5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[l,2
,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[l,2,4]triazol-3-one
(60 mg).
To a solution of 60 mg of this compound in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 70 mg
of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-({[l-(3-fluoropyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(
8-methoxychroman-6-yl)methyl}amino)benzamidine acetate (29 mg).
Mass spectrum (ESI)m/z: 490 (M+H)+
29 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (10.1 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 1.94-2.01 (m, 2H) 2.78 (t, J=6.4Hz,
2H) 3.80 (s, 3H) 4.18 (t, J=5.2Hz, 2H) 5.53 (s, 1H) 6.83-6.87 (m, 3H)
6.95 (d, J=2.0Hz, 1H) 7.53 (sept, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H)
7.81 (dt, J=1.2, 8.4Hz, 1H) 8.37 (d, J=4.4Hz, 1H)
HPLC retention time: 8 min
[0433] Example 30: (R) and
('S)-4-r(n-r3-fluoropvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-(9-methoxv-3,4-dihvdro-2H-benzo[b][l,4]dioxepin-7-vl)methyl}arnin o)benzamidine acetate [0434] (30a)
9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-carbaldehyde [0435] [Chemical Formula 147]


After adding 1.5 g of potassium carbonate and 1.2 g of 1,3-dibromopropane to a solution of 920 mg of 3,4-dihydroxy-5-methoxybenzaldehyde [CAS No.859785-71-0] in 10 ml of DMF, the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (604 mg) as an oil.
'H-NMR (CDC13) 8 2.29 (quint, J=6.0Hz, 2H) 3.92 (s, 3H) 4.33 (t, J=5.6Hz, 2H) 4.45 (t, J=5.6Hz, 2H) 7.10-7.11 (m, 1H) 7.12 (br.s, 1H) 9.78 (d, J=1.6Hz, 1H) [0436] (30b)
2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth yI-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide [0437] [Chemical Formula 148]

To a solution of 626 mg of Yb(OTf)3 in 30 ml of dichloromethane there
were added 1.77 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,
2.11 g of
9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-carbaldehyde, 2 g of MS3A and 2.6 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure.
To a solution of the residue in 100 ml of an ethanohTHF = 6:4 mixed solvent there was added 50 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred at 40°C for 2 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give the title compound (4.7 g,
crude product) as a light yellow solid.
'H-NMR (d6-DMSO) 5 2.02-2.11 (m, 2H) 2.58 (s, 3H) 3.73 (s, 3H)
4.01-4.12 (m, 4H) 5.12 (d, J=6.0Hz, 1H) 6.67 (d, J=5.6Hz, 1H) 6.73 (d,
J=8.8Hz, 2H) 6.76 (d, J=2.0Hz, 1H) 6.92 (s, 1H) 7.69 (d, J=8.8Hz, 2H)
9.50 (br.s, 1H) 9.77 (br.s, 1H)
[0438] (30c)
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester
[0439] [Chemical Formula 149]

After adding 1.63 g of Me30+BF4" to a solution of 4.7 g of 2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 50 ml of acetonitrile, the mixture was stirred at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give
2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester. To a solution of this compound in 60 ml of ethyl acetate there was added 16 g of manganese dioxide, and the mixture was stirred at room

temperature. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure.
To a solution of the residue in 50 ml of toluene there were added 4 ml of
2,4,6-collidine and 2 ml of methyl chloroformate, and the mixture was
stirred at 80°C under a nitrogen atmosphere. After cooling the reaction
mixture, IN hydrochloric acid was added and extraction was performed
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate-heptane) to
give the title compound (1.997 g) as a yellow solid.
'H-NMR (CDC13) 5 2.26-2.50 (m, 2H) 2.32 (s, 3H) 2.65 (s, 3H) 3.65 (s,
3H) 3.92 (s, 3H) 4.29 (t, J=5.6Hz, 2H) 4.40 (t, J=6.0Hz, 2H) 7.01 (d,
J=2.0Hz, 1H) 7.15 (d, J=8.0Hz, 2H) 7.27 (d, J=1.6Hz, 1H) 8.00 (d,
J=8.0Hz, 2H)
[0440] (30d) (R) and
(S)-4-({[l-(3-fluoropyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-
yl]-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)m ethyl }amin
o)benzamidine acetate
[0441] [Chemical Formula 150]

After adding 28 mg of (3-fluoropyridin-2-yl)hydrazine and 50 u.1 of
triethylamine to a solution of 119 mg of
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb amic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3

ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate
to the reaction mixture, it was stirred at room temperature for 1 hour.
Water was added to the reaction mixture and extraction was performed
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
2-(3-fluoropyridin-2-yl)-5-{(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dio
xepin-7-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4
-dihydro-[ 1,2,4]triazol-3-one.
To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent, 100 mg of iron powder was added and the mixture
was stirred overnight at 60°C under a nitrogen atmosphere. After
filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-({[l-(3-fIuoropyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yI]-(
9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)methyl}amino)be
nzamidine acetate (60 mg).
Mass spectrum (ESI)m/z: 506 (M+H)+
60 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (21 mg) of the title
compound was obtained.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 2.13 (t, J=5.2Hz, 2H) 3.77 (s, 3H)
4.05-4.15 (m, 4H) 5.54 (s, IH) 6.79 (d, J=2.4Hz, IH) 6.84 (d, J=8.8Hz,
2H) 6.89 (d, J=1.6Hz, IH) 7.51 (sept, J=4.0Hz, IH) 7.59 (d, J=8.8Hz,
2H) 7.80 (dt, J=1.2, 9.6Hz, IH) 8.36 (d, J=4.4Hz, IH)
HPLC retention time: 9 min
[0442] Example 3Jj (R) and
(S)-4-(r(7-methoxv-2.3-dihvdrobenzofuran-5-vl)-(5-oxo-l-pvrimidin-2-y l-4.5-dihvdro-lH-n.2.41triazol-3-vDmethyl]amino}benzamidine acetate [0443] (31a)

{2-(7-methoxy-2,3-dihydrobenzofuraB-5-yl)-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester

To a solution of 426 mg of Yb(OTf>3 in 30 ml of THF there were added
1.2 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 1.22 g of
7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde [CAS
No.363185-46-0], 1 g of MS3A and 1.9 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
To a solution of this compound in 45 ml of an ethanolrTHF = 2:1 mixed solvent there was added 15 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenylamino]thioacetamide.
To a solution of this compound in 50 ml of acetonitrile there was added 1.12 g of Me30+BF4~, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under

reduced pressure.
To a solution of the residue in 50 ml of toluene there were added 2 ml of 2,4,6-collidine and 1 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (369 mg, isomeric mixture) as a yellow solid. Mass spectrum (ESI)m/z: 467 (M+H)+
[0445] (31b) (R) and
(S)-4-{[(7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidin-2-y l-4,5-dmydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0446] [Chemical Formula 152]

After adding 27 mg of 2-hydrazinopyrimidine and 50 u.1 of triethylamine
to a solution of 128 mg of
[2-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was

concentrated under reduced pressure. The residue was purified by NAM
silica gel column chromatography (methanol-ethyl acetate) to give
5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol
-3-one.
To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 100 mg of iron powder, and the
mixture was stirred overnight at 60°C under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{[(7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
(18.1 mg).
Mass spectrum (ESI)m/z: 459 (M+H)+
18.1 mg of this compound was optically resolved using a SUM1CHIRAL
OA-2500 column, and the first eluting enantiomer (7.6 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.19 (t, J=8.4Hz, 2H) 3.82 (s, 3H) 4.56
(t, J=8.8Hz, 2H) 5.54 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.01 (s, 1H) 7.03 (s,
1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 17 min
[0447] Example 32j (R) and
(S)-4-{[(5-fluoro-8-methoxv-4H-benzon.31dioxin-6-vl)-(5-oxo-l-pvrimi
din-2-yl-4.5-dihydro-lH-[l. 2.4"}triazol-3-yl)methvl"| amino} benzamidine
acetate
[0448] (32a) 5-fluoro-8-methoxy-4H-benzo[l,3]dioxine
[0449] [Chemical Formula 153]

To a solution of 6.85 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No.457628-15-8] in 200 ml of an ethanohTHF =1:1 mixed solvent

there was added 1.52 g of sodium borohydride while cooling on ice.
After stirring at room temperature for 30 minutes, IN hydrochloric acid
was added to the reaction mixture while cooling on ice. The reaction
mixture was extracted with ethyl acetate and dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off, and the
filtrate was concentrated under reduced pressure to give
3-fluoro-2-hydroxymethyl-6-methoxyphenol (6.1 g, crude product).
To a solution of the 6.1 g of 3-fluoro-2-hydroxymethyl-6-methoxyphenol
in 90 ml of DMF there was added 3 g of sodium hydride (60% oily
suspension) while cooling on ice, and the mixture was stirred at room
temperature for 30 minutes. After adding 2.55 ml of
bromochloromethane and 510 mg of sodium iodide to the reaction mixture, it was stirred at 80°C for 6 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.086 g).
'H-NMR (CDC13) 5 3.85 (s, 3H) 4.91 (s, 2H) 5.29 (s, 2H) 6.59 (t, J=9.2Hz, 1H) 6.70 (dd, J=5.2, 9.2Hz, 1H)
[0450] (32b) 5-fluoro-8-methoxy-4H-benzo[l ,3]dioxine-6-carbaldehyde [0451] [Chemical Formula 154]

To a solution of the 1.086 g of 5-fluoro-8-methoxy-4H-benzo[l,3]dioxine and 1.28 ml of N,N,N',N',N"-pentamethyldiethylenetriamine in 10 ml of THF there was added dropwise 2.4 ml of n-butyllithium (2.55 M, hexane solution) at -74°C. The mixture was stirred at -74°C for 1 hour, and then 0.7 ml of N-formylmorpholine was added. After stirring at room
1

temperature for 1 hour, IN hydrochloric acid was added thereto while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (153 mg) as an oil. 'H-NMR (CDCI3) 5 3.91 (s, 3H) 4.95 (s, 2H) 5.36 (s, 2H) 7.22 (d, J=6.4Hz, 1H) 10.21 (s, 1H) [0409] (32c)
{2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0452] [Chemical Formula 155]

To a solution of 45 mg of Yb(OTf>3 in 3 ml of THF there were added 126
mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 153 mg of
5-fluoro-8-methoxy-4H-benzo[l,3]dioxine-6-carbaldehyde, 0.2 g of
MS3A and 192 yd of trimethyisilyl cyanide under a nitrogen atmosphere,
and the mixture was stirred overnight at room temperature. The
reaction mixture was filtered through celite, and the celite was washed
with THF. The organic layer was concentrated under reduced pressure
to give
(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxa diazol-3-yI)phenylamino]acetonitrile (crude product). To a solution of this compound in 9 ml of an ethanol:THF = 2:1 mixed solvent there was added 3 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at 50°C for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium

sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give
2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]
oxadiazol-3-yl)phenylamino]thioacetamide (310 mg, crude product).
To a solution of 310 mg of this compound in 4 ml of acetonitrile there
was added 120 mg of Me30+BF4_, and the mixture was stirred at room
temperature for 30 minutes. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 2 ml of ethyl acetate there was added 1.5 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 4 ml of toluene there were added 0.8 ml of 2,4,6-collidine and 0.4 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (213 mg, isomeric mixture) as a yellow solid. 'H-NMR (CDC13) Two main isomers:
5 2.32 (s, 3H) 2.65 (s, 3H) 3.63 (s, 3H) 3.93 (s, 3H) 4.92 (s, 2H) 5.34 (s,
2H) 7.08 (d, J= 8.4Hz, 2H) 7.39 (d, J=6.4Hz, 1H) 8.01 (d, J=8.8Hz, 2H)
8 2.48 (s, 3H) 2.63 (s, 3H) 3.61 (s, 3H) 3.63 (s, 3H) 4.77 (s, 2H) 5.25 (s,
2H) 6.42 (d, J=6.4Hz, 1H) 6.83 (d, J=8.4Hz, 2H) 7.91 (d, J=8.8Hz, 2H)
[0454] (32d) (R) and
(S)-4-{[(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimi din-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate


After adding 21 mg of 2-hydrazinopyrimidine and 50 u.1 of triethylamine
to a solution of 105 mg of
{2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85°C
under a nitrogen atmosphere. The reaction mixture was concentrated,
and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic
acid. After adding 100 mg of sodium cyanotrihydroborate to the
reaction mixture, the mixture was stirred at room temperature for 1 hour.
Water was added to the reaction mixture and extraction was performed
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
5-{(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]o xadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4] triazol-3-one (74 mg) as a light brown solid.
To a solution of 74 mg of this compound in 3.5 ml of a
methanol:water:acetic acid = 1:1:1.5 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-1 H-[ 1,2,4]triazol-3 -yl)methyl]amino} benzamidine

acetate (47 mg).
Mass spectrum (ESI)m/z: 493 (M+H)+
47 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (16.5 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.75 (s, 3H) 4.92 (m, 2H) 5.23 (d,
J=1.6Hz, 2H) 5.87 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.03 (d, J=7.2Hz, 1H)
7.29 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 17 min
[0456] Example 33: (R) and
fS)-4-{[(5-fiuoro-8-methoxvchroman-6-yl)-(5-oxo-1-pyrimidin-2-vl-4.5-dihydro-lH-[1.2.4]triazol-3-yl)methvl]amino}benzamidine acetate [0457] (33a) 3-fluoro-2-(3-hydroxypropyl)-6-methoxyphenol [0458] [Chemical Formula 157]

To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranilidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:l. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding IN hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off

and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give the title compound (4.78 g) as a solid.
'H-NMR (CDCI3) 5 1.85 (sept, J=6.8Hz, 2H) 2.80 (dt, J=1.6, 6.8Hz, 2H)
3.59 (t, J=6.0Hz, 2H) 3.86 (s, 3H) 6.54 (t, J=9.2Hz, 1H) 6.64 (dd, J=4.8,
8.8Hz, 1H)
[0459] (33b) 5-fluoro-8-methoxychromane
[0460] [Chemical Formula 158]

After dissolving 4.78 g of
3-fluoro-2-(3-hydroxypropyl)-6-methoxyphenol and 9.4 g of triphenylphosphine in 70 ml of THF under a nitrogen atmosphere, the solution was cooled to -74°C. Next, 7 ml of DIAD was added to the reaction mixture, and the temperature was allowed to rise to room temperature prior to stirring overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.6 g) as an oil.
[0461] (33c) 5-fluoro-8-methoxychromane-6-carbaldehyde [0462] [Chemical Formula 159]

To a solution of 3.6 g of 5-fluoro-8-methoxychromane and 4.2 ml of N,N,N',N',N"-pentamethyldiethylenetriarnine in 130 ml of THF there was added dropwise 8 ml of n-butyllithium (2.55 M, hexane solution) at -74°C. After stirring at -74°C for 1 hour, N-formylmorpholine was added. After further stirring at room temperature for 1 hour, IN hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.50 g) as a white solid. 'H-NMR (CDCI3) 8 2.03-2.10 (m, 2H) 2.80 (t, J=6.4Hz, 2H) 3.90 (s, 3H) 4.36 (t, J=5.2Hz, 2H) 7.16 (d, J=6.4Hz, 1H) 10.24 (s, 1H) [0463] (33d)
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester [0464] [Chemical Formula 160]

After adding 940 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 1.125 g of 5-fluoro-8-methoxychromane-6-carbaldehyde, 1 g of MS3A and 1.43 ml of trimethylsilyl cyanide to a solution of 330 mg of Yb(OTf)3 in 20 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give (5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylamino]acetonitrile (crude product).
'H-NMR (CDCI3) 5 2.00-2.09 (m, 2H) 2.64 (s, 3H) 2.78 (t, J=6.4Hz, 2H) 3.90 (s, 3H) 4.30 (t, J=4.8Hz, 2H) 5.58 (d, J=6.4Hz, 1H) 6.84 (d, J=8.4Hz, 2H) 6.89 (d, J=6.8Hz, 1H) 7.98 (d, J=8.4Hz, 2H) To a solution of this compound in 45 ml of an ethanohTHF = 2:1 mixed solvent there was added 15 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the

filtrate was concentrated under reduced pressure to give 2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazoI-3-yl)-2-phenylamino]thioacetamide (crude product).
'H-NMR (d6-DMSO) 8 1.85-1.93 (m, 2H) 2.59 (s, 3H) 2.66 (t, J=6.0Hz, 2H) 3.69 (s, 3H) 4.12 (t, J=6.0Hz, 2H) 5.38 (d, J=6.4Hz, 1H) 6.70-6.81 (m, 3H) 6.95 (d, J=6.8Hz, 1H) 7.73 (d, J=8.4Hz, 2H) 9.50 (s, 1H) 9.89 (s, 1H)
To a solution of this compound in 40 ml of acetonitrile there was added
900 mg of Me30+BF4_, and the mixture was stirred at room temperature
for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to
the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give
2-(5-fluoro-8-methoxychroman-6-yI)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)-2-phenylamino]thioacetamide acid methyl ester (crude product). 'H-NMR (CDC13) 5 1.90-2.06 (m, 2H) 2.35 (s, 3H) 2.61 (s, 3H) 2.79 (t, J=6.4Hz, 2H) 3.80 (s, 3H) 4.26 (t, J=5.2Hz, 2H) 5.36 (br.s, 2H) 6.64-6.70 (m, 3H) 6.86 (d, J=8.8Hz, 2H) 7.98 (d, J=8.4Hz, 2H) To a solution of this compound in 50 ml of ethyl acetate there was added 10 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 40 ml of toluene there were added 4 ml of 2,4,6-collidine and 2 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.09 g, isomeric mixture) as a yellow solid. 'H-NMR (CDCI3) Two main isomers:

8 2.01-2.06 (m, 2H) 2.33 (s, 3H) 2.65 (s, 3H) 2.76 (t, J=6.4Hz, 2H) 3.58
(s, 3H) 3.91 (s, 3H) 4.32 (t, J=4.8Hz, 2H) 7.30 (d, J=7.2Hz, 1H) 7.09 (d,
J= 8.0Hz, 2H) 8.00 (d, J=8.4Hz, 2H)
5 1.93-2.00 (m, 2H) 2.48 (s, 3H) 2.63 (s, 3H) 2.61-2.64 (m, 2H) 3.58 (s,
3H) 3.62 (s, 3H) 4.23 (t, J=4.8Hz, 2H) 6.30 (d, J=6.0Hz, 1H) 6.84 (d,
J=8.4Hz, 2H) 7.90 (d, J=8.0Hz, 2H)
[0465] (33e) (R) and
(S)-4-{[(5-fluoro-8-methoxychroman-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0466] [Chemical Formula 161]

After adding 23 mg of 2-hydrazinopyrimidine and 35 p.1 of triethylamine
to a solution of 113 mg of
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazoI-3-
yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester
in 2 ml of DMF, the mixture was stirred overnight at 85°C under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid.
After adding 100 mg of sodium cyanotrihydroborate to the reaction
mixture it was stirred at room temperature for 1 hour. Water was added
to the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by NAM silica gel column
chromatography (methanol-ethyl acetate) to give
5-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-on e (82 mg) as a light brown solid.

'H-NMR (CDCb) 8 1.94-2.00 (m, 2H) 2.58 (s, 3H) 2.71 (t, J=6.4Hz, 2H)
3.60 (s, 3H) 4.21 (t, J=4.4Hz, 2H) 6.00 (br.s, 2H) 6.78 (d, J=8.8Hz, 2H)
6.94 (d, J=6.8Hz, 1H) 7.15 (t, J=4.4Hz, 1H) 7.80 (d, J=8.8Hz, 2H) 8.70
(d, J=4.8Hz, 2H) 10.57 (br.s, 1H)
To a solution of 82 mg of this compound in 3.5 ml of a
methanol:water:acetic acid = 1:1:1.5 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(5-fluoro-8-methoxychroman-6-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy
dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (47 mg).
Mass spectrum (ESI)m/z: 491 (M+H)+
47 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (17.0 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 1.96-2.00 (m, 2H) 2.76 (t, J=6.4Hz,
2H) 3.72 (s, 3H) 4.18 (t, J=5.6Hz, 2H) 5.88 (s, 1H) 6.85 (d, J=9.2Hz, 2H)
6.93 (d, J=7.2Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.75
(d, J=4.4Hz, 2H)
HPLC retention time: 15 min
[0467] Example 34j (R) and
fSV^fin-O-aminopvridin^-vn-S-oxo^.S-dihvdro-lH-fl^^ltriazol-S-
vll-(9-methoxy-3.4-dihvdro-2H-benzorb][1.41oxepin-7-vOmethvUamino)
benzamidine acetate
[0468] (34a)
5- {(9-methoxy-3,4-dihydro-2H-benzo[b] [ 1,4]dioxepin-7-yl)-[4-(5 -methyl
-[l,2,4]oxadiazol-3-yl)phenylamino]methyl]-2-(3-nitropyridin-2-yl)-2,4-
dihydro-[l,2,4]triazol-3-one
[0469] [Chemical Formula 162]


After adding 37.3 mg of (3-nitropyridin-2-yl)hydrazine and 37 ul of
triethylamine to a solution of 109 mg of
[2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carba mic acid methyl ester (Example (30c)) in 5 ml of DMF under a nitrogen atmosphere, the mixture was heated at 85°C for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 20 ml of a methanol:THF = 1:1 mixed solvent, 83 mg of sodium cyanotrihydroborate and 32 ul of acetic acid were added and the mixture was stirred at room temperature for 24 hours. After adding 100 ml of ethyl acetate and 50 ml of water, filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate (1:40)) to give the title compound (59 mg) as a light yellow solid. 'H-NMR (CDC13) 5 2.18 (quint, J=5.9Hz, 2H) 2.60 (s,3H) 3.58 (s, 3H) 4.44 (t, J=5.9Hz, 2H) 4.57 (t, J=5.9Hz, 2H) 5.52 (s,lH) 6.72 (d, J=2.3Hz, 1H) 6.75 (d, J=2.3Hz, 1H) 6.75 (d, J=8.2Hz, 2H) 7.53 (dd, J=7.6,5.3Hz, 1H) 7.75 (d, J=8.2Hz, 2H) 8.36 (dd, J=7.6,0.9Hz, 1H) 8.52 (dd, J=5.3,0.9Hz, 1H) [0470] (34b)
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-( 9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)methyl}amino)be nzamidine trifluoroacetate [0471] [Chemical Formula 163]


To a solution of 59 mg of
5-{(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(5-methyl
-[l,2,4]oxadiazol-3-yI)phenylamino]methyl]-2-(3-nitropyridin-2-yl)-2,4-
dihydro-[l,2,4]triazol-3-one in 4.5 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 69 mg of iron powder, and the
mixture was stirred at 55°C for 15 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give the title compound (22 mg) as a white solid.
'H-NMR (CD3OD) S 2.16 (quint, J=5.8Hz, 2H) 3.83 (s, 3H) 4.15 (q,
J=5.8Hz,4H) 5.65 (s, 1H) 6.80 (d, J=2.1Hz, 1H) 6.87 (d, J=8.8Hz, 2H)
6.88 (d, J=2.1Hz, 1H) 7.31 (dd, J=8.0,5.5Hz, 1H) 7.44 (d, J=8.0Hz, 1H)
7.64 (d, J=8.8Hz, 2H) 7.84 (d, J=5.5Hz, 1H)
[0472] (34c) (R) and
(S)-4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-
yl]-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)methyl}amin
o)benzamidine acetate
[0473] [Chemical Formula 164]

A SUMICHIRAL OA-2500 column was used for optical resolution of 22
mg of
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(

9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yI)methyI}amino)be nzamidine trifluoroacetate, and the first eluting enantiomer (5.9 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.93 (s,3H) 2.16 (quint, J=5.8Hz, 2H) 3.82 (s,3H) 4.15 (q, J=5.8Hz,4H) 5.59 (s, 1H) 6.81 (d, J=2.3Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 6.89 (d, J=2.3Hz, 1H) 7.22 (dd, J=8.4,4.9Hz, 1H) 7.33 (dd, J=8.4,1.9Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 7.83 (dd, J=4.9,1.9Hz, 1H) HPLC retention time: 8 min
[0474] Example 35j (R) and
rSV4-((n-(3-aminoPvridin-2-vn-5-oxo-4.5-dihvdro-lH-fl.2.4]triazol-3-vl]-(3-ethoxv-4-methoxvphenvOmethvUamino')benzamidine acetate [0475] (35a)
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-( 3-ethoxy-4-methoxyphenyl)methyl}amino)benzamidine trifluoroacetate [0476] [Chemical Formula 165]

After adding 28 mg of (3-nitropyridin-2-yl)hydrazine and 32 u,l of
tri ethyl amine to a solution of 105 mg of
{2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (17e)) in 3 ml of DMF, the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 4 ml of a methanol:THF = 1:1 mixed solvent. After adding 46 \i\ of acetic acid and 71 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 59 mg of

5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylamino]methyl]-2-(3-nitropyridin-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one
To a solution of this compound in 3 ml of a methanohwatenacetic acid =
1:1:1 mixed solvent there was added 30 mg of iron powder, and the
mixture was stirred at 55°C for 20 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give the title compound (13 mg) as a white solid.
'H-NMR (CD3OD) 8 1.38 (t, J=7.8Hz, 3H) 3.83 (s, 3H) 4.03-4.10 (m,
2H) 5.66 (s, 1H) 6.88 (d, J=8.4Hz, 2H) 6.99 (d, J=8.2Hz, 1H) 7.09 (dd,
J=8.2,1.3Hz, 1H) 7.12 (d, J=1.3Hz, 1H) 7.27 (dd, J=8.4,4.7Hz, 1H) 7.39
(dd, J=8.4,1.6Hz, 1H) 7.62 (d, J=8.4Hz, 2H) 7.83 (dd, J=4.7,1.6Hz, 1H)
[0477] (35b) (R) and
(S)-4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(3-ethoxy-4-methoxyphenyl)methyl}arnino)benzamidine acetate [0478] [Chemical Formula 166]

A SUMICHIRAL OA-2500 column was used for optical resolution of 13
mg of
4-( {[ 1 -(3 -aminopyridin-2-yl)-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-3 -yl]-( 3-ethoxy-4-methoxyphenyl)methyl}amino)}benzamidine trifluoroacetate, and the first eluting enantiomer (2.2 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.37 (t, J=7.8Hz, 3H) 1.91 (s, 3H) 3.83 (s, 3H) 4.03-4.10 (m, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.95 (d, J=8.4Hz, 1H) 7.09 (dd, J=8.4,1.3Hz, 1H) 7.13 (d, J=1.3Hz, 1H) 7.21 (dd, J=8.3,4.4Hz, 1H) 7.33 (dd, J=8.3,1.6Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 7.83

(dd, J=4.4,1.6Hz, 1H) HPLC retention time: 7 min
[0479] Example 36j (R) and
(S)-2-{3-[(4-carbamimidoylphenylamino)-(3.4-dimethoxvphenvOmethvl] -5-0X0-4.5-dihvdro-n,2.41triazol-l-vUbenzoic acid acetate [0480] (36a)
(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yI)phenylamino] acetonitrile

After adding 0.887 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 0.831 g of 3,4-dimethoxybenzaldehyde, 1 g of MS3A and 1 ml of trimethylsilyl cyanide to a solution of 0.31 g of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 22 hours. After then adding 200 ml of ethyl acetate to the reaction mixture, it was filtered through celite and the celite was washed with 200 ml of ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.75 g) as a light yellow solid.
'H-NMR (CDC13) 8 2.63 (s, 3H) 3.91 (s, 3H) 3.92 (s, 3H) 4.30 (d, J=5.5Hz, 1H) 5.44 (d, J=5.5Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 6.93 (d, J=7.8Hz, 1H) 7.06 (d, J=2.0Hz, 1H) 7.18 (dd, J=7.8,2.0Hz, 1H) 7.98 (d, J=8.8Hz, 2H) [0482] (36b)
2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylam ino]thioacetamide


To a solution of 1.25 g of
(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino] acetonitrile in 120 ml of an ethanohTHF = 2:1 mixed solvent there was added 10 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 60 hours. Next, 500 ml of ethyl acetate and 400 ml of water were added to the reaction solution, and the organic layer was washed twice with 300 ml of water and once with 300 ml of saturated brine, and was then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and after concentrating the filtrate under reduced pressure, 10 ml of t-butyl methyl ether was added to the residue prior to filtration. The solid was washed with 10 ml of t-butyl methyl ether to give the title compound (1.34 g) as a white solid.
'H-NMR (CDC13) 5 2.63 (s, 3H) 3.88 (s, 3H) 3.89 (s, 3H) 4.95 (br.s, 1H) 5.15 (s , 1H) 6.72 (d, J=8.8Hz, 2H) 6.88 (d, J=7.8Hz, 1H) 6.96 (d, J=2.0Hz, 1H) 7.04 (dd, J=7.8,2.0Hz, 1H) 7.57 (br.s, 1H) 7.90 (d, J=8.8Hz,2H) 8.10 (br.s, 1H) [0484] (36c)
2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylam ino]thioacetimidic acid methyl ester

After adding 170 mg of Me30+BF4" to a solution of 385 mg of 2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylam ino]thioacetamide in 30 ml of dichloromethane under a nitrogen

atmosphere, the mixture was stirred at room temperature for 18 hours. Next, 200 ml of ethyl acetate and 100 ml of a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was washed 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (371 mg, crude product).
'H-NMR (CDC13) 8 2.30 (br.s, 3H) 2.61 (s, 3H) 3.88 (s, 6H) 5.1 (br.s, 1H) 6.66 (d, J=8.8Hz, 2H) 6.87 (d, J=7.8Hz, 1H) 6.90-7.05 (br.s, 2H) 7.86 (d, J=8.8Hz, 2H) [0486] (36d)
[2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]-l-methylsulfanylethylidene]carbamic acid methyl ester

To a solution of 0.784 g of
2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylam ino]thioacetimidic acid methyl ester in 21.1 ml of toluene there were added 0.393 ml of 2,4,6-coIIidine and 0.304 ml of methyl chloroformate under a nitrogen atmosphere, and the mixture was stirred at 80°C for 15 hours. After cooling the reaction mixture, 150 ml of ethyl acetate and 50 ml of water were added and the pH was adjusted to 4 with a few drops of sulfuric acid. The organic layer was washed with 50 ml of water and 50 ml of saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.436 g) as a light yellow solid.
'H-NMR (CDCI3) 5 2.35 (s, 3H) 2.66 (s, 3H) 3.64 (s, 3H) 3.95 (s, 3H) 3.96 (s, 3H) 6.90 (d, J=7.8Hz, IH) 7.09 (dd, J=8.8Hz, 2H) 7.31 (dd,

J=7.8,2.0Hz, 1H) 7.61 (d, J=2.0Hz, 1H) 8.03 (d, J=8.8Hz, 2H) [0487] (36e)
2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid [0488] [Chemical Formula 170]

After adding 38 mg of 2-hydrazinobenzoic acid hydrochloride and 0.056 ml of triethylamine to a solution of 91 mg of [2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]-l-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of DMF, the mixture was stirred at 90°C for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 30 ml of water was added, hydrochloric acid was added (for adjustment to pH 3-4), and extraction was performed with 50 ml of ethyl acetate. The organic layer was washed twice with 30 ml of water and once with 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-dichloromethane) to give the title compound (34 mg) as a light yellow solid.
'H-NMR (CD3OD) 5 2.63 (s, 3H) 3.58 (s, 3H) 3.79 (s, 3H) 6.85-6.88 (m, 2H) 6.92 (d, J=8.8Hz, 2H) 7.03 (dd, J=7.8,2.0Hz, 1H) 7.54 (t, J=7.5Hz, 1H) 7.59 (d, J=7.5Hz, 1H) 7.68 (t, J=7.5Hz, 1H) 7.90 (d, J=8.8Hz, 2H) 7.99 (d, J=7.5Hz, 1H) Mass spectrum (ESI)m/z: 527 (M+H)+ [0489] (36f)
2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyla mino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid

[0490] [Chemical Formula 171]

After adding 16.3 mg of sodium cyanotrihydroborate and 0.0074 ml of acetic acid to a solution of 34 mg of 2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid in 6 ml of a methanohTHF = 2:1 mixed solvent, the mixture was stirred at room temperature for 20 hours. Next, 0.1 ml of 5N hydrochloric acid was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes, after which 10 ml of ethyl acetate and 5 ml of water were added and filtration was performed with celite. The aqueous layer was extracted with 10 ml of ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-dichloromethane) to give the title compound (25 mg) as a white solid.
'H-NMR (CD3OD) 8 2.59 (s, 3H) 3.83 (s, 3H) 3.86 (s, 3H) 5.58 (s, 1H)
6.84 (d, J=8.8Hz, 2H) 6.98 (d, J=7.8Hz, 1H) 7.09 (dd, J=7.8,2.0Hz, 1H)
7.15 (d, J=2.0Hz, 1H) 7.52 (t, J=7.5Hz, 1H) 7.53 (d, J=7.5Hz, 1H) 7.65
(t, J=7.5Hz, 1H) 7.80 (d, J=8.8Hz, 2H) 7.96 (d, J=7.5Hz, 1H)
[0491] (36g) (R) and
(S)-2-{3-[(4-carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl] -5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid acetate [0492] [Chemical Formula 172]


To a solution of 25 mg of
2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyla
mino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid in 6 ml
of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 26
mg of iron powder under a nitrogen atmosphere, and the mixture was
stirred at 45°C for 15 hours and at 55°C for 6 hours. After filtering the
reaction mixture, it was purified by reverse-phase high performance
liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to
give 14 mg of
2-{3-[(4-carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl]-5-o
xo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid trifluoroacetate.
Mass spectrum (ESI)m/z: 527 (M+H)+
A 10 mg portion of this compound was optically resolved using a
SUM1CHIRAL OA-2500 column, and the first eluting enantiomer (1.3
mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.83 (s, 3H) 3.85 (s, 3H) 5.57 (s, 1H)
6.88 (d, J=9.0Hz, 2H) 6.98 (d, J=8.2Hz, 1H) 7.10 (dd, J=8.2,2.1Hz, 1H)
7.16 (d, J=2.1Hz, 1H) 7.35-7.45 (m, 3H) 7.61 (d, J=9.0Hz, 2H) 7.71 (dd,
J=7.7,2.0Hz, 1H)
HPLC retention time: 14 min
[0493] Example 37: (R) and
(S)-2-{3-f(4-carbamimidovl-3-fluorophenvlamino)-(3,4-dimethoxvphenvl )methvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vUbenzoic acid acetate [0494] (37a)
[2-(4-cyano-3-fluorophenylimino)-2-(3,4-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester [0495] [Chemical Formula 173]


After adding 541 mg of 2-fluoro-4-aminobenzonitrile [CAS No.53312-80-4], 500 mg of MS3A, 493 mg of Yb(OTf)3 and 1.1 ml of trimethylsilyl cyanide to a solution of 795 mg of 3,4-dimethoxybenzaldehyde in 20 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of 4-{[cyano-(3,4-dimethoxyphenyl)methyl]amino}-2-fluorobenzonitrile. To a solution of this compound in 40 ml of a methanol:THF = 1:1 mixed solvent there was added 6.8 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-(4-cyano-3-fluorophenylamino)-2-(3,4-dimethoxyphenyl)thioacetamide
To a solution of this compound in 20 ml of acetonitrile there was added 618 mg of Me30+BF4\ and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. After adding 3.46 g of manganese dioxide to a solution of the residue in 20 ml of ethyl acetate, the mixture was stirred at room temperature for 35

minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
After adding 1.57 ml of 2,4,6-collidine and 0.62 ml of methyl chloroformate to a solution of the residue in 30 ml of toluene, the mixture was stirred at 80°C for 4 hours and 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture, 0.5N hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.3 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDCls) Main isomer:
5 2.37 (s, 3H) 3.62 (s, 3H) 3.95 (s, 3H) 3.96 (s, 3H) 6.88 (d, J=8.4Hz, 1H) 6.96-7.00 (m, 2H) 7.27 (m, 1H) 7.54 (t, J=8.0Hz, 2H) [0496] (37b)
2-{3-[(4-cyano-3-fluorophenylamino)-(3,4-dimethoxyphenyl)methyl]-5-o xo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid [0497] [Chemical Formula 174]

After adding 55 mg of 2-hydrazinobenzoic acid hydrochloride and 101 ul of triethylamine to a solution of 120 mg of [2-(4-cyano-3-fluorophenylimino)-2-(3,4-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF = 1:1 mixed solvent. After adding 58 u.1 of acetic acid and 91 mg of sodium cyanotrihydroborate to the solution, the

mixture was stirred at room temperature for 15 hours. Ethyl acetate was then added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (100 mg) as a light yellow solid. 'H-NMR (CD3OD) 5 3.75 (s, 3H) 3.78 (s, 3H) 5.43 (s, 1H) 6.30 (d, J=l 1.2Hz, 1H) 6.38 (d, J=8.4Hz, 1H) 6.78 (d, J=8.4Hz, 1H) 6.91-6.94 (m, 2H) 7.21 (t, J=8.0Hz, 1H) 7.50-7.57 (m, 2H) 7.69 (t, J=7.2Hz, 1H) 7.88 (d, J=7.6Hz, 1H)
[0498] (37c) (R) and
(S)-2-{3-[(4-carbamimidoyl-3-fluorophenylamino)-(3,4-dimethoxyphenyl )methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid acetate [0499] [Chemical Formula 175]

After adding 131 mg of hydroxylammonium chloride and 367 u,l of
triethylamine to a solution of 175 mg of
2-{3-[(4-cyano-3-fluorophenylamino)-(3,4-dimethoxyphenyl)methyl]-5-o xo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid in 10 ml of ethanol, the mixture was stirred at 75°C for 23 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of acetic acid. After adding 0.2 ml of acetic anhydride and 50 mg of palladium-carbon to the solution, the mixture was stirred for 2 hours and 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1%

trifluoroacetic acid) to give 70 mg of
2-{3-[(4-carbamimidoyl-3-fluorophenylamino)-(3,4-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid trifluoroacetate
as a light yellow solid.
Mass spectrum (ESI)m/z: 507 (M+H)+
A 60 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (19.5
mg) of the title compound was obtained as a white solid.
^-NMR (CD3OD) 5 3.82 (s, 3H) 3.85 (s, 3H) 5.58 (s, 1H) 6.59 (dd,
J=14.4, 2.0Hz, 1H) 6.72 (dd, J=8.8, 2.0Hz, 1H) 6.98 (d, J=8.0Hz, 1H)
7.09 (dd, J=8.4, 2.0Hz, 1H) 7.14 (d, J=2.0Hz, 1H) 7.35-7.50 (m, 4H)
7.71 (dd, J=7.6, 1.6Hz, 1H)
HPLC retention time: 17 min (Column name: SUMICHIRAL OA-2500,
30 mmtp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[0500] Example 38; (R) and
(S)-2-0-[(4-carbamimidovlphenvlamino)-f2-methoxv-6-methvlpvridin-4 -yDmethvl]-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vUbenzoic acid acetate [0501] [Chemical Formula 176]

After adding 39 mg of 2-hydrazinobenzoic acid hydrochloride and 57 fil of triethylamine to a solution of 90 mg of 2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylimino]thioacetamide (Example (19b)) in 3 ml of DMF, the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF =1:1 mixed solvent. After adding 41 u.1 of

acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction
mixture, the mixture was stirred at room temperature for 4 hours. After
filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
2-(3{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid (35 mg).
To a solution of this compound in 2.4 ml of a methanol:water:acetic acid
= 1:1:1 mixed solvent there was added 40 mg of iron powder, and the
mixture was stirred at 55°C for 16 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give 15 mg of
2-{3[(4-carbamimidoylphenylamino)-(2-methoxy-6-methylpyridin-4-yl) methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid acetate. 1H-NMR (d6-DMSO) 5 2.37 (s, 3H) 3.81 (s, 3H) 5.45 (br.s, 1H) 6.74 (d, J=8.4Hz, 2H) 6.79 (s, 1H) 7.01 (s, 1H) 7.29-7.35 (m, 3H) 7.45 (d, J=8.4Hz, 2H) 7.64 (d, J=7.2Hz, 1H) 8.34 (br.s, 2H) Mass spectrum (ESI)m/z: 474 (M+H)+
15 mg of this compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (6.1 mg) of the title compound was obtained. HPLC retention time: 13 min
[0502] Example 39: (R) and
(S)-4-{[(2-methoxv-6-methvl-pyridin-4-vl)-(5-oxo-l-pvrimidin-2-yl-4.5-dihydro-lH-fl.2,4]triazol-3-vl)methvl]aminolbenzamidine acetate
[0503] [Chemical Formula 177]


The same procedure was carried out as in Examples (17f) -(17g), except
that
2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (19b)) was used instead of the
2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phe
nylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in
Example (17f), to give
4-{[(2-methoxy-6-methyl-pyridin-4-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy
dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
'H-NMR (CD3OD) 8 1.94 (s, 3H) 2.40 (s, 3H) 3.86 (s, 3H) 5.65 (s, 1H)
6.77 (s, 1H) 6.85 (d, J=8.4Hz, 2H) 6.98 (s, 1H) 7.32 (t, J=5.2Hz, 1H)
7.61 (d, J=8.4Hz, 2H) 8.78 (d, J=5.2Hz, 2H)
Mass spectrum (ESI)m/z: 432 (M+H)+
A 6.0 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (2.2
mg) of the title compound was obtained.
HPLC retention time: 14 min
[0504] Example 40j (R) and
(S)-4-{[(4-fluoro-7-methoxv-2.3-dihydrobenzofuran-5-yn-(5-oxo-l-pyri
midin-2-vl-4.5-dihvdro-lH-fl,2.41triazol-3-vnmethvnamino}benzamidin
e acetate
[0505] (40a) 4-fluoro-7-methoxy-2,3-dihydrobenzofuran
[0506] [Chemical Formula 178]


To a suspension of 50 g of methyltriphenylphosphonium bromide in 300
ml of toluene there was added 45 ml of n-butyllithium (2.55 M, hexane
solution) while cooling on ice under a nitrogen atmosphere. After
stirring at room temperature for 2 hours, the reaction mixture was
allowed to stand. A 150 ml portion of the supernatant was added
dropwise to a solution of 5.00 g of
6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No.457628-15-8] in
90 ml of toluene while cooling on ice. After stirring the mixture at
room temperature for 1 hour, saturated aqueous ammonium chloride was
added to the reaction mixture. The reaction mixture was extracted with
ethyl acetate The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give
3-fluoro-6-methoxy-2-vinylphenol (4.33 g) as a solid.
This compound was dissolved in 20 ml of DMF, and then 3.00 g of
imidazole and 5.50 g of chlorotriisopropylsilane were added and the
mixture was stirred overnight at 50°C. Water was added to the reaction
mixture and extraction was performed with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
(3-fluoro-6-methoxy-2-vinylphenoxy)triisopropylsilane (3.35 g) as an oil.
To a solution of this compound in 20 ml of THF there was added 10 ml of borane-tetrahydrofuran complex (1.0 M, THF solution) while cooling on ice. After stirring overnight at room temperature, 10 ml of saturated aqueous sodium hydrogencarbonate and 10 ml of 30% hydrogen peroxide water were added to the reaction mixture while cooling on ice, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The

desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure.
The residue was dissolved in 20 ml of THF, and then 20 ml of TBAF (1.0
M, THF solution) was added and the mixture was stirred at room
temperature for 1 hour. Saturated aqueous ammonium chloride was
added to the reaction mixture, and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give
3-fluoro-2-(2-hydroxyethyl)-6-methoxyphenol (1.09 g) as an oil.
This compound and 2.10 g of triphenylphosphine were dissolved in 20 ml
of THF, and the mixture was cooled to -74°C. Next, 1.8 ml of DIAD
was added to the reaction mixture, and the temperature was allowed to
rise to room temperature prior to stirring overnight. The reaction
mixture was concentrated, and the residue was purified by silica gel
column chromatography (ethyl acetate-heptane) to give the title
compound (802 mg) as an oil.
'H-NMR (CDC13) 5 3.27 (t, J=8.8Hz, 2H) 3.84 (s, 3H) 4.67 (t, J=8.8Hz,
2H) 6.49 (t, J=8.8Hz, 1H) 6.66 (dd, J=4.4, 8.8Hz, 1H)
[0507] (40b) 4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde
[0508] [Chemical Formula 179]

To a solution of 665 mg of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran and 740 mg of N,N,N',N',N"-pentamethyldiethylenetriamine in 15 ml of THF there was added dropwise 1.66 ml of n-butyllithium (2.55 M, hexane solution) at -74°C. The mixture was stirred at -74°C for 1 hour, and then 500 ul of N-formylmorpholine was added. After further stirring at room temperature for 1 hour, IN hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was

extracted with ethyl acetate and dried over anhydrous magnesium sulfate.
The desiccating agent was filtered off and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (321
mg) as an oil.
'H-NMR (CDCI3) 5 3.34 (t, J=9.2Hz, 2H) 3.89 (s, 3H) 4.83 (t, J=9.2Hz,
2H) 7.24 (d, J=5.6Hz, 1H) 10.18 (s, 1H)
[0509] (40c)
{2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2
,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester
[0510] [Chemical Formula 180]

After adding 287 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine
[CAS No.10185-68-9], 321 mg of
4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde, 300 mg of
MS3A and 0.44 ml of trimethylsilyl cyanide to a solution of 102 mg of
Yb(OTf)3 in 5 ml of THF under a nitrogen atmosphere, the mixture was
stirred overnight at room temperature. The reaction mixture was
filtered through celite, and the celite was washed with ethyl acetate.
The organic layer was concentrated under reduced pressure to give
(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)phenylamino]acetonitrile (crude product).
To a solution of this compound in 150 ml of an ethanol:THF = 2:1 mixed
solvent there was added 50 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred at 50°C for 2 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give

2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2,
4]oxadiazol-3-yl)phenylamino]thioacetamide (700 mg, crude product).
To a solution of this compound in 20 ml of dichloromethane there was
added 300 mg of Me30+BF4", and the mixture was stirred at room
temperature for 3 hours. Saturated aqueous sodium hydrogencarbonate
was added to the reaction mixture and extraction was performed with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give
2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2, 4]oxadiazol-3-yl)phenylamino]thioacetamide acid methyl ester (crude product).
To a solution of this compound in 20 ml of ethyl acetate there was added 3 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 10 ml of toluene there were added 1 ml of 2,4,6-collidine and 500 ul of methyl chloroformate, and the mixture was stirred at 80DC for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (595 mg, isomeric mixture) as a yellow solid. 'H-NMR (CDC13) Two main isomers:
5 2.32 (s, 3H) 2.65 (s, 3H) 3.31 (t, J=9.2Hz, 2H) 3.63 (s, 3H) 3.90 (s, 3H) 4.78 (t, J=8.8Hz, 2H) 7.37 (d, J=5.2Hz, 1H) 7.10 (d, J=8.8Hz, 2H) 7.90 (d, J=8.8Hz, 2H)
6 2.48 (s, 3H) 2.63 (s, 3H) 3.17 (t, J=9.2Hz, 2H) 3.60 (s, 3H) 3.63 (s, 3H) 4.67 (t, J=8.8Hz, 2H) 6.41 (d, J=5.2Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.90 (d, J=8.8Hz, 2H)
[0511] (40d) (R) and

(S)-4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidin
e acetate
[0512] [Chemical Formula 181]

After adding 22 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine
to a solution of 105 mg of
{2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2 ,4]oxadiazol-3-yl)-phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give
5-{(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2, 4]triazol-3-one (76 mg) as a light brown solid.
To a solution of this compound in 3.0 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 86 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)

to give
4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine
acetate (44 mg).
Mass spectrum (ESI)m/z: 477 (M+H)+
44 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (16.5 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.22 (t, J=8.8Hz, 2H) 3.69 (s, 3H) 4.61
(t, J=8.8Hz, 2H) 5.88 (s, 1H) 6.84 (d, J=9.2Hz, 2H) 6.93 (d, J=6.4Hz,
1H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 8.72 (d, J=4.8Hz, 2H)
HPLC retention time: 11 min
[0513] Example 4Jj (R) and
(S)-4-([(5-fluoro-8-methoxv-2.3-dihvdrobenzo[1.4]dioxin-6-yl)-(5-oxo-l
-pvrimidin-2-vl-4.5-dihydro-lH-[1.2.4]triazol-3-vl)methvnamino}benza
midine acetate
[0514] (41a) 4-bromo-3-fluoro-6-methoxybenzene-l,2-dioI
[0515] [Chemical Formula 182]

After adding 3.11 g of N-bromosuccinimide to a solution of 2.98 g of 6-fIuoro-2-hydroxy-3-methoxybenzaldehyde [CAS No.457628-15-8] in 15 ml of acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3.13 g of 5-bromo-6-fluoro-2-hydroxy-3-methoxybenzaldehyde (crude product). To a solution of this compound in 60 ml of chloroform there was added 4.00 g of 60% metachloroperbenzoic acid, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in 20 ml of methanol, 5 ml of 5N aqueous sodium

hydroxide was added and the mixture was stirred overnight at room temperature. After adding IN hydrochloric acid to render the reaction mixture acidic, the precipitated crystals were filtered out. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.82 g, crude product). [0516] (41b)
6-bromo-5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxine [0517] [Chemical Formula 183]
After adding 830 mg of 1,2-dibromoethane and 1.4 g of potassium
carbonate to a solution of 880 mg of
4-bromo-3-fluoro-6-methoxybenzene-l,2-diol in 10 ml of DMF, the mixture was stirred at 80°C for 6 hours. Next, IN hydrochloric acid was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (549 mg) as a solid.
'H-NMR (CDC13) 8 3.84 (s, 3H) 4.32-4.38 (m, 4H) 6.60 (d, J=5.6Hz, 1H) [0518] (41c)
5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxine-6-carbaldehyde [0519] [Chemical Formula 184]

To a solution of 549 mg of
6-bromo-5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxine in 15 ml of

THF there was added dropwise 0.86 ml of n-butyllithium (2.55 M,
hexane solution) at -70°C under a nitrogen atmosphere. After stirring at
-72°C for 30 minutes, 0.3 ml of N-formylmorpholine was added and the
temperature was raised from -78°C to 0°C over a period of 30 minutes.
Saturated aqueous ammonium chloride was added to the reaction
mixture, and extraction was performed with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (247 mg) as a solid.
'H-NMR (CDC13) 5 3.90 (s, 3H) 4.35-4.38 (m, 2H) 4.43-4.45 (m, 2H) 6.92 (d, J=5.6Hz, 1H) 10.24 (s, 1H) [0520] (4Id)
[2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-meth yl-[1.2,4]oxadiazol-3-yl)phenyIimino]-l-methylsulfanylethylidene]carba mic acid methyl ester [0521] [Chemical Formula 185]

To a solution of 71 mg of Yb(OTf)3 in 4 ml of THF there were added 204
mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 247 mg of
5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxine-6-carbaldehyde, 250
mg of MS3A and 0.30 ml of trimethylsilyl cyanide under a nitrogen
atmosphere, and the mixture was stirred overnight at room temperature.
The reaction mixture was filtered through celite, and the celite was
washed with ethyl acetate. The organic layer was concentrated under
reduced pressure to give
(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-methyl-[l, 2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).

To a solution of this compound in 12 ml of an ethanokTHF = 2:1 mixed
solvent there was added 4 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred at 50°C for 4 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give
2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yI)-2-[4-(5-methyI
-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (crude product).
To a solution of this compound in 7 ml of acetonitrile there was added
220 mg of Me30+BF4_, and the mixture was stirred at room temperature
for 0.5 hour. Saturated aqueous sodium hydrogencarbonate was added
to the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give
2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-methyl -[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide acid methyl ester (crude product).
To a solution of this compound in 10 ml of ethyl acetate there was added 3 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 5 ml of toluene there were added 0.6 ml of 2,4,6-collidine and 0.3 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (266 mg, isomeric mixture) as a yellow solid. Mass spectrum (ESI)m/z: 501 (M+H)+

[0522] (41e) (R) and
(S)-4-{[(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-(5-oxo-l -pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benza midine acetate

After adding 21 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine
to a solution of 105 mg of
[2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-meth
yl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carba
mic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight
at 85°C under a nitrogen atmosphere. The reaction mixture was
concentrated, and the residue was dissolved in 3 ml of methanol and 0.3
ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate
to the reaction mixture it was stirred at room temperature for 1 hour.
Water was added to the reaction mixture and extraction was performed
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
5-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydr o-[l,2,4]triazol-3-one (58 mg) as a light brown solid. To a solution of this compound in 3.0 ml of a methanol:waterracetic acid = 1:1:1 mixed solvent there was added 70 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high

performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{[(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-(5-oxo-l-pyr
imidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidi
ne acetate (32 mg).
Mass spectrum (ESI)m/z: 493 (M+H)+
32 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (11.4 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.69 (s, 3H) 4.21-4.35 (m, 4H) 5.91 (s,
1H) 6.65 (d, J=6.0Hz, 1H) 6.85 (d, J=9.2Hz, 2H) 7.31 (t, J=4.8Hz, 1H)
7.61 (d, J=9.2Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 17 min
[0524] Example 42j (R) and
rS)-4-(r(6-fluoro-9-methoxv-3.4-dihvdro-2H-benzorbl[1.41dioxepin-7-vl )-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vl)methvllami nolbenzamidine acetate [0525] (42a)
7-bromo-6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepine [0526] [Chemical Formula 187]

After adding 830 mg of 1,3-dibromopropane and 1.4 g of potassium
carbonate to a solution of 880 mg of
4-bromo-3-fluoro-6-methoxybenzene-l,2-diol (Example (41a)) in 10 ml of DMF, the mixture was stirred at 80°C for 6 hours. After adding IN hydrochloric acid to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl

acetate-heptane) to give the title compound (548 mg) as a solid. 'H-NMR (CDCb) 8 2.26 (Sept, J=5.6Hz, 2H) 3.82 (s, 3H) 4.32 (dd, J=4.8, 10.4Hz, 4H) 6.09 (d, J=6.0Hz, 1H) [0527] (42b)
6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-carbaldehy de

To a solution of 548 mg of
7-bromo-6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepine in 15 ml of THF there was added dropwise 0.81 ml of n-butyllithium (2.55 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -72°C for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from -78°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (239 mg) as a solid.
'H-NMR (CDCI3) 8 2.33 (Sept, J=6.0Hz, 2H) 3.87 (s, 3H) 4.40 (t, J=6.0Hz, 2H) 4.48 (t, J=6.0Hz, 2H) 6.98 (d, J=5.6Hz, 1H) 10.24 (s, 1H) [0529] (42c)
[2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[ 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylid ene]carbamic acid methyl ester [0530] [Chemical Formula 189]


After adding 185 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,
239 mg of
6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-carbaldehy de, 250 mg of MS3A and 0.28 ml of trimethylsilyl cyanide to a solution of 65 mg of Yb(OTf)3 in 4 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give
(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(5-
methyl-[l ,2,4]oxadiazol-3-yI)phenylamino]acetonitrile (crude product).
To a solution of this compound in 12 ml of an ethanohTHF = 2:1 mixed
solvent there was added 4 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred at 50°C for 4 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off, and the filtrate was
concentrated under reduced pressure to give
2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4
-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]thioacetamide (crude
product).
To a solution of this compound in 7 ml of acetonitrile there was added
220 mg of Me30+BF4", and the mixture was stirred at room temperature
for 0.5 hour. Saturated aqueous sodium hydrogencarbonate was added
to the reaction mixture and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give

2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4 -(5-methyl-[ 1,2,4]oxadiazol-3-yI)phenylamino]thioacetamide acid methyl ester (crude product).
To a solution of this compound in 10 ml of ethyl acetate there was added 3 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 5 ml of toluene there were added 0.6 ml of 2,4,6-colIidine and 0.3 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, IN hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (297 mg, isomeric mixture) as a yellow solid. Mass spectrum (ESI)m/z: 515 (M+H)+
[0531] (42d) (R) and
(S)-4- {[(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[bj [1,4] dioxepin-7-yl )-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]ami no}benzamidine acetate

After adding 20 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine
to a solution of 103 mg of
[2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[ 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylid ene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred

overnight at 85°C under a nitrogen atmosphere. The reaction mixture
was concentrated, and the residue was dissolved in 3 ml of methanol and
0.3 ml of acetic acid. After adding 200 mg of sodium
cyanotrihydroborate to the reaction mixture, it was stirred at room
temperature for 1 hour. Water was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(
5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2
,4-dihydro-[l,2,4]triazol-3-one (67 mg) as a light brown solid.
To a solution of this compound in 3.0 ml of a methanol:water:acetic acid
= 1:1:1 mixed solvent there was added 70 mg of iron powder, and the
mixture was stirred overnight at 60°C under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic
acid), to give
4-{[(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-(5-
oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}b
enzamidine acetate (35 mg).
Mass spectrum (ESI)m/z: 507 (M+H)+
35 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (11.1 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 2.16-2.22 (m, 2H) 3.71 (s, 3H)
4.09-4.27 (m, 4H) 5.92 (s, IH) 6.81 (d, J=6.4Hz, IH) 6.85 (d, J=9.2Hz,
2H) 7.30 (t, J=4.8Hz, IH) 7.61 (d, J=9.2Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 15 min
[0533] Example 43j (R) and
(S)-4-(([3-methvl-5-(l-methvlpiperidin-4-vldxy')phenvn-(5-oxo-l-pvrimi din-2-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vl)methyl)amino)benzamidine

diacetate
[0534] (43a) 3-methyl-5-triisopropylsilanyloxybenzaldehyde
[0535] [Chemical Formula 191]

After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No.60549-26-0] in 20 ml of DMF, the reaction mixture was cooled to 0°C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
'H-NMR (CDC13) 5 1.12 (d, J=7.6Hz, 18H) 1.24-1.33 (m, 3H) 2.39 (s, 3H) 6.97 (s, 1H) 7.16 (s, 1H) 7.27 (s, 1H) 9.90 (s, 1H) [0536] (43b)
{2-(3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0537] [Chemical Formula 192]

To a solution of 819 mg of Yb(OTf)3 in 80 ml of dichloromethane there were added 2.43 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 3.86 g of 3-methyl-5-triisopropylsilanyloxybenzaldehyde, 3.8 g of MS3A and 3.67 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred at room temperature for 19 hours. The reaction

mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give a white sticky solid (4.05 g). To a solution of 4.05 g of the obtained white sticky solid in 100 ml of ethanol there was added 14.5 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 14 hours and 30 minutes. Water was added to the reaction mixture, and extraction was performed twice with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
Next, 100 ml of dichloromethane was added to the obtained residue for dissolution. After adding 1.38 g of Me30+BF4~ to the solution, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the obtained residue in 80 ml of toluene there were added 3.93 ml of 2,4,6-collidine and 1.97 ml of methyl chloroformate, and the mixture was stirred at 85°C for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the

filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (heptane-ethyl acetate) to
give a yellow oil (1.9 g).
To a solution of 1.9 g of the obtained yellow oil in 20 ml of THF there
was added 3.6 ml of TBAF (1.0 M, THF solution), and the mixture was
stirred at room temperature for 2 hours. After adding saturated aqueous
ammonium chloride to the reaction mixture, the solvent was distilled off
under reduced pressure. Water was added to the residue and extraction
was performed with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (heptane-ethyl acetate) to give the title compound (1.1
g, isomeric mixture).
'H-NMR (CDC13) Main isomer:
5 2.32 (s, 3H) 2.35 (s, 3H) 2.65 (s. 3H) 3.62 (s, 3H) 5.14 (br.s, 1H) 6.83
(br.s, 1H) 7.15-7.17 (m, 3H) 7.23 (br.s, 1H) 8.00-8.03 (m, 2H)
[0538] (43c) (R) and
(S)-4-({[3-methyl-5-(l-methylpiperidin-4-yloxy)phenyl]-(5-oxo-l-pyrimi
din-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
diacetate
[0539] [Chemical Formula 193]

After adding 32.6 mg of l-methylpiperidin-4-ol and 93 mg of triphenylphosphine to a solution of 100 mg of {2-(3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of THF, the mixture was stirred for 35 minutes while cooling on ice. After adding 0.100 ml of DIAD to the reaction mixture and stirring for
30 minutes while cooling on ice, the mixture was stirred at room
temperature for 3 hours. The reaction mixture was concentrated and the
residue was crudely purified by NAM silica gel column chromatography
(ethyl acetate-methanol) to give 78 mg of a crude product.
To a solution of 78 mg of the obtained crude product in 2 ml of DMF
there were added 14.8 mg of 2-hydrazinopyrimidine and 0.031 ml of
triethylamine, and the mixture was stirred at 85°C for 10 hours under a
nitrogen atmosphere. The reaction mixture was concentrated under
reduced pressure.
The obtained residue was dissolved in 2 ml of methanol, 1 ml of THF
and 0.070 ml of acetic acid. After adding 100 mg of sodium
cyanotrihydroborate to the reaction mixture it was stirred at room
temperature for 3 hours. The reaction mixture was crudely purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 1.8 ml of a
methanokwatenacetic acid = 1:1:1 mixed solvent there was added 80 mg
of iron powder, and the mixture was stirred at 60°C for 10 hours under a
nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid).
The obtained product was optically resolved using a SUM1CHIRAL
OA-2500 column, and the first eluting enantiomer (3.16 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.88 (br.s, 2H) 1.92 (s, 6H) 2.02 (br.s, 2H) 2.30 (s,
3H) 2.51 (s, 3H) 2.71 (br.s, 2H) 2.94 (br.s, 2H) 4.50 (br.s, 1H) 5.58 (s,
1H) 6.73 (br.s, 1H) 6.85 (d, J=9.2Hz, 2H) 6.96 (br.s, 1H) 6.98 (br.s, 1H)
7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30
mmtp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 40 ml/min)
[0540] Example 44: (R) and

(SV243-[(4-carbamimidovlphenvIaminoW5-oxo-l-pvrimidin-2-yl-4.5-di
hvdro-lH-[1.2.4]triazol-3-vOmethyl]-5-methylphenoxy}-N.N-dimethylac
etamide acetate
[0541] [Chemical Formula 194]

To a solution of 100 mg of
{2-(3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enyIimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (43b)) in 2 ml of DMF there were added 65 mg of potassium carbonate, 18 mg of tetrabutylammonium iodide and 0.049 ml of 2-chloro-N,N-dirnethylacetarnide, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Ethyl acetate and water were added to the reaction mixture, and extraction was performed three times with ethyl acetate. The organic layer was filtered through PRESEP™ and the filtrate was concentrated.
To a solution of the obtained residue in 2 ml of DMF there were added 23.4 mg of 2-hydrazinopyrimidine and 0.050 ml of triethylamine, and the mixture was stirred at 85°C for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in 2 ml of methanol, 1 ml of THF and 0.070 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 3 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product. To a solution of the obtained crude product in 1.8 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 80 mg of iron powder, and the mixture was stirred at 60°C for 10 hours under a

nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid).
The obtained product was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (1.4 mg) of the title
compound was obtained as a white solid.
^-NMR (CD3OD) 5 1.91 (s, 3H) 2.30 (s, 3H) 2.92 (s, 3H) 3.05 (s, 3H)
4.77 (s, 2H) 5.57 (s, 1H) 6.74 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.94 (s, 1H)
7.00 (s, 1H) 7.30 (t, J=4.4Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.77 (d,
J=4.4Hz, 2H)
HPLC retention time: 9 min (Column name: SUMICHIRAL OA-2500, 30
mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 40 ml/min)
[0542] Example 45 (]} 4-fffR) and
rS)-('5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-ri.2.41triazol-3-vn-{3-frS)-ftetrahydrofuran-3-yOoxy1-5-vinylphenvl}methyI)amino]benzamidine acetate and
£2) 4-[ffR) and
(S)-{3-ethvnvl-5-[(S)-(tetrahydrofuran-3-vl')oxv"|phenyU -(5-oxo- 1-pvrim
idin-2-vl-4.5-dihydro-lH-n.2.41triazol-3-yl)methvOamino]benzamidine
acetate
[0543] (45a) 3-ethynyl-5-triisopropylsilanyloxybenzaldehyde
[0544] [Chemical Formula 195]

To a solution of 2.0 g of 3-ethynyl-5-hydroxybenzaldehyde [CAS No.871345-34-5] in 20 ml of DMF there were added 1.87 g of imidazole and 4.4 ml of chlorotriisopropylsilane. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic

layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.92 g) as a light yellow oil.
'H-NMR (CDCb) 5 1.11 (d, J=6.8Hz, 18H) 1.23-1.32 (m, 3H) 3.13 (s, 1H) 7.21-7.23 (m, 1H) 7.34 (d, J=1.2Hz, 1H) 7.55 (dd, J=1.2,1.6Hz, 1H) 9.90 (s, 1H) [0545] (45b)
{2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0546] [Chemical Formula 196]

After adding 2.51 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yI)phenylamine, 8 g of MS3A, 806 mg of Yb(OTf>3 and 4.9 ml of trimethylsilyl cyanide to a solution of 3.92 g of 3-ethynyl-5-triisopropylsilanyloxybenzaldehyde in 100 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a light yellow solid (6.06 g). To a solution of 6.06 g of the obtained light yellow solid in 150 ml of a methanol:THF = 2:1 mixed solvent there was added 100 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 25 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and

the filtrate was concentrated under reduced pressure. To a solution of the residue in 20 ml of DMF there were added 383 mg of imidazole and 1.2 ml of chlorotriisopropylsilane. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a light yellow solid (5.58 g).
To a solution of 5.58 g of the obtained light yellow solid in 50 ml of acetonitrile there was added 1.74 g of Me30+BF4_, and the mixture was stirred at 0°C for 10 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a yellow oil (5.87 g). To a solution of 5.87 g of the obtained yellow oil in 100 ml of ethyl acetate there was added 15 g of manganese dioxide, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give an orange oil (5.6 g).
To a solution of 5.6 g of the obtained orange oil in 60 ml of toluene there were added 4.84 ml of 2,4,6-collidine and 2.42 ml of methyl chloroformate, and the mixture was stirred at 80°C for 1 hour and 30 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a yellow oil (4.71 g).

To a solution of 4.71 g of the obtained yellow oil in 60 ml of THF there
was added 8.77 ml of TBAF (1.0 M, THF solution), and the mixture was
stirred at 0°C for 1 hour. Saturated aqueous ammonium chloride was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was washed with water and saturated brine
and dried over anhydrous magnesium sulfate. The desiccating agent
was filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give the title compound (3.28 g) as a yellow solid.
'H-NMR (CDC13) Main isomer:
8 2.32 (s, 3H) 2.66 (s, 3H) 3.10 (s, 1H) 3.65 (s, 3H) 7.12 (dd,
J=1.2,2.4Hz, 1H) 7.15 (d, J=8.8Hz, 2H) 7.38 (dd, J=1.6,2.4Hz, 1H) 7.51
(d, J=1.2,1.6Hz, 1H) 8.03 (d, J=8.8Hz, 2H)
[0547] (45c) 4-[((R) and
(S)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)-{3-[(S)-
(tetrahydrofuran-3-yl)oxy]-5-vinylphenyl}methyl)amino]benzamidine
acetate (45C-1) and
4-[((R) and
(S)-{3-ethynyl-5-[(S)-(tetrahydrofuran-3-yl)oxy]phenyl}-(5-oxo-l-pyrim
idin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)amino]benzarnidine
acetate (45C-2)
[0548] [Chemical Formula 197]

[0549] [Chemical Formula 198]


After adding 0.0744 ml of (R)-(-)-3-hydroxytetrahydrofuran, 121 mg of
triphenylphosphine and 0.0891 ml of diisopropyl azodicarboxylate to a
solution of 100 mg of
{2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of THF at 0°C, the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction mixture was concentrated, and the residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give 116 mg of a crude product. To a solution of 105 mg of the obtained crude product in 1 ml of DMF there were added 23 mg of 2-hydrazinopyrimidine and 0.029 ml of triethylamine, and the mixture was stirred at 85°C for 19 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml of THF and 0.08 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred at 65°C for 47 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-[((5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)-{3-[(S)-(tetrahydrofuran-3-yl)oxy]-5-vinylphenyl}methyl)amino]benzamidine































































'H-NMR (CDCI3) Main isomer:
5 1.24 (t, J=7.6Hz, 3H) 2.33 (s, 3H) 2.60-2.70 (m, 5H) 3.61 (s, 3H) 5.00
(br.s, 1H) 6.84-6.88 (m, 1H) 7.14-7.19 (m, 3H) 7.23 (br.s, 1H) 8.01 (d,
J=8.8Hz, 2H)
[0643] (74b) (R) and
(S)-4-({[3-ethyl-5-(2-fluoroethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate
[0644] [Chemical Formula 242]

The same procedure was carried out as in Examples (6a)-(6b), except that {2-(3-ethyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylirnino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester and l-fluoro-2-iodoethane were used instead of respectively the {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbarnic acid methyl ester in Example (6a) and l-bromo-2-methoxyethane, to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.17 (t, J=7.6Hz, 3H) 1.91 (s, 3H) 2.58 (q, J=7.6Hz, 2H) 4.08-4.25 (m,2H) 4.55-4.78 (m, 2H) 5.62 (s, 1H) 6.74 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.97 (s, 1H) 7.01 (s, 1H) 7.29 (t, J=5.2Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=5.2Hz, 2H) HPLC retention time: 11 min
[0645] Example 75: (R) and
(S)-4-([(3-ethvl-5-methoxvphenvl)-(5-oxo-l-pyrimidin-2-vl-4.5-dihydro-lH-[1.2.4]triazol-3-vOmethyl]amino}benzamidine acetate [0646] [Chemical Formula 243]


The same procedure was carried out as in Examples (6a)-(6b), except that
{2-(3-ethyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen
ylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (74a)) and methyl iodide were used instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in
Example (6a) and l-bromo-2-methoxyethane in Example (6a), to give the
first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.19 (t, J=7.6Hz, 3H) 1.92 (s, 3H) 2.60 (q, J=7.6Hz,
2H) 3.75 (s, 3H) 5.62 (s, 1H) 6.72 (s, 1H) 6.86 (d, J=9.2Hz, 2H) 6.94 (s,
1H) 6.98 (s, 1H) 7.32 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.77 (d,
J=4.8Hz, 2H)
HPLC retention time: 11 min
[0647] Example 76: (R) and
fS)-4-f{[3-ethyl-5-f2-methoxyethoxy)phenyl1-f5-oxo-1-pyrimidin-2-yl-4.
5-dihvdro-lH-n.2.4]triazol-3-vl)methvUamino)benzamidine
trifluoroacetate
[0648] (76a)
4-({[3-ethyl-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-1 H-[ 1,2,4]triazol-3-yl)methyl} amino)benzamidine acetate
[0649] [Chemical Formula 244]

The same procedure was carried out as in Example (6a), except that

{2-(3-ethyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yI)phen
ylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (74a)) was used instead of the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazoi-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give the title compound.
'H-NMR (CD3OD) 8 1.21 (t, J=7.6Hz, 3H) 1.96 (s, 3H) 2.61 (q, J=7.6Hz,
2H) 3.38 (s, 3H) 3.65-3.75 (m,2H) 4.02-4.15 (m, 2H) 5.66 (s, 1H) 6.78
(s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.96 (s, 1H) 6.99 (s, 1H) 7.36 (t, J=4.8Hz,
1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 489 (M+H)+
[0650] (76b) (R) and
(S)-4-({[3-ethyl-5-(2-methoxyethoxy)phenyl]-(5-oxo-I-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
trifluoroacetate
[0651] [Chemical Formula 245]

The same procedure was carried out as in Example (12b), except that
4-({[3-ethyl-5-(2-methoxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate was
used instead of the
4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.20 (t, J=7.6Hz, 3H) 2.63 (q, J=7.6Hz, 2H) 3.39 (s, 3H) 3.63-3.77 (m,2H) 4.03-4.17 (m, 2H) 5.67 (s, 1H) 6.79 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.96 (s, 1H) 7.00 (s, 1H) 7.37 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H) HPLC retention time: 11 min

[0652] Example 77:
4-{[(3-cvanomethoxy-5-ethylphenvl)-(5-oxo-l-pyrimidin-2-yl-4.5-dihydr o-lH-fl.2.4]triazol-3-vnmethvnamino}benzamidine acetate [0653] [Chemical Formula 246]

The same procedure was carried out as in Example (6a), except that {2-(3-ethyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (74a)) and bromoacetonitrile were used instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylirnino]-l-methylsulfanylethylidene}carbamic acid methyl ester and 1 -bromo-2-methoxyethane, to give the title compound. 'H-NMR (CD3OD) 8 1.21 (t, J=7.6Hz, 3H) 1.92 (s, 3H) 2.65 (q, J=7.6Hz, 2H) 4.96 (s, 2H) 5.63 (s, 1H) 6.77-6.93 (m, 3H) 7.06 (s, 1H) 7.13 (s, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 470 (M+H)+
[0654] Example 78j (RJ and
(S)-4-({[3-ethoxv-5-(2-fluoroethoxv)phenvl]-(5-oxo-l-pvrimidin-2-vl-4.
5-dihvdro-lH-[1.2.4"|triazol-3-yl)methvUamino)benzamidine
trifluoroacetate
[0655] (78a)
{2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
[0656] [Chemical Formula 247]


The same procedure was carried out as in Examples (4a)-(4c), except that
3-ethoxy-5-hydroxybenzaldehyde was used instead of the
3-hydroxy-5-methoxybenzaldehyde in Example (4a), to give the title
compound.
'H-NMR (CDCb) Main isomer:
5 1.41 (t, J=6.8Hz, 3H) 2.32 (s, 3H) 2.65 (s, 3H) 3.65 (s, 3H) 4.06 (q,
J=6.8Hz, 2H) 6.56 (t, J=2.4Hz, 1H) 6.92 (dd, J=1.6, 2.4Hz, 1H) 7.01 (t,
J=1.6Hz, 1H) 7.16 (d, J=8.8Hz, 2H) 8.02 (d, J=8.8Hz, 2H)
[0657] (78b)
4-({[3-ethoxy-5-(2-fluoroethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro- 1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetate
[0658] [Chemical Formula 248]

The same procedure was carried out as in Example (6a), except that {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester and l-fluoro-2-iodoethane were used instead of respectively the {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester and 1 -bromo-2-methoxyethane, to give the title compound. 'H-NMR (CD3OD) 5 1.32 (t, J=7.2Hz, 3H) 1.93 (s, 3H) 3.97 (q, J=7.2Hz, 2H) 4.06-4.25 (m,2H) 4.56-4.77 (m, 2H) 5.61 (s, 1H) 6.44 (dd, J=2.0, 2.4Hz, 1H) 6.68-6.78 (m, 2H) 6.87 (d, J=8.8Hz, 2H) 7.32 (t, J=4.8Hz,

1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 493 (M+H)+
[0659] (78c) (R) and
(S)-4-({[3-ethoxy-5-(2-fluoroethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yI)methyl}amino)benzamidine
trifluoroacetate
[0660] [Chemical Formula 249]

The same procedure was carried out as in Example (12b), except that
4-({[3-ethoxy-5-(2-fluoroethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-1 H-[ 1,2,4]triazol-3 -yl)methyl} amino)benzamidine acetate was
used instead of the
4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.36 (t, J=6.8Hz, 3H) 4.02 (q, J=6.8Hz, 2H) 4.12-4.29 (m,2H) 4.60-4.80 (m, 2H) 5.65 (s, 1H) 6.50 (dd, J=2.0, 2.4Hz, 1H) 6.70-6.79 (m, 2H) 6.88 (d, J=8.8Hz, 2H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0661] Example 79: (R) and
(S)-4-{r(3.5-diethoxvphenvn-(5-oxo-l-pyrimidin-2-vl-4.5-dihvdro-lH-ri ,2,4]triazol-3-vl)methvl]amino)benzamidine trifluoroacetate [0662] (79a)
4-{[(3,5-diethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4 ]triazoI-3-yl)methyl]amino}benzamidine acetate [0663] [Chemical Formula 250]


The same procedure was carried out as in Example (6a), except that
{2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (78a)) and bromoethane were used instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and
l-bromo-2-methoxyethane, to give the title compound.
'H-NMR (CD3OD) 8 1.34 (t, J=7.2Hz, 6H) 1.93 (s, 3H) 3.98 (q, J=7.2Hz,
4H) 5.59 (s, 1H) 6.41 (t, J=2.0Hz, 1H) 6.69 (d, J=2.0Hz, 2H) 6.87 (d,
J=8.8Hz, 2H) 7.34 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d,
J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 475 (M+H)+
[0664] (79b) (R) and
(S)-4-{[(3,5-diethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l
,2,4]triazol-3-yl)methyl]amino}benzamidine trifluoroacetate
[0665] [Chemical Formula 251]

The same procedure was carried out as in Example (12b), except that 4-{[(3,5-diethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4 ]triazol-3-yl)methyl]amino}benzamidine acetate was used instead of the 4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, to give

the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.36 (t, J=6.8Hz, 6H) 4.01 (q, J=6.8Hz, 4H) 5.63 (s, 1H) 6.44 (t, J=2.0Hz, 1H) 6.68 (d, J=2.0Hz, 2H) 6.87 (d, J=8.8Hz, 2H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0666] Example 80: (R) and
(S)-4-({[3-ethoxv-5-(2-fluoroethoxv)phenyl]-(5-oxo-l-pvridazin-3-yl-4.5 -dihydro-1 H-[ 1.2,4]triazol-3-vnmethvl) amino)benzamidine acetate [0667] [Chemical Formula 252]

The same procedure was carried out as in Example 7, except that
{2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (78a)) and l-fluoro-2-iodoethane were used instead of
respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and
l-bromo-2-methoxyethane, to give the first eluting enantiomer of the
title compound.
'H-NMR (CD3OD) 8 1.24 (t, J=6.8Hz, 3H) 1.84 (s, 3H) 3.89 (q, J=6.8Hz,
2H) 4.00-4.17 (m,2H) 4.47-4.69 (m, 2H) 5.50 (s, 1H) 6.33 (dd, J=2.0,
2.4Hz, 1H) 6.62-6.70 (m, 2H) 6.78 (d, J=9.2Hz, 2H) 7.51 (d, J=9.2Hz,
2H) 7.66 (dd, J=4.8, 9.2Hz, 1H) 8.47 (dd, J=1.6, 9.2Hz, 1H) 8.92 (dd,
J=1.6, 4.8Hz, 1H)
HPLC retention time: 12 min
[0668] Example 81j (R) and
(S)-4-({[4-(2-fluoroethoxv)-3-methoxvphenvl'|-(5-oxo-l-pvrimidin-2-vl-4,5-dihvdro-lH-[1.2.41triazol-3-vl)methyUamino)benzamidine acetate


The same procedure was carried out as in Examples (6a)-(6b), except that
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylamino]-l-methylsulfanylethylidene}carbamic acid methyl
ester(18d) and 1 -fluoro-2-iodoethane were used instead of respectively the
{2-(3-hydroxy-5-methoxyphenyI)-2-[4-(5-methyI-[l,2,4]oxadiazol-3-yI)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (6a) and l-bromo-2-methoxyethane in Example (6a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 3.82 (s, 3H) 4.12-4.27 (m, 2H) 4.58-4.79 (m, 2H) 5.87 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.94 (d, J=8.4Hz, 1H) 7.08 (dd, J=2.0, 8.4Hz, 1H) 7.20 (d, J=2.0Hz, 1H) 7.27 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 8 min (Column name: SUM1CHIRAL OA-2500, 4.6 mmq> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 1 ml/min)
[0670] Example 82: (R) and
(S)-4-({(3,7-dimethoxy-2.3-dihvdrobenzofuran-5-vl)-(5-oxo-l-pvrimidin
-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[0671] (82a)
7-methoxy-3-triisopropylsilanyloxy-2,3-dihydrobenzofuran-5-carbaldehy
de
[0672] [Chemical Formula 254]


After adding 4.3 g of potassium carbonate and 2.35 mi of methyl
bromoacetate to a solution of 5.39 g of
5-bromo-2-hydroxy-3-methoxybenzoic acid methyl ester in 40 ml of DMF, the mixture was stirred for a day at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of 4.41 g of the residue in 60 ml of a methanohwater = 1:1 mixed solvent there was added 12 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and filtration was performed to give a light yellow solid (3.75 g). After adding 3 ml of acetic acid and 1.51 g of sodium acetate to a solution of the obtained light yellow solid in 26 ml of acetic anhydride, the mixture was heated to reflux for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a light yellow solid (2.26 g).
To a solution of the obtained light yellow solid in 20 ml of methanol there were added 7.5 ml of water and 5 ml of IN hydrochloric acid, and the mixture was stirred at 75°C for 10 hours. Water was added to the reaction mixture, and filtration was performed to give 5-bromo-7-methoxy-benzofuran-3-one as a light brown solid (1.78 g). 'H-NMR (CDC13) 8 3.96 (s, 3H) 4.71 (s, 2H) 7.19 (d, J=1.2Hz, 1H) 7.39 (d, J= 1.2Hz, 1H)

To a solution of the obtained light brown solid in 30 ml of methanol there was added 554 mg of sodium borohydride at 0°C, and the mixture was stirred for 3 hours and 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 30 ml of DMF there were added 956 mg of imidazole and 2.7 ml of chlorotriisopropylsilane, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 2.59 g of a light yellow solid. To a solution of the obtained light yellow solid in 30 ml of THF there was added 2.71 ml of n-butyllithium (2.62 M, hexane solution) at -78°C under a nitrogen atmosphere. After stirring for 3 hours, 0.843 ml of N-formylmorpholine was added and. the mixture was stirred at room temperature for 2 hours and 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.83 g) as a light yellow oil.
'H-NMR (CDC13) 8 0.95-1.25 (m, 21H) 3.95 (s, 3H) 4.55 (dd, J=3.6, 10.4Hz, 1H) 4.72 (dd, J=6.8, 10.4Hz, 1H) 5.66 (dd, J=3.6, 6.8Hz, 1H) 7.40 (d, J=1.2Hz, 1H) 7.51 (d, J=1.2Hz, 1H) 9.85 (s, 1H)

[0673] (82b)
{2-(3-hydroxy-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyI-[
l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester
[0674] [Chemical Formula 255]

The same procedure was carried out as in Examples (4b)-(4c), except that
7-methoxy-3-triisopropylsilanyloxy-2,3-dihydrobenzofuran-5-carbaldehy
de was used instead of the
3-methoxy-5-triisopropylsilanyloxybenzaldehyde in Example (4b), to
give the title compound.
!H-NMR (CDCI3) Main isomer:
8 2.34 (s, 3H) 2.66 (s, 3H) 3.64 (s, 3H) 3.97 (s, 3H) 4.62 (dd, J=2.4,
10.8Hz, 1H) 4.71 (dd, 3=6A, 10.8Hz, 1H) 5.45 (dt, J=2.4, 6.4Hz, 1H)
7.17 (d, J=8.8Hz, 2H) 7.45 (d, J=1.6Hz, 1H) 7.60 (d, J=1.6Hz, 1H) 8.02
(d, J=8.8Hz, 2H)
[0675] (82c)
{2-(3,7-dimethoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester
[0676] [Chemical Formula 256]

After adding 201 mg of 1,8-bis (dimethylamino)naphthalene and 138 mg of trimethyloxonium tetrafluoroborate to a solution of 150 mg of {2-(3-hydroxy-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of acetonitrile at 0°C, the mixture was stirred
for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to
the reaction mixture, and extraction was performed with ethyl acetate.
After washing the organic layer with water and saturated brine, it was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give the title compound (80 mg) as a yellow oil.
[0677] (82d) (R) and
(S)-4-({(3,7-dimethoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidin -2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate

The same procedure was carried out as in Examples (10d)-(10e), except
that
{2-(3,7-dimethoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester was used instead of the
{2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol
-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester in Example (lOd), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) isomer mixture
8 1.91 (s, 3H) 3.28, 3.34 (each s, total 3H) 3.84, 3.85 (each s, total 3H)
4.45 (dd, J=6.4, 10.8Hz, 1H) 4.54, 4.55 (each dd, J=2.4, 10.8Hz, total
1H) 4.99 (dd, J=2.4, 6.4Hz, 1H) 5.61 (s, 1H) 6.87 (d, J=8.8Hz, 2H)
7.13-7.28 (m, 2H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d,
J=4.8Hz, 2H)

HPLC retention time: 16 min
[0679] Example 83:
4-{[(3-ethoxv-5-methoxvmethvlphenvl)-(5-oxo-l-pyrimidin-2-vl-4,5-dih vdro-lH-[1.2.41triazol-3-yl)methyl]amino}benzamidine acetate [0680] (83a)
{2-(3-ethoxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0681] [Chemical Formula 258]

The same procedure was carried out as in Example (lie), except that
bromoethane was used instead of the methyl iodide, to give the title
compound.
]H-NMR (CDC13) Main isomer:
8 1.43 (t, J=7.2Hz, 3H) 2.34 (s, 3H) 2.66 (s, 3H) 3.62 (s, 3H) 4.10 (q,
J=7.2Hz, 2H) 4.72 (s, 2H) 7.10 (br.s, 1H) 7.16 (d, J=8.4Hz, 2H) 7.36
(br.t, J=2.0Hz, 1H) 7.39 (s, 1H) 8.02 (d, J=8.4Hz, 2H)
[0682] (83b)
{2-(3-ethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazoI-
3-yl)phenylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl
ester
[0683] [Chemical Formula 259]

The same procedure was carried out as in Example (82c), except that {2-(3-ethoxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3 -yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

was used instead of the
{2-(3-hydroxy-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenyIimino]-l-methylsulfanyIethyIidene}carbamic acid methyl ester, to give the title compound. [0684] (83c)
4-{[(3-ethoxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dih ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0685] [Chemical Formula 260]

The same procedure was carried out as in Example (lOd), except that
{2-(3-ethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester was used instead of the
{2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyI-[l,2,4]oxadiazol
-3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid methyl
ester, to give the title compound.
'H-NMR (CD3OD) 5 1.33 (t, J=6.8Hz, 3H) 1,92 (s, 3H) 3.33 (s, 3H) 4.00
(q, J=6.8Hz, 2H) 4.39 (s, 2H) 5.65 (s, 1H) 6.83 (s, 1H) 6.86 (d, J=8.8Hz,
2H) 7.04 (s, 1H) 7.09 (s,lH) 7.31 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H)
8.77 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 475 (M+H)+
[0686] Example 84:
4-{[r3-ethoxy-5-fluoromethylphenvl)-('5-oxo-l-pvrimidin-2-vl-4.5-dihvdr o-lH-[1.2,4]triazol-3-yl')methvl]aminolbenzamidine acetate [0687] [Chemical Formula 261]


The same procedure was carried out as in Examples (llf)-(Hg), except
that
{2-(3-ethoxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3
-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (83a)) was used instead of the
{2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol
-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester in Example (llf), to give the title compound.
'H-NMR (CD3OD) 5 1.37 (t, J=6.8Hz, 3H) 1.97 (s, 3H) 4.06 (q, J=6.8Hz,
2H) 5.35 (d, J=47.6Hz, 2H) 5.72 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.94 (s,
1H) 7.11 (s, 1H) 7.15 (s, 1H) 7.37 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H)
8.80 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 463 (M+H)+
[0688] Example 85j 4-fffR) and
CS)-('3-allvloxv-5-methoxymethvlphenvl)-('5-oxo-l-pvrimidin-2-vl-4.5-di
hydro-lH-[L2.4]triazol-3-yl)methvl]amino)benzamidine acetate
[0689] (85a)
{2-(3-allyloxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[0690] [Chemical Formula 262]

The same procedure was carried out as in Example (lie), except that

allyl bromide was used instead of the methyl iodide, to give the title
compound.
[0691] (85b)
{2-(3-allyloxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol
-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[0692] [Chemical Formula 263]

The same procedure was carried out as in Example (82c), except that
{2-(3-allyloxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester was used instead of the
{2-(3-hydroxy-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[
l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester, to give the title compound.
[0693] (85c) 4-{[(R) and
(S)-(3-allyloxy-5-methoxymethylphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-lH-[l,2,4]triazoI-3-yl)methyI]amino}benzamidine acetate
[0694] [Chemical Formula 264]

The same procedure was carried out as in Examples (10d)-(10e), except that
{2-(3-allyloxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl

ester was used instead of the
{2-(3-methoxy-5-methoxymethyIphenyl)-2-[4-(5-methyI-[l,2,4]oxadiazol
-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester in Example (lOd), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 3.34 (s, 3H) 4.40 (s, 2H) 4.53 (ddd,
J=1.6, 1.6, 5.2Hz, 2H) 5.20 (tdd, J=1.6, 1.6, 10.8Hz, 1H) 5.36 (tdd,
J=1.6, 1.6, 17.2Hz, 1H) 5.58 (s, 1H) 6.01 (tdd, J=5.2, 10.8, 17.2Hz, 1H)
6.84 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.08 (s, 1H) 7.12 (s, 1H) 7.26 (t,
J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 6 min (Column name: SUM1CHIRAL OA-2500,
4.6 mm(p * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 1 ml/min)
[0695] Example 861
4-f rf 5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-ri.2.41triazol-3-vn-(3.4.5-tr imethoxyphenvl)methyl]aminolbenzamidine acetate [0696] (86a)
{2-(4-hydroxy-3,5-dimethoxyphenyI)-2-[4-(5-methyl-[l,2,4]oxadiazoI-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0697] [Chemical Formula 265]

The same procedure was carried out as in Example (9a), except that
4-(t-butyldimethylsiIanyloxy)-3,5-dimethoxybenzaldehyde [CAS
No. 106852-80-6] was used instead of the
3-methoxy-5-triisopropylsilanyloxybenzaldehyde, to give the title
compound.
1 H-NMR (CDCI3) Main isomer:
8 2.32 (s, 3H) 2.65 (s, 3H) 3.63 (s, 3H) 3.94 (s, 6H) 5.89 (s, 1H) 7.15 (s,
2H) 7.19 (d, J=8.4Hz, 2H) 8.01 (d, J=8.4Hz, 2H)

[0698] (86b)
4- {[(5-oxo-1 -pyrimidin-2-yl-4,5-dihydro-1 H-[ 1,2,4]triazol-3-yl)-(3,4,5-tr
imethoxyphenyl)methyl]amino}benzamidine acetate
[0699] [Chemical Formula 266]

The same procedure was carried out as in Example (6a), except that
{2-(4-hydroxy-3,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
and methyl iodide were used instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-rnethylsulfanylethylidene}carbamic acid methyl ester and
l-bromo-2-methoxyethane, to give the title compound.
'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.73 (s, 3H) 3.80 (s, 6H) 5.64 (s, 1H)
6.88 (d, J=8.8Hz, 2H) 6.90 (s, 2H) 7.34 (t, J=5.2Hz, 1H) 7.61 (d,
J=8.8Hz, 2H) 8.78 (d, J=5.2Hz, 2H)
Mass spectrum (ESI)m/z: 477 (M+H)+
[0700] Example 87i
4-({[3.5-dimethoxv-4-(2-methoxvethoxy)phenyl]-[l-(2-methoxvphenvn-
5-oxo-4.5-dihvdro-lH-[1.2,4]triazol-3-vl]methvUamino)benzamidine
acetate
[0701] [Chemical Formula 267]

The same procedure was carried out as in Example (6a), except that

{2-(4-hydroxy-3,5-dimethoxyphenyI)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (86a)) and 2-methoxyphenylhydrazine hydrochloride were used
instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-]-methylsulfanylethylidene}carbamic acid methyl ester and 2-hydrazinopyrimidine, to give the title compound.
'H-NMR (CD3OD) 6 1.91 (s, 3H) 3.39 (s, 3H) 3.62-3.69 (m, 2H) 3.81 (s, 3H) 3.84 (s, 6H) 4.01-4.09 (m, 2H) 5.62 (s, 1H) 6.86 (s, 2H) 6.87 (d, J=8.8Hz, 2H) 7.03 (ddd, J=1.2, 7.6, 8.0Hz, 1H) 7.15 (dd, J=1.2, 8.4Hz, 1H) 7.31 (dd, J=2.0, 8.0Hz, 1H) 7.44 (ddd, J=2.0, 7.6, 8.4Hz, 1H) 7.64 (d, J=8.8Hz, 2H) Mass spectrum (ESI)m/z: 549 (M+H)+
[0702] Example 88: 4-(rfR) and
(S)-r5-oxo-l-pvridazin-3-vl-4.5-dihvdro-lH-fl.2.41triazol-3-vn-(3.4.5-tri methoxvphenvl)rnethvl]amino)benzarnidine trifluoroacetate [0703] (88a)
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0704] [Chemical Formula 268]

The same procedure was carried out as in Examples (4a)-(4c), except that
3-hydroxy-4,5-dimethoxybenzaldehyde was used instead of the
3-hydroxy-5-methoxybenzaldehyde in Example (4a), to give the title
compound.
'H-NMR (CDCI3) Main isomer:
8 2.32 (s, 3H) 2.65 (s, 3H) 3.65 (s, 3H) 3.93 (s, 3H) 3.97 (s, 3H) 5.82 (s,
1H) 7.00 (d, J=2.0Hz, 1H) 7.14 (d, J=8.8Hz, 2H) 7.19 (d, J=2.0Hz, 1H)
8.00 (d, J=8.8Hz, 2H)

[0705] (88b)
4-{[(5-oxo-l-pyridazin-3-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)-(3,4,5-tr imethoxyphenyl)methyl]amino}benzamidine acetate [0706] [Chemical Formula 269]

The same procedure was carried out as in Example (6a), except that
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[ 1,2,4] oxadiazol-3-
yl)phenylimino]-l-methylsulfanyIethyIidene}carbamic acid methyl ester,
methyl iodide and 3-hydrazinopyridazine hydrochloride were used
instead of respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester,
l-bromo-2-methoxyethane and 2-hydrazinopyrimidine, to give the title
compound.
'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.73 (s, 3H) 3.83 (s, 6H) 5.65 (s, 1H)
6.89 (d, J=9.2Hz, 2H) 6.91 (s, 2H) 7.62 (d, J=9.2Hz, 2H) 7.78 (dd, J=4.8,
8.8Hz, 1H) 8.51 (dd, J=l .6, 8.8Hz, 1H) 9.04 (dd, J=1.6, 4.8Hz, 1H)
Mass spectrum (ESI)m/z: 477 (M+H)+
[0707] (88c) 4-{[(R) and
(S)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)-(3,4,5-tri
methoxyphenyl)methyl]amino}benzamidine trifluoroacetate
[0708] [Chemical Formula 270]

The same procedure was carried out as in Example (12b), except that
4-{[(5-oxo-l-pyridazin-3-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)-(3,4,5-tr
imethoxyphenyl)methyl]amino}benzamidine acetate was used instead of
the
4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-di
hydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, to give
the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 3.75 (s, 3H) 3.85 (s, 6H) 5.70 (s, 1H) 6.90 (s, 2H)
6.91 (d, J=8.8Hz, 2H) 7.63 (d, J=8.8Hz, 2H) 7.81 (dd, J=4.8, 9.2Hz, 1H)
8.45 (d, J=9.2Hz, 1H) 9.08 (d, J=4.8Hz, 1H)
HPLC retention time: 11 min
[0709] Example 89: 4-{[OP and
fS)-[3-(2-fluoroethoxy)-4.5-dimethoxyphenyl|-(5-oxo-l-pyridazin-3-yl-4 .5-dihvdro-lH-[1.2,4]triazol-3-yl)methvllamino|benzamidine acetate [0710] [Chemical Formula 271]

The same procedure was carried out as in Example 7, except that
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (88a)) and l-fluoro-2-iodoethane were used instead of
respectively the
{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and 1 -bromo-2-methoxyethane, to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.75 (s, 3H) 3.82 (s, 3H) 4.12-4.32 (m, 2H) 4.58-4.78 (m, 2H) 5.58 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.90 (d, J=2.0Hz, 1H) 6.93 (d, J=2.0Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 7.75 (dd,

J=4.8, 9.2Hz, 1H) 8.56 (dd, J=1.6, 9.2Hz, 1H) 9.00 (dd, J=1.6, 4.8Hz,
1H)
HPLC retention time: 6 min (Column name: SUMICHIRAL OA-2500,
4.6 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 1 ml/min)
[0711] Example 90:
4-{[(3-ethoxvphenyl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-fl.2,4]tri azol-3-vr)methvl]amino)benzamidine acetate [0712] (90a)
{2-(3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino ]-l-methylsulfanylethylidene}carbamic acid methyl ester [0713] [Chemical Formula 272]

The same procedure was carried out as in Examples (4a)-(4c), except that
3-hydroxybenzaldehyde was used instead of the
3-hydroxy-5-methoxybenzaldehyde in Example (4a), to give the title
compound.
'H-NMR (CDC13) Main isomer:
5 2.33 (s, 3H) 2.65 (s, 3H) 3.61 (s, 3H) 5.61 (br.s, 1H) 6.96-7.05 (m, 1H)
7.16 (d, J=8.4Hz, 2H) 7.28 (m, 3H) 8.01 (d, J=8.4Hz, 2H)
[0714] (90b)
4- {[(3-ethoxyphenyl)-(5-oxo-1 -pyrimidin-2-y 1-4,5 -dihydro-1 H-[ 1,2,4]tri
azol-3-yl)methyl]amino}benzamidine acetate
[0715] [Chemical Formula 273]


The same procedure was carried out as in Example (6a), except that {2-(3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino ]-l-methylsulfanylethylidene}carbamic acid methyl ester and bromoethane were used instead of respectively the {2-(3-hydroxy-5-methoxyphenyI)-2-[4-(5-methyl-[l,2,4]oxadiazoI-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and 1 -bromo-2-methoxyethane, to give the title compound. 'H-NMR (CD3OD) 5 1.34 (t, J=6.8Hz, 3H) 1.94 (s, 3H) 4.00 (q, J=6.8Hz, 2H) 5.66 (s, 1H) 6.80-6.95 (m, 3H) 7.03-7.18 (m, 2H) 7.27 (t, J=8.4Hz, 1H) 7.32 (t, J=4.8Hz, 1H) 7.60 (d, J=8.4Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 431 (M+H)+
[0716] Example 9k.
4-({[2-fluoro-3-(2-fluoroethoxv)-5-methvlphenvl]-[l-(2-methoxvphenvn
-5-oxo-4.5-dihvdro-lH-n.2.4]triazol-3-yl]methvUamino)benzamidine
trifluoroacetate
[0717] [Chemical Formula 274]

The same procedure was carried out as in Example (14c), except that 1 -fluoro-2-iodoethane was used instead of the iodomethane, to give the title compound as a white solid.
'H-NMR (CD3OD) 5 2.30 (s, 3H) 3.81 (s, 3H) 4.23-4.32 (m, 2H) 4.66-4.80 (m, 2H) 5.96 (s, 1H) 6.84-6.89 (m, 3H) 6.95 (dd, J=1.6,7.6Hz, 1H) 7.02 (dt, J=1.2,7.6Hz, 1H) 7.13 (dd, J=1.2,8.4Hz, 1H) 7.30 (dd,

J=1.6,7.6Hz, 1H) 7.43 (ddd, J=1.6,7.6,8.4Hz, 1H) 7.62-7.65 (m, 2H) Mass spectrum (ESI)m/z: 509 (M+H)+
[0718] Example 92: 4-(|YR) and
(S)-[2-fluoro-5-methoxy-3-(2-methoxyethoxy')phenvll-(5-oxo-l-pvrimidi
n-2-yl-4.5-dihydro-lH-[l,2,4]triazol-3-yDmethyl]amino)benzamidine
acetate
[0719] [Chemical Formula 275]

The same procedure was carried out as in Example 15, except that
1-bromo-2-methoxyethane was used instead of the
2-chioro-N,N-dirnethylacetamide, to give the first eluting enantiomer of
the title compound as a white solid.
^-NMR (CD3OD) 5 1.91 (s, 3H) 3.42 (s, 3H) 3.71 (s, 3H) 3.74-3.76 (m,
2H) 4.15-4.17 (m, 2H) 5.92 (s, 1H) 6.60-6.62 (m, 1H) 6.65-6.67 (m, 1H)
6.85 (d, J=8.8Hz, 2H) 7.27 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75
(d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 509 (M+H)+ (mass of racemic mixture)
HPLC retention time: 15 min
[0720] Example 93: 4-{[fR) and
(S)-D-methoxy-5-methvlphenvl)-f5-oxo-l-pyrimidin-2-yl-4.5-dihydro-l H-[1.2,4]triazol-3-yl)methyl]amino)benzamidine acetate [0721] [Chemical Formula 276]

The same procedure was carried out as in Examples (3e)-(3h), except that

{2-(3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-I-methylsulfanylethylidene}carbamic acid methyl ester (Example (43b)) and iodomethane were used instead of respectively the [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-1 -methylsulfanylethylidene]carbamic acid methyl ester in Example (3e) and l-fluoro-2-iodoethane in Example (3e), to give the first eluting enantiomer of the title compound as a white solid. 'H-NMR (CD3OD) 8 1.91 (s, 3H) 2.29 (s, 3H) 3.75 (s, 3H) 5.57 (s, 1H) 6.69 (br.s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.92 (br.s, 1H) 6.95 (br.s, 1H) 7.30 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0722] Example 94j 4-U(R) and
(S)-|"3-(2-methoxvethoxv")-5-methvlphenvl1-(5-oxo-l-pvrimidin-2-vl-4.5-dihydro-lH-F1.2,41triazol-3-yl)methvl]amino)benzamidine acetate [0723] [Chemical Formula 277]

The same procedure was carried out as in Examples (3e)-(3h), except that
{2-(3-hydroxy-5-methylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbarnic acid methyl ester
(Example (43b)) and l-bromo-2-methoxyethane were used instead of
respectively the
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl ester in Example (3e) and 1-fluoro-2-iodoethane in Example (3e), to give the first eluting enantiomer of the title compound as a white solid. 'H-NMR (CD3OD) 8 1.90 (s, 3H) 2.29 (s, 3H) 3.38 (s, 3H) 3.67-3.70 (m, 2H) 4.05-4.07 (m, 2H) 5.56 (s, 1H) 6.70 (br.s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.94 (br.s, 1H) 6.97 (br.s, 1H) 7.27 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)

HPLC retention time: 12 min
[0724] Example 95: 4-fUR) and
(S)-(8-methoxv-4H-benzo[13]dioxin-6-yl)-[l-(2-methoxvphenvl)-5-oxo-4.5-dihvdro-lH4L2.4]triazol-3-yl]methyl)amino')benzamidine acetate [0725] [Chemical Formula 278]

The same procedure was carried out as in Examples (21i)-(21k), except that (2-methoxyphenyl)hydrazine hydrochloride was used instead of the 2-hydrazinopyrimidine in Example (21i), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 5 1.89 (s, 3H) 3.79 (s, 3H) 3.80 (s, 3H) 4.84 (s, 2H) 5.23 (s, 2H) 5.55 (s, 1H) 6.78 (d, J=1.2Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.00-7.04 (m, 2H) 7.13 (dd, J=1.2, 7.6Hz, 1H) 7.30 (dd, J=1.2, 7.6Hz, 1H) 7.42 (m, 1H) 7.61 (d, J=8.8Hz, 2H)
HPLC retention time: 15 min (Column name: SUMICHIRAL OA-2500, 20 rnmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 5 ml/min)
[0726] Example 96: 4-U(R) and
(S)-(5-ethoxy-2-fluorophenvlW5-oxo-l-pvrimidin-2-vl-4,5-dihvdro-lH-r 1.2,4]triazol-3-yl)methvl]amino}benzamidine acetate [0727] (96a)
(2-[2-fluoro-5-hydroxyphenyl]-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phe nylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0728] [Chemical Formula 279]


The same procedure was carried out as in Examples (4b)-(4c), except that
5-(t-butyldimethylsilanyloxy)-2-fluorobenzaldehyde [CAS
No.113984-67-1] was used instead of the
3-methoxy-5-triisopropylsilanyloxybenzaldehyde in Example (4b), to
give the title compound (isomeric mixture) as a yellow solid.
!H-NMR (CDCb) Two main isomers:
5 2.31 (s, 3H) 2.65 (s, 3H) 3.58 (s, 3H) 6.75-6.83 (m, 1H) 6.96-7.00 (m,
1H) 7.10 (d, J=8.0Hz, 2H) 7.32-7.35 (m, 1H) 8.00 (d, J=8.0Hz, 2H)
5 2.45 (s, 3H) 2.61 (s, 3H) 3.61 (s, 3H) 6.56-6.61 (m, 1H) 6.75-6.83 (m,
3H) 6.96-7.00 (m, 1H) 7.85 (d, J=8.0Hz, 2H)
[0729] (96b) 4-{[(R) and
(S)-(5-ethoxy-2-fluorophenyl)-(5-oxo-l-pyrimidin-2-yl-4?5-dihydro-lH-[
1,2,4]triazol-3-yl)methyI]amino}benzamidine acetate
[0730] [Chemical Formula 280]

The same procedure was carried out as in Examples (3e)-(3h), except that {2-[2-fluoro-5-hydroxyphenyl]-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phe nylimino]-]-methylsulfanylethylidene}carbarnic acid methyl ester and iodoethane were used instead of respectively the [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)-phenylimino]-1 -methylsulfanylethylidene]carbamic acid methyl ester in Example (3e) and l-fluoro-2-iodoethane in Example (3e), to give the first eluting enantiomer of the title compound as a white solid. 'H-NMR (CD3OD) 5 1.27 (t, J=6.8Hz, 3H) 1.90 (s, 3H) 3.90 (q, J=6.8Hz,

2H) 5.90 (s, IH) 6.79-6.85 (m, IH) 6.84 (d, J=8.8Hz, 2H) 7.02 (t, J=9.2Hz, IH) 7.08 (dd, J=3.2, 6.0Hz, IH) 7.26 (t, J=4.8Hz, IH) 7.59 (d, J=8.8Hz, 2H) 8.73 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0731] Example 97: 4-1 \(R) and
(S)-(8-methvl-4H-benzo[13]dioxin-6-yl)-(5-oxo-l-pvrimidin-2-vl-4.5-di hydro-lH-[l,2,41triazol-3-yl)methvl]amino)benzamidine acetate [0732] (97a) 6-bromo-8-methyl-4H-benzo[l,3]dioxine [0733] [Chemical Formula 281]

To a solution of 10 g of 2-hydroxy-3-methylbenzoic acid in 200 ml of DMF there was added 11.7 g of N-bromosuccinimide at room temperature. After the reaction mixture was stirred for 23 hours, water was added, and extraction was performed twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (14.7 g). A 5 g portion of the 14.7 g of obtained crude product was dissolved in 80 ml of THF, and the mixture was cooled and stirred at an external temperature of 0°C. To this solution there was added 22 ml of borane-THF complex (1M, THF solution) over a period of 30 minutes. After stirring the reaction mixture at room temperature for 8 hours, it was again cooled to an external temperature of 0°C, and 4.2 ml of borane-methyl sulfide complex (10 M, methyl sulfide solution) was added over a period of 15 minutes. The reaction mixture was stirred at room temperature for 18 hours and 45 minutes, and then 5 ml of water was carefully added and the mixture was stirred at room temperature for 30 minutes. After adding saturated aqueous ammonium chloride to the solution, it was concentrated under reduced pressure. Ethyl acetate was added to the residue and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a crude product (3.17 g).
A 1.5 g portion of 3.17 g of the obtained crude product was slowly added to a solution of 830 mg of sodium hydride (60% oily suspension) in 50 ml of DMF which had been cooled and stirred at an external temperature of 0°C. The reaction mixture was stirred at room temperature for 30 minutes, and then 0.51 ml of chlorobromomethane and 210 mg of sodium iodide were added at room temperature. The reaction mixture was heated at an external temperature of 80°C, stirred overnight, and then air-cooled. After carefully adding water, extraction was performed twice with t-butyl methyl ether. The combined organic layers were washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.3 g) as a light yellow solid. 'H-NMR (CDCh) 5 2.17 (s, 3H) 4.85 (s, 2H) 5.24 (s, 2H) 6.92-6.94 (m, 1H) 7.13-7.15 (m, 1H)
[0734] (97b) 8-methyl-4H-benzo[l,3]dioxine-6-carbaldehyde [0735] [Chemical Formula 282]

The same procedure was carried out as in Example (21c), except that
6-bromo-8-methyl-4H-benzo[l,3]dioxine was used instead of
6-bromo-8-methoxy-4H-benzo[l,3]dioxine, to give the title compound as
a light yellow solid.
'H-NMR (CDCI3) 5 2.26 (s, 3H) 4.94 (s, 2H) 5.34 (s, 2H) 7.37 (br.s, 1H)
7.57 (br.s, 1H) 9.83 (s, 1H)
[0736] (97c) 4-{[(R) and

(S)-(8-methyl-4H-benzo[l,3]dioxin-6-yI)-(5-oxo-l-pyrimidin-2-yI-4,5-di hydro-lH-[l,2,4]triazol-3-yI)methyl]amino}benzamidine acetate [0737] [Chemical Formula 283]

The same procedure was carried out as in Examples (21d)-(21k), except that 8-methyI-4H-benzo[l,3]dioxine-6-carbaldehyde was used instead of the 8-methoxy-4H-benzo[l,3]dioxine-6-carbaIdehyde in Example (21 d), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 2.13 (s, 3H) 4.80 (s, 2H) 5.21 (s, 2H) 5.53 (s, 1H) 6.83 (d. J=8.8Hz, 2H) 7.01 (br.s, 1H) 7.19 (br.s, m) 7.29 (t, J=4.4Hz, 1H) 7.58 (d, J=8.8Hz, 2H) 8.75 (d, J=4.4Hz, 2H) HPLC retention time: 13 min
[0738] Example 98j 4-{ffR) and
fS)-[2-fluoro-3.5-bis-(2-fluoroethoxy')phenyl]-(5-oxo-l-pvrirnidin-2-yl-4. 5-dihvdro-lH-[1.2.4]triazol-3-vnmethvnamino)benzamidine acetate [0739] (98a) l-fluoro-4-(2-fIuoroethoxy)benzene [0740] [Chemical Formula 284]
After adding 7.34 g of potassium carbonate and 8.31 g of l-fluoro-2-iodoethane to a solution of 4.5 g of 4-fluorophenol in 50 ml of DMF, the mixture was stirred at room temperature for 27 hours. Water was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography

(ethyl acetate-heptane) to give the title compound (4.6 g) as a colorless
liquid.
}H-NMR (CDCI3) 8 4.13-4.22 (m, 2H) 4.67-4.81 (m, 2H) 6.84-6.90 (m,
2H) 6.95-7.01 (m, 2H)
[0741] (98b)
2-fluoro-5-(2-fluoroethoxy)-3-triisopropylsilanyloxybenzaldehyde
[0742] [Chemical Formula 285]

The same procedure was carried out as in Examples (3a)-(3b), except that
l-fluoro-4-(2-fluoroethoxy)benzene was used instead of the
1 -fluoro-4-methoxybenzene in Example (3a), to give the title compound
as a colorless oil.
'H-NMR (CDCb) 5 1.11 (d, J=7.2Hz, 18H) 1.24-1.34 (m. 3H) 4.14-4.23
(m, 2H) 4.68-4.81 (m, 2H) 6.81-6.87 (m, 2H) 10.32 (s, 1H)
[0743] (98c)
{2-[2-fluoro-3-hydroxy-5-(2-fluoroethoxy)phenyl]-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbarnic acid
methyl ester
[0744] [Chemical Formula 286]

The same procedure was carried out as in Examples (3c)-(3d), except that
2-fluoro-5-(2-fluoroethoxy)-3-triisopropylsilanyloxybenzaldehyde was
used instead of the
2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde in Example (3c), to give the title compound (isomeric mixture). 'H-NMR (CDCb) Two main isomers:

5 2.34 (s, 3H) 2.66 (s, 3H) 3.61 (s, 3H) 4.17-4.28 (m, 2H) 4.67-4.81 (m,
2H) 5.34 (d, J=5.2Hz, 1H) 6.79 (dd, J=3.2, 6.4Hz, 1H) 6.96 (dd, J=3.2,
4.8Hz, 1H) 7.08-7.13 (m, 2H) 8.01-8.05 (m, 2H)
5 2.47 (s, 3H) 2.63 (s, 3H) 3.63 (s, 3H) 3.99-4.08 (m, 2H) 4.59-4.74 (m,
2H) 5.20 (d, J=4.0Hz, 1H) 6.24 (dd, J=3.2, 4.0Hz, 1H) 6.58 (dd, J=3.2,
7.2Hz, 1H) 6.81-6.85 (m, 2H) 7.88-7.92 (m, 2H)
[0745] (98d) 4-{[(R) and
(S)-[2-fluoro-3,5-bis-(2-fluoroethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0746] [Chemical Formula 287]

The same procedure was carried out as in Examples (3e)-(3h), except that
{2-[2-fluoro-3-hydroxy-5-(2-fluoroethoxy)phenyl]-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester was used instead of the
[2-(2-fluoro-3-hydroxy-5-methoxy-phenyl)-2-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)-phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in Example (3e), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 4.06-4.32 (m, 4H) 4.55-4.80 (m, 4H) 5.93 (s, 1H) 6.67-6.72 (m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.25-7.30 (m, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75 (d, J=4.4Hz, 2H) HPLC retention time: 13 min
[0747] Example 99: 4-1 \(R) and
('S')-[3-(2,2-difluoroethoxv')-2-fluoro-5-methoxvphenvl1-(5-oxo-l-pvrimid
in-2-vl-4,5-dihvdro-lH-[l,2,41triazol-3-vnmethvnamino)benzamidine
acetate
[0748] [Chemical Formula 288]


The same procedure was carried out as in Examples (3e)-(3h), except that l,l-difluoro-2-iodoethane was used instead of the l-fluoro-2-iodoethane in Example (3e), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.71 (s, 3H) 4.29 (dt, J=4.0, 13.6Hz, 2H) 5.96 (s, IH) 6.18 (tt, J=4.0, 54.8Hz, 1H) 6.67 (dd, J=2.8, 6.8Hz, 1H) 6.72 (d, J=2.8, 4.8Hz, IH) 6.86 (d, J=8.8Hz, 2H) 7.31 (t, J=4.8Hz, IH) 7.62 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[0749] Example H)pj 4-{[(R) and
(S)-[2-fluoro-3-(2-fluoroethoxv)-5-methoxvphenvll-(5-oxo-l-pvrazin-2-v l-4.5-dihvdro-lH-[1.2.4]triazol-3-y])methvl1amino)benzamidine acetate [0750] [Chemical Formula 289]

The same procedure was carried out as in Examples (3f)-(3h), except that
2-hydrazinopyrazine [CAS No.54608-52-5] was used instead of the
2-hydrazinopyrimidine in Example (3f), to give the first eluting
enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.70 (s, 3H) 4.21-4.31 (m, 2H)
4.65-4.79 (m, 2H) 5.93 (s, IH) 6.61 (dd, J=2.8, 6.8Hz, IH) 6.69 (d,
J=2.8, 4.8Hz, IH) 6.85 (d, J=8.8Hz, 2H) 7.60 (d, J=8.8Hz, 2H) 8.37 (d,
J=2.4Hz, IH) 8.45 (s, IH) 9.44 (s, IH)
HPLC retention time: 25 min (Column name: SUMICHIRAL OA-2500,

20 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 5 ml/min)
[0751] Example 101j 4-IIYR') and
(S)-('2-fluoro-4.5-dimethoxvphenvl)-f5-oxo-l-pvrazin-2-vl-4,5-dihvdro-l H-[1.2.4]triazol-3-vl)methvllamino)benzamidine acetate [0752] [Chemical Formula 290]

The same procedure was carried out as in Examples (119a)-(119b), except that 2-hydrazinopyrazine [CAS No.54608-52-5] was used instead of the 3-hydrazinopyridazine hydrochloride in Example (119a), to give the first eluting enantiomer of the title compound as a white solid. 'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.74 (s, 3H) 3.81 (s, 3H) 5.90 (s, 1H) 6.82 (d, J=31.6Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.11 (d, J=6.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.39 (d, J=2.8Hz, 1H) 8.46 (m, 1H) 9.41 (d, J=1.2Hz, 1H)
HPLC retention time: 27 min (Column name: SUM1CHIRAL OA-2500, 20 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 5 ml/min)
[0753] Example K)2j 4-([(R) and
(S)-(8-methoxv-4H-benzo[1.3]dioxin-6-vl)-(5-oxo-l-pvrazin-2-vl-4.5-dih vdro-lH-fl.2.41triazol-3-vnmethvl]amino>benzamidine acetate [0754] [Chemical Formula 291]


The same procedure was carried out as in Examples (21i)-(21k), except that 2-hydrazinopyrazine was used instead of the 2-hydrazinopyrimidine in Example (21i), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.82 (s, 3H) 4.86 (s, 2H) 5.22 (s, 2H) 5.53 (s, 1H) 6.82 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.06 (s, 1H) 7.59 (d, J=8.8Hz, 2H) 8.38 (d, J=2.4Hz, 1H) 8.47 (s, 1H) 9.45 (s, 1H) HPLC retention time: 16 min
[0755] Example 103: 4-frOO and
fS)-f2-fluoro-3-fluoromethoxy-5-methoxyphenvlH5-oxo-l-pvrimidin-2-yl-4,5-dihydro-lH-[1.2,4]triazol-3-vDmethyl1amino}benzamidine acetate [0756] [Chemical Formula 292]

The same procedure was carried out as in Examples (3e)-(3h), except that toluene-4-sulfonic acid fluoromethyl ester [CAS No. 114435-86-8] was used instead of the 1-fluoro-2-iodoethane in Example (3e), to give the first eluting enantiomer of the title compound as a white solid. 'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.72 (s, 3H) 5.75 (d, J=54.0Hz, 2H) 5.93 (s, 1H) 6.76 (dd, J=2.8, 6.4Hz, 1H) 6.82-6.86 (m, 1H) 6.85 (d, J=8.8Hz, 2H) 7.27 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H) HPLC retention time: 14 min

[0757] Example 104j 4-W10 and
(S)-f3-fluoromethoxv-5-methoxyphenvO-(5-oxo-l-pvrimidin-2-yl-4.5-dih vdro-lH-[1.2.4]triazol-3-vnmethvl]amino>benzamidine acetate [0758] [Chemical Formula 293]

The same procedure was carried out as in Examples (6a)-(6b), except that toluene-4-sulfonic acid fluoromethyl ester was used instead of the l-bromo-2-methoxyethane in Example (6a), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.77 (s, 3H) 5.61 (s, 1H) 5.71 (d, J=54.4Hz, 2H) 6.59 (t, J=2.4Hz, 1H) 6.86 (d, J=9.2Hz, 2H) 6.89-6.90 (m, 2H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 14 min
[0759] Example 105:
2-{3-f(4-carbamimidovl-phenvlamino)-(4-dimethvlcarbamovlmethoxv-3-
methoxyphenyl)methyl1-5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-l-vl)benza
mide trifluoroacetate
[0760] (105a)
{2-(4-dimethylcarbamoylmethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2
,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester
[0761] [Chemical Formula 294]

The same procedure was carried out as in Example (18e), except that

2-chloro-N,N-dimethylacetamide was used instead of the iodoethane in
Example (18e), to give the title compound.
[0762] (105b)
2-{3-[(4-carbamimidoyI-phenyIamino)-(4-dimethylcarbamoylmethoxy-3-
methoxy-phenyl)methyl]-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl}benzo
ic acid trifluoroacetate
[0763] [Chemical Formula 295]

The same procedure was carried out as in Example (16b), except that
{2-(4-dimethylcarbamoylmethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2
,4]oxadiazol-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester was used instead of the
{2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester, to give the title compound.
Mass spectrum (ESI)m/z: 560 (M+H)+
[0764] (105c)
2-{3-[(4-carbamimidoyl-phenylamino)-(4-dimethylcarbamoylmethoxy-3-
methoxy-phenyl)methyl]-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl}benza
mide trifluoroacetate
[0765] [Chemical Formula 296]


After adding 20.4 mg of BOP reagent, 5.3 mg of 1 -hydroxybenzotriazole,
20.5 fxl of N,N-diisopropylethylamine and 3.1 mg of ammonium chloride
to a solution of 11.5 mg of
2-{3-[(4-carbamimidoyl-phenylamino)-(4-dimethylcarbamoylmethoxy-3-
methoxy-phenyl)methyl]-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-1 -yl} benzo
ic acid trifluoroacetate in 1 ml of DMF, the mixture was stirred at room
temperature for 22 hours. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give 4.3 mg of the title
compound.
'H-NMR (CD3OD) 5 2.96 (s, 3H) 3.09 (s, 3H) 3.87 (s, 3H) 4.81 (s, 2H)
5.63 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.94 (d, J=8.4Hz, 1H) 7.10 (dd, J=8.4,
2.4Hz, 1H) 7.17 (d, J=2.4Hz, 1H) 7.44-7.68 (m, 5H) 8.28 (br.s, 1H) 8.79
(br.s, 1H)
Mass spectrum (ESI)m/z: 559 (M+H)+
[0766] Example 106:
2-(3[f4-carbamimidoylphenylaminoVphenvl-methvl1-5-oxo-4.5-dihvdro-1 H-fl.2.4]triazol-l-vl}benzoic acid trifluoroacetate [0767] [Chemical Formula 297]

The same procedure was carried out as in Examples (la)-(l g), except
that benzaldehyde was used instead of the

2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to give the title
compound.
'H-NMR (CD3OD) 8 5.72 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 7.26-7.34 (m,
8H) 7.63 (d, J=8.8Hz, 2H) 7.95 (d, J=8.0,1.6Hz, 1H)
[0768] Example 107:
4-f ([ 1 -f 2-aminophenvn-5-oxo-4.5-dihvdro-1 H-[ 1.2.41triazol-3-vn-f 2-flu oro-4,5-dimethoxvphenyl)methvUamino)benzamidine trifluoroacetate [0769] [Chemical Formula 298]

The same procedure was carried out as in Examples (135h)-(135i),
except that
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)benzoi
c acid (Example (If)) was used instead of the
2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-meth
yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,
2,4]triazol-l-yI)benzoic acid in Example (135h), to give
2-(2-aminophenyl)-5-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2
,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[l,2,4]triazol-3-one.
The same procedure was carried out as in Example (lg), except that this
compound was used instead of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)benzoi
c acid, to give the title compound.
1 H-NMR (CD3OD) 8 3.78 (s, 3H) 3.84 (s, 3H) 5.98 (s, 1H) 6.85-7.37 (m,
6H) 6.87 (d, J=8.8Hz, 2H) 7.64 (d, J=8.8Hz, 2H)
Mass spectrum (ESI)m/z: 478 (M+H)+
[0770] Example LQ8j (R) and

(SV2-(3-[(4-carbamimidoylphenvlamino>-(2-fluoro-4.5-dimethoxvphenyl
)methvll-5-oxo-4.5-dihvdro-ri.2.41triazol-l-vUbenzoic acid methvl ester
acetate
[0771] (108a)
2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid methyl ester
trifluoroacetate
[0772] [Chemical Formula 299]

To a solution of 150 mg of
2-(3-{(2-fluoro-4,5-dimethoxyphenyI)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyI}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)benzoi c acid (Example (If)) in 4.5 ml of a THF:methanol = 2:1 mixed solvent there was added 150 ul of trimethylsilyldiazomethane (2.0 M, hexane solution) in an ice bath under a nitrogen atmosphere, and the mixture was stirred for 14 hours while raising the temperature to room temperature. Next, 70 ul of trimethylsilyldiazomethane (2.0 M, hexane solution) was added in an ice bath and the mixture was stirred for 90 minutes. After adding 5 drops of acetic acid, the reaction mixture was concentrated under reduced pressure. To a solution of the residue in 4.5 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 46 mg of the title compound.
^-NMR (CD3OD) 8 3.76 (s, 3H) 3.85 (s, 3H) 3.88 (s, 3H) 5.99 (s, 1H) 6.92 (d, J=8.8Hz, 2H) 6.93 (m, 1H) 7.10 (d, J=6.8Hz, 1H) 7.68 (d,

J=8.8Hz, 2H) 7.52-7.70 (m, 3H) 7.90 (dd, J=7.6, 1.6Hz, 1H)
Mass spectrum (ESI)m/z: 521 (M+H)+
[0773] (108b) - (S)-2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI}benzoic acid methyl ester
acetate
[0774] [Chemical Formula 300]

A CHIRALPAK™ AD (column size: 2 cm

Daicel Chemical Industries, Ltd., Mobile phase: 2-propanol/hexane=l/4,
0.1% trifluoroacetic acid, Elution rate: 9 ml/min) was used for optical
resolution of 12 mg of
2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid methyl ester trifluoroacetate (retention time for the first eluting enantiomer: 30 min, retention time for the second eluting enantiomer: 50 min). Triethylamine was added to the obtained second eluting enantiomer and the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the second eluting enantiomer (4.7 mg) of the title compound.
[0775] Example 109j (R) and
(S)-2-(3-[(4-carbamimidovlphenvlamino)-(2-fluoro-4.5-dimethoxyphenvl )methvl]-5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-l-vUbenzamide acetate [0776] (109a)
2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me thyl]-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-1-y 1} benzamide trifluoroacetate

[0777] [Chemical Formula 301]

After adding 152 mg of BOP reagent, 39.5 mg of 1-hydroxybenzotriazole, 153 fxl of N,N-diisopropylethylamine and 23.5 mg of ammonium chloride to a solution of 80 mg of 2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)benzoi c acid (Example (If)) in 3 ml of DMF, the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated under reduced pressure. To a solution of the residue in 4.5 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 80 mg of iron powder, and the mixture was stirred at 55°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 41 mg of the title compound.
'H-NMR (CD3OD) 5 3.84 (s, 3H) 3.87 (s, 3H) 5.97 (s, 1H) 6.90 (d, J=11.6Hz, 1H) 6.91 (d, J=8.8Hz, 2H) 7.10 (d, J=6.8Hz, 1H) 7.68 (d, J=8.8Hz, 2H) 7.47-7.70 (m, 4H) Mass spectrum (ESI)m/z: 506 (M+H)+
[0778] (109b) (R) and
(S)-2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyI )methyl]-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-1 -yl}benzamide acetate [0779] [Chemical Formula 302]


A SUMICHIRAL OA-2500 column was used for optical resolution of 58
mg of
2-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzamide trifluoroacetate, and the first eluting enantiomer (13.1 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 3.79 (s, 3H) 3.83 (s, 3H) 5.89 (s, 1H) 6.84 (d, J=l 1.6Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.07 (d, J=6.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 7.44-7.68 (m, 4H)
HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500, 30 mm(p * 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[0780] Example lipj (R) and
CS')-2-{3-[r4-carbamimidovlphenvlamino)-r3.4-dimethoxvphenvl')methvl] -5-oxo-4.5-dihvdro-lH-|"1.2.4"ltriazol-l-vl}benzamide acetate

The same procedure was carried out as in Examples (109a)-(109b),
except that
2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyla mino]methyl} -5-oxo-4.5-dihvdro-1 H-f 1.2.41triazol-1 -vHbenzoic acid

(Example (36f)) was used instead of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-0X0-4,5-dihydro-lH-[l,2,4]triazol-l-yl)benzoi c acid in Example (109a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.90 (s, 3H) 3.83 (s, 3H) 3.85 (s, 3H) 5.60 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.98 (d, J=8.4Hz, 1H) 7.09 (dd, J=8.4,2.4Hz, 1H) 7.14 (d, J=2.4Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 7.46-7.68 (m, 4H) HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500, 30 mmq> * 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[0782] Example LUJ 4-IIYR) and
(S)-(2-fluoro-4,5-dimethoxvphenvO-(5-oxo-l-pyrimidin-2-vl-4.5-dihvdro -lH-[1.2,4]triazol-3-vl)methvl")amino}benzamidine acetate [0783] [Chemical Formula 304]

The same procedure was carried out as in Examples (17f)-(17g), except that
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)
phenyIimino]-l-methylsuIfanylethyIidene]carbamic acid methyl ester
(Example (If)) was used instead of the
{2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in
Example (17f), to give
5-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one. A 40 mg portion of this compound was optically resolved using a

CHIRALPAK™ AD-H (column size: 2 cm

To a solution of the residue in 2.4 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 20 mg of iron powder, and the mixture was stirred at 60°C for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give one optical isomer (1.94 mg) of the title compound. 'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.75 (s, 3H) 3.82 (s, 3H) 5.95 (s, 1H) 6.82-6.89 (m, 3H) 7.07 (d, J=6.8Hz, 1H) 7.63 (t, J=5.2Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.78 (d, J=5.2Hz, 2H) Mass spectrum (ESI)m/z: 465 (M+H)
[0784] Example 112:
4-({(4-methoxv-3.5-dimethvlphenvl)-fl-(2-methoxvphenvl)-5-oxo-4.5-di hydro-lH-|"1.2.41triazol-3-vnmethvUamino)benzamidine acetate [0785] [Chemical Formula 305]

The same procedure was carried out as in Examples (la)-(lg), except that 3,5-dimethyl-4-methoxybenzaldehyde [CAS No.39250-90-3] was used instead of the 2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), and 2-methoxyphenylhydrazine hydrochloride was used instead of the 2-hydrazinobenzoic acid hydrochloride in Example (le). 'H-NMR (CD3OD) 6 1.93 (s, 3H) 2.29 (s, 6H) 3.71 (s, 3H) 3.81 (s, 3H)

5.55 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.61 (td, J=7.6, 1.2Hz, 1H) 7.14 (dd, J=8.4, 1.2Hz, 1H) 7.17 (s, 2H) 7.31 (dd, J=7.6, 2.0Hz, 1H) 7.43 (ddd, J=8.4, 7.6, 2.0Hz, 1H) 7.63 (d, J=8.8Hz, 2H) Mass spectrum (ESI)m/z: 473 (M+H)+
[0786] Example Lili (R) and
(S)-4-(f(2-fluoro-5-(2-fluoroethoxv)-4-methoxyphenvl)-(5-oxo-1-pvrimi
din-2-vl-4.5-dihvdro-lH-ri,2.41triazol-3-vl)methvl]amino>benzamidine
acetate
[0787] [Chemical Formula 306]

The same procedure was carried out as in Examples (17e)-(17g), except that
{2-(2-fluoro-5-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester (Example (120c)) and l-fluoro-2-iodoethane were used instead of
respectively the
{2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]~l-methylsulfanylethylidene}carbarnic acid methyl ester in Example (17e) and iodoethane in Example (17e), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.81 (s, 3H) 4.10 (dm, J=28.8Hz, 2H) 4.60 (dm, J=47.6Hz, 2H) 5.91 (s, 1H) 6.83 (d, J=11.6Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.13 (d, J=7.2Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 497 (M+H)+
[0788] Example UAl
4- ([(4-cvanomethoxv- 3-ethoxvpheny D-f 5 -oxo-1 -pvrimidin-2-vl -4.5 -dihy dro-1H-F1.2.4]triazol-3-vDmethvl]amino} benzamidine trifluoroacetate

[0789] (114a)
{2-(4-hydroxy-3-ethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0790] [Chemical Formula 307]

The same procedure was carried out as in Examples (18a)-(18d), except
that 4-t-butyldimethylsilanyloxy-3-ethoxybenzaldehyde [CAS
No.581800-64-8] was used instead of the
4-t-butyldimethylsilanyloxy-3-methoxybenzaldehyde in Example (18a), to give the title compound. [0791] (114b)
4-{[(4-cyanomethoxy-3-ethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine trifluoroacetate [0792] [Chemical Formula 308]

The same procedure was carried out as in Examples (16a)-(16b), except
that
{2-(4-hydroxy-3-ethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylamino]-l-methylsulfanylethylidene}carbamic acid methyl ester was
used instead of the
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylamino]-l-methylsulfanylethylidene}carbamic acid methyl ester in
Example (16a), to give the title compound.
'H-NMR (CD3OD) 8 1.41 (t, J=7.2Hz, 3H) 4.10 (q, J=7.2Hz, 2H) 4.96 (s,

2H) 5.71 (s, 1H) 6.88 (d, J=9.2Hz, 2H) 7.13 (br.s, 2H) 7.24 (br.s, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 8.80 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 486 (M+H)+
[0793] Example U5j (R) and
fS)-4-([f5-ethoxv-2-fluoro-4-methoxvphenyQ-(5-oxo-l-pvrimidin-2-vl-4. 5-dihvdro-lH-[1.2.4]triazol-3-vOmethvnamino}benzamidine acetate [0794] (115a) 5-ethoxy-2-fluoro-4-methoxybenzaldehyde [0795] [Chemical Formula 309]

To a solution of 2.62 ml of morpholine in 50 ml of THF there was added 11.2 ml of n-butyllithium (2.71 M, hexane solution) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -40°C for 30 minutes. To this solution there was added dropwise a solution of 6.5 g of 2-bromo-5-ethoxy-4-methoxybenzaldehyde [CAS No.56517-30-7] in 40 ml of THF at -78°C, and the mixture was stirred at -78°C for 1 hour. After further adding 14.8 ml of n-butyllithium (2.71 M, hexane solution) at -78°C, the mixture was stirred at -78°C for 40 minutes, and then a solution of 15.8 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at -78°C and the mixture was stirred overnight while raising the temperature to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.33 g) as a light yellow solid.
'H-NMR (CDC13) 8 1.47 (t, J=7.2Hz, 3H) 3.94 (s, 3H) 4.11 (q, J=7.2Hz, 2H) 6.63 (d, J=11.6Hz, 1H) 7.26 (d, J=6.4Hz, 1H) 10.29 (s, 1H) [0796] (115b)

4-{[(5-ethoxy-2-fluoro-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-d
ihydro-lH-[l,2,4]triazol-3-yl)methyI]amino}benzamidine
trifluoroacetate
[0797] [Chemical Formula 310]

The same procedure was carried out as in Examples (la)-(ld), except that
5-ethoxy-2-fluoro-4-methoxybenzaldehyde was used instead of the
2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to give
(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazo
l-3-yl)phenylimino]-l-methylsulfanyl-ethylidene}carbamic acid methyl
ester.
The same procedure was carried out as in Example (16b), except that this
compound was used instead of the
{2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenyIimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester in Example (16b), to give the title compound.
'H-NMR (CD3OD) 8 1.33 (t, J=7.2Hz, 3H) 3.83 (s, 3H) 3.99 (q, J=7.2Hz,
2H) 5.95 (s, 1H) 6.86 (d, J=9.6Hz, 1H) 6.87 (d, J=8.8Hz, 2H) 7.04 (d,
J=7.2Hz, 1H) 7.38 (t, J=4.8Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 8.79 (d,
J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 479 (M+H)+
[0798] (115c) (R) and
(S)-4-{[(5-ethoxy-2-fluoro-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0799] [Chemical Formula 311]


A SUMICHIRAL OA-2500 column was used for optical resolution of 12
mg of
4-{[(5-ethoxy-2-fluoro-4-methoxyphenyI)-(5-oxo-l-pyrimidin-2-yl-4,5-d ihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first eluting enantiomer (5.1 mg) of the title compound was obtained. HPLC retention time: 13 min
[0800] Example U6: OP and
(S)-4-{[(3-fluoro-4.5-dimethoxvphenvl)-(5-oxo-l-pvrimidin-2-yl-4.5-dih ydro-lH-[1.2.4]triazol-3-yl)methyl]amino)benzamidine acetate [0801] (116a)
3-fluoro-5-methoxy-4-triisopropylsiIahyloxy-benzaldehyde [0802] [Chemical Formula 312]

After adding 0.52 g of imidazole and 1.49 ml of chlorotriisopropylsilane to a solution of 1.0 g of 3-fluoro-5-methoxy-4-hydroxybenzaldehyde [CAS No.79418-78-3] in 15 ml of DMF, the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.67 g) as a colorless oil.

^-NMR (CDCI3) 5 1.09 (d, J=7.6Hz, 18H) 1.30 (m, 3H) 3.89 (s, 3H)
7.21-7.25 (m, 2H) 9.80 (d, J=1.2Hz, 1H)
[0803] (116b) (R) and
(S)-4-{[(3-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dih
ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0804] [Chemical Formula 313]

The same procedure was carried out as in Examples (18a)-(18h), except
that 3-fluoro-5-methoxy-4-triisopropylsilanyloxybenzaldehyde and
iodomethane were used instead of respectively the
4-t-butyldimethylsilanyloxy-3-methoxybenzaldehyde in Example (18a) and iodoethane in Example (18e), to give the first eluting enantiomer of the title compound. HPLC retention time: 12 min
[0805] Example 3_T7j (R) and
(S)-4-({[3-(2-fluoroethoxv)-4-methoxvphenvl]-(5-oxo-l-pvrimidin-2-vl-4,5-dihydro-IH-[1.2.4]triazol-3-vl)methvl)amino)benzamidine acetate [0806] [Chemical Formula 314]

The same procedure was carried out as in Examples (16a)-(16c), except that
{2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

(Example (17d)) and 1 -fluoro-2-iodoethane were used instead of
respectively the
{2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henyIimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (16a) and iodoethane in Example (16a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 3.73 (s, 3H) 4.13 (m, 2H) 4.59 (m, 2H) 5.56 (s, 1H) 6.76 (d, J=9.2Hz, 2H) 6.90 (d, J=8.4Hz, 1H) 7.02 (dd, J=8.4,2.0Hz, 1H) 7.07 (d, J=2.0Hz, 1H) 7.26 (t, J=4.8Hz, 1H) 7.51 (d, J=9.2Hz, 2H) 8.68 (d, J=4.8Hz, 2H) (racemic mixture, trifluoroacetate data) Mass spectrum (ESI)m/z: 479 (M+H)+ (data for racemic mixture) HPLC retention time: 13 min
[0807] Example U8: (R) and
fSV4-{[f3-allvloxv-4-methoxyphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihv dro-lH-[1.2.4]triazol-3-yl)methvl]amino}benzamidine acetate [0808] (118a)
4-{[(3-allyloxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0809] [Chemical Formula 315]

The same procedure was carried out as in Examples (17e)-(17g), except that allyl bromide was used instead of the iodoethane in Example (17e), to give the title compound.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.82 (s, 3H) 4.54 (d, J=5.2Hz, 2H) 5.17 (dd, J=10.4, 1.6Hz, 1H) 5.33 (dd, J=17.2, 1.6Hz, 1H) 5.62 (s, 1H) 6.00 (m, 1H) 6.86 (d, J=8.8Hz, 2H) 6.96 (d, J=8.4Hz, 1H) 7.10 (dd, J=8.4, 2.0Hz, 1H) 7.15 (d, J=2.0Hz, 1H) 7.34 (t, J=5.2Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=5.2Hz, 2H)

Mass spectrum (ESI)m/z: 473 (M+H)+
[0810] (118b) (R) and
(S)-4-{[(3-allyloxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy
dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0811] [Chemical Formula 316]

A SUMICHIRAL OA-2500 column was used for optical resolution of
11.0 mg of
4-{[(3-allyloxy-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-
lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first
eluting enantiomer (3.9 mg) of the title compound was obtained as a
white solid.
HPLC retention time: 13 min
[0812] Example LL9j CR) and
(S)-4-{[(2-fluoro-4.5-dimethoxvphenyl)-(5-oxo-l-pvridazin-3-vl-4,5-dih vdro-lH-fl.2.41triazoI-3-vI)methvnamino>benzamidine acetate [0813] (119a)
4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro -1 H-[ 1,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0814] [Chemical Formula 317]

To a solution of 98 mg of
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)

phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester
(Example (Id)) in 3 ml of DMF there were added 30.5 mg of
3-hydrazinopyridazine hydrochloride [CAS No. 117043-87-5] and 29 \iof triethylamine, and the mixture was stirred at 85°C for 18 hours under
a nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 3 ml of a methanol:THF =1:1 mixed solvent.
After adding 44 uJ of acetic acid and 65 mg of sodium
cyanotrihydroborate to the reaction mixture, it was stirred at room
temperature for 6 hours. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give
5-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylamino]methyl}-2-pyridazin-3-yl-2,4-dihydro-[l,2,4]triazol-3-one
(60 mg).
To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 80 mg of iron powder, and the
mixture was stirred at 55°C for 15 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give 39 mg of the title compound.
'H-NMR (CD3OD) 8 1.97 (s, 3H) 3.76 (s, 3H) 3.82 (s, 3H) 5.98 (s, 1H)
6.84-6.90 (m, 3H) 7.08 (d, J=7.2Hz, 1H) 7.63 (d, J=8.8Hz,2H) 7.80 (dd,
J=8.8, 4.8Hz, 1H) 8.45 (dd, J=8.8, 1.6Hz, 1H) 9.06 (dd, J=4.8, 1.6Hz,
1H)
Mass spectrum (ESI)m/z: 465 (M+H)+
[0815] (119b) (R) and
(S)-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dih
ydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0816] [Chemical Formula 318]


A SUMICHIRAL OA-2500 column was used for optical resolution of 39
mg of
4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro -lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate, and the first eluting enantiomer (13.1 mg) of the title compound was obtained. HPLC retention time: 13 min
[0817] Example L20j (R) and
(S)-4-{[(3-allvloxv-2-fluoro-4-methoxvphenvlW5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[l,2,4]triazol-3-y0methyl1amino}benzamidine acetate [0818] (120a)
2-brorno-4-rnethoxy-5-triisopropylsilanyloxybenzaldehyde [0819] [Chemical Formula 319]

After adding 10.9 g of sodium hydrogen carbonate and 2.32 ml of
bromine to a solution of 10 g of
4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 200 ml of chloroform at 0°C, the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium sulfite was then added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (11.7 g) as a light yellow oil.

'H-NMR (CDCI3) 8 1.08 (d, J=7.2Hz, 18H) 1.22-1.27 (m, 3H) 3.88 (s, 3H) 7.01 (s, 1H) 7.40 (s, 1H) 10.13 (s, 1H)
[0820] (120b) 2-fluoro-4-methoxy-5-triisopropylsilanyloxybenzaldehyde [0821] [Chemical Formula 320]

To a solution of 2.01 ml of morpholine in 50 ml of THF there was added
8.69 ml of n-butyllithium (2.66 M, hexane solution) at -78°C under a
nitrogen atmosphere, and the mixture was stirred at -40°C for 30
minutes. A solution of
2-bromo-4-methoxy-5-triisopropylsilanyloxybenzaldehyde in 15 ml of THF was then added dropwise at -78°C, and the mixture was further stirred at -78°C for 40 minutes. After further adding 11.1 ml of n-butyllithium (2.66 M, hexane solution) at -78°C, the mixture was stirred at -78°C for 40 minutes, and then a solution of 10.6 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at -78°C and the reaction mixture was stirred overnight while raising the temperature to room temperature. Dilute hydrochloric acid was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.96 g) as a light yellow solid. 'H-NMR (CDCI3) 8 1.09 (d, J=7.2Hz, 18H) 1.22-1.27 (m, 3H) 3.87 (s, 3H) 6.59 (d, J=11.6Hz, 1H) 7.27 (d, J=6.8Hz, 1H) 10.16 (s, 1H) [0822] (120c)
{2-(2-fIuoro-5-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester

[0823] [Chemical Formula 321]

The same procedure was carried out as in Examples (17a)-(17d), except that 2-fluoro-4-methoxy-5-triisopropylsilanyloxybenzaldehyde was used instead of the 4-methoxy-3-triisopropylsilanyloxybenzaldehyde in Example (17a), to give the title compound.
[0824] (120d) (R) and
(S)-4-{[(3-allyloxy-2-fluoro-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate [0825] [Chemical Formula 322]

The same procedure was carried out as in Examples (17e)-(17g), except that
{2-(2-fluoro-5-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and allyl bromide were used instead of respectively the {2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (17e) and iodoethane in Example (17e), to give 4-{[(3-allyloxy-2-fluoro-4-methoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate. 'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.82 (s, 3H) 4.46 (d, J=5.6Hz, 2H) 5.11 (dd, J=10.8, 1.6Hz, 1H) 5.27 (dd, J=17.6, 1.6Hz, 1H) 5.92 (s, 1H) 5.95 (m, 1H) 6.83 (d, J=11.6Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.08 (d, J=7.2Hz,

1H) 7.33 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 491 (M+H)+
An 84 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (31.4
mg) of the title compound was obtained.
HPLC retention time: 12 min
[0826] Example 121j (R) and
(S)-4-{[(3-ethoxv-4-methoxvphenyl)-(5-oxo-l-pvridazin-3-vl-4.5-dihvdr o-lH-[1.2,4]triazol-3-vDmethvl1amino}benzamidine acetate [0827] [Chemical Formula 323]

The same procedure was carried out as in Examples (119a)-(l 19b) except
that
{2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example 0?e)) was used instead of
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)
phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in
Example (119a), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.34 (t, J=6.8Hz, 3H) 1.93 (s, 3H) 3.79 (s, 3H) 4.01
(q, J=6.8Hz, 2H) 5.64 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.91 (d, J=8.4Hz,
1H) 7.08 (dd, J=8.4, 2.4Hz, 1H) 7.14 (d, J=2.0Hz, 1H) 7.59 (d, J=8.8Hz,
2H) 7.76 (dd, J=9.2, 4.8Hz, 1H) 8.45 (dd, J=9.2, 1.6Hz, 1H) 9.03 (dd,
J=4.8, 1.6Hz, 1H) (data for racemic mixture)
Mass spectrum (ESI)m/z: 461 (M+H)+ (data for racemic mixture)
HPLC retention time: 12 min
[0828] Example 122j (R) and

fS)-2-{3rf4-carbamimidovlphenylaminoW5-ethoxv-2-fluoro-4-methoxvp henvOmethvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l -vllbenzoic acid acetate [0829] [Chemical Formula 324]

After adding 16 mg of 2-hydrazinobenzoic acid hydrochloride and 25 u.1 of triethylamine to a solution of 85 mg of {2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazo l-3-yl)phenylimino]-l-methylsulfanyl-ethylidene}carbamic acid methyl ester (see Example (115b)) in 3 ml of DMF, the mixture was stirred at 90°C for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanokTHF = 2:1 mixed solvent. After adding 35 p.1 of acetic acid and 55 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 2-(3-{(5-ethoxy-2-fluoro-4-methoxyphenyl)-[4-(5-methyl-[l ,2,4]oxadiaz ol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)b enzoic acid (30 mg).
To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 30 mg of iron powder, and the
mixture was stirred at 60°C for 12 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 6.0 mg of
2-{3[(4-carbamimidoylphenylamino)-(5-ethoxy-2-fluoro-4-methoxyphen
yl)methyl]-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl}benzoic acid
trifluoroacetate.

'H-NMR (CD3OD) 5 1.34 (t, J=7.2Hz, 3H) 3.84 (s, 3H) 3.98 (q, J=7.2Hz,
2H) 5.93 (s, 1H) 6.85 (d, J=12Hz, 1H) 6.87 (d, J=8.8Hz, 2H) 7.03 (d,
J=7.2Hz, 1H) 7.46-7.74 (m, 3H) 7.64 (d, J=8.8Hz, 2H) 7.97 (dd, J=8.0,
1.2Hz, 1H)
Mass spectrum (ESI)m/z: 521 (M+H)+
6 mg of this compound was optically resolved using a SUM1CHIRAL
OA-2500 column, and the first eluting enantiomer (1.9 mg) of the title
compound was obtained.
HPLC retention time: 12 min
[0830] Example 123; (R) and
rSV4-r(n-G-fluoropvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-
yl]-f7-methoxv-2.3-dihvdrobenzofuran-5-yOmethvnamino)benzamidine
acetate
[0831] [Chemical Formula 325]

The same procedure was carried out as in Example (30d), except that
{2-(7-methoxy-2,3-dihydro-benzofuran-5-yl)-2-[4-(5-methyl-[l,2,4]oxad
iazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester (Example (31a)) was used instead of the
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester, to give the first eluting enantiomer of the title
compound.
1 H-NMR (CD3OD) 5 1.91 (s, 3H) 3.20 (t, J=8.4Hz, 2H) 3.83 (s, 3H) 4.57
(t, J=8.4Hz, 2H) 5.55 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.01 (d, J=9.6Hz,
2H) 7.49-7.54 (m, 1H) 7.60 (d, J=9.2Hz, 2H) 7.80 (t, J=10.0Hz, 1H) 8.36
(d, J=4.8Hz, 1H)
Mass spectrum (ESI)m/z: 494 (M+H)+ (data for racemic mixture)

HPLC retention time: 9 min
[0832] Example 124:
4-((("2-fluoro-4.5-dimethoxvphenvn-n-r3-methoxvpvridin-2-vn-5-oxo-4. 5-dihydro-lH-[1.2.4]triazol-3-yl]methyUamino)benzamidine acetate [0833] [Chemical Formula 326]

The same procedure was carried out as in Examples (le)-(lg), except that (3-methoxypyridin-2-yl)hydrazine was used instead of the 2-hydrazinobenzoic acid hydrochloride in Example (le), to give the title compound.
'H-NMR (CD3OD) 5 1.96 (s, 3H) 3.77 (s, 3H) 3.83 (s, 3H) 3.87 (s, 3H) 5.94 (s, 1H) 6.85 (d, J=4.0Hz, 1H) 6.86 (d, J=9.2Hz, 2H) 7.05 (d, J=7.2Hz, 1H) 7.53 (dd, J=4.8, 8.4Hz, 1H) 7.63 (d, J=9.2Hz, 2H) 7.68 (dd, J=1.2, 8.4Hz, 1H) 8.10 (dd, J=1.2, 4.8Hz, 1H) Mass spectrum (ESI)m/z: 494 (M+H)+
[0834] Example 125:
4-f(('2-fluoro-4.5-dimethoxvphenvl)-[l-('3-fluoropvridin-2-vn-5-oxo-4.5-dihydro-lH-[1.2.4]triazol-3-vl]methvUamino')benzamidine acetate [0835] [Chemical Formula 327]

The same procedure was carried out as in Examples (le)-(lg), except that (3-fluoropyridin-2-yl)hydrazine was used instead of the 2-hydrazinobenzoic acid hydrochloride in Example (le), to give the title
compound.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.74 (s, 3H) 3.81 (s, 3H) 5.93 (s, 1H)
6.83 (d, J=l 1.6Hz, 1H) 6.85 (d, J=9.2Hz, 2H) 7.09 (d, J=7.2Hz, 1H)
7.51-7.56 (m, 1H) 7.61 (d, J=8.8Hz, 2H) 7.82 (ddd, J=1.2, 8.4, 10.8Hz,
lH)8.36(d, J=4.4Hz, 1H)
Mass spectrum (ESI)m/z: 482 (M+H)+
[0836] Example 126:
2-(4-{(4-carbamimidovlphenylarnino")-[l-f3-methoxvpvridin-2-vl)-5-oxo-4.5-dihydro-lH-[l,2.4]triazol-3-yl]methyl}-2-ethoxyphenoxv)-N-methvl-acetamide acetate [0837] (126a)
{2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0838] [Chemical Formula 328]

The same procedure was carried out as in Examples (18a)-(18d), except
that 4-t-butyldimethylsilanyloxy-3-ethoxybenzaldehyde [CAS
No.5 81800-64-8] was used instead of the
4-t-butyldimethylsilanyloxy-3-methoxybenzaldehyde in Example (18a), to give the title compound. [0839] (126b)
{2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [0840] [Chemical Formula 329]


After adding 200 mg of potassium carbonate and 78 mg of 2-bromo-N-methyl-acetamide to a solution of 154 mg of {2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of acetone, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with 0.5N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (161 mg) as a yellow solid. Mass spectrum (ESI)m/z: 526 (M+H)+ [0841] (126c)
2-(4-{(4-carbamimidoyl-phenylamino)-[l-(3-methoxy-pyridin-2-yl)-5-ox o-4,5-dihydro-lH-[l,2,4]triazol-3-yl]methyl}-2-ethoxy-phenoxy)-N-meth yl-acetamide acetate [0842] [Chemical Formula 330]

The same procedure was carried out as in Examples (21i)-(21j), except that
{2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid

methyl ester and (3-methoxy-pyridin-2-yl)hydrazine were used instead of
respectively the
{2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)-phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (21i) and 2-hydrazinopyrimidine in Example (21i), to give the title compound.
'H-NMR (CD3OD) 5 1.41 (t, J=6.8Hz, 3H) 1.96 (s, 3H) 2.81 (s, 3H) 3.86 (s, 3H) 4.08-4.15 (m, 2H) 4.50 (s, 2H) 5.66 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.02 (d, J=8.4Hz, 1H) 7.07 (dd, J=2.0, 8.4Hz, 1H) 7.19 (d, J=2.0Hz, 1H) 7.53 (dd, J=4.8, 8.4Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 7.68 (dd, J=1.6, 8.4Hz, 1H) 8.10 (dd, J=1.2, 4.8Hz, 1H) Mass spectrum (ESI)m/z: 547 (M+H)+
[0843] Example 127:
2-f4-ff4-carbamimidoylphenvlamino)-ri-(3-methylpyridin-2-vl)-5-oxo-4.
5-dihydro-lH-[1.2,4]triazol-3-vnmethyU-2-ethoxyphenoxy)-N-methvlac
etamide acetate
[0844] [Chemical Formula 331]

The same procedure was carried out as in Examples (21i)-(21j), except that
{2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[ 1,2,4]
oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester (Example (126a)) and (3-methylpyridin-2-yl)hydrazine were
used instead of respectively the
(2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)-phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (21 i) and 2-hydrazinopyrimidine in Example (21 i), to give the title compound.

'H-NMR (CD3OD) 5 1.41 (t, J=7.2Hz, 3H) 1.98 (s, 3H) 2.27 (s, 3H) 2.81 (s, 3H) 4.08-4.14 (m, 2H) 4.50 (s, 2H) 5.69 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.03 (d, J=8.4Hz, 1H) 7.08 (dd, J=2.0, 8.4Hz, 1H) 7.20 (d, J=2.0Hz, 1H) 7.41-7.47 (m, 1H) 7.63 (d, J=8.8Hz, 2H) 7.87 (d, J=7.6Hz, 1H) 8.38 (br.s, 1H) Mass spectrum (ESI)m/z: 531 (M+H)+
[0845] Example 128:
4-({[3-ethoxy-4-f2-methoxvethoxy)phenyl]-[l-f3-methvlpvridin-2-vl)-5-
oxo-4,5-dihydro-lH-n.2.4]triazol-3-yl]methvllamino)benzamidine
acetate
[0846] (128a)
{2-[3-ethoxy-4-(2-methoxyethoxy)phenyl]-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenyIimino]-l -methylsulfanylethylidene}carbamic acid methyl
ester
[0847] [Chemical Formula 332]

After adding 200 mg of potassium carbonate, 10 mg of
tetrabutylammonium iodide and 200 mg of l-bromo-2-methoxyethane to
a solution of
{2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example 126a) in 1 ml of DMF, the mixture was stirred overnight at
room temperature. Water was added to the reaction mixture, extraction
was performed with ethyl acetate, and the organic layer was washed with
0.5 N hydrochloric acid and saturated brine in that order. The organic
layer was dried over anhydrous magnesium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (193

mg) as a yellow solid.
Mass spectrum (ESI)m/z: 513 (M+H)+
[0848] (128b)
4-({[3-ethoxy-4-(2-methoxyethoxy)phenyl]-[l-(3-methyl-pyridin-2-yl)-5-
oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine
acetate
[0849] [Chemical Formula 333]

The same procedure was carried out as in Examples (21i)-(21j), except that
{2-(3-ethoxy-4-(2-methoxyethoxy)phenyl]-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester and (3-methylpyridin-2-yl)hydrazine were used instead of
respectively the
{2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (21 i) and 2-hydrazinopyrimidine in Example (211), to give the title compound.
'H-NMR (CD3OD) 5 1.37 (t, J=6.8Hz, 3H) 1.90 (s, 3H) 2.26 (s, 3H) 3.41 (s, 3H) 3.71-3.77 (m, 2H) 4.06-4.11 (m, 2H) 4.12-4.14 (m, 2H) 5.60 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.98 (d, J=8.0Hz, 1H) 7.06 (dd, J=2.0, 8.0Hz, 1H) 7.14 (d, J=1.6Hz, 1H) 7.42 (dd, J=5.2, 7.6Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 7.85 (d, J=8.0Hz, 1H) 8.36 (d, J=4.8Hz, 1H) Mass spectrum (ESI)m/z: 518 (M+H)+
[0850] Example 129: (R) and
(S)-4-({[3.4-dimethoxv-5-(2-methoxvethvn-phenvl]-(5-oxo-l-pvrimidin-
2-vl-4,5-dihydro-lH-[1.2.4]triazol-3-vl)methvUamino)benzamidine
acetate

[0851] (129a) 5-bromo-l,2-dimethoxy-3-(2-methoxyethyI)benzene [0852] [Chemical Formula 334]

After dissolving 3 g of 2-allyl-4-brorno-6-rnethoxy-phenol [CAS No.352019-92-2] in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50°C for 4 hours. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane. Ozone gas was blown into a solution of this compound in 140 ml of a dichloromethane:methanol=l:l mixed solvent for 40 minutes at -78°C. After blowing oxygen gas for 5 minutes to remove the dissolved ozone, 2 g of sodium borohydride was added. After stirring the mixture at room temperature for 2 hours, saturated aqueous ammonium chloride was added to the reaction mixture while cooling on ice. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(5-bromo-3-methoxy-2-triisopropylsilanyloxyphenyl)ethanol (3.808 g) as an oil.
After dissolving 2.2 g of this compound in 20 ml of THF, 7 ml of TBAF
(1.0 M, THF solution) was added and the mixture was stirred at room
temperature. Saturated aqueous ammonium chloride was added to the
reaction mixture, and extraction was performed with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
4-bromo-2-(2-hydroxyethyl)-6-methoxyphenol as an oil.

To a solution of this compound in 30 ml of t-butyl methyl ether there were added 20 ml of 40% aqueous sodium hydroxide, 200 mg of tetrabutylammonium iodide and 5 ml of iodomethane, and the mixture was stirred at 50°C for 5 hours and at room temperature for 48 hours. Water was added to the reaction mixture, and extraction was performed with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (493 mg) as an oil.
'H-NMR (CDCb) 5 2.86 (t, J=7.2Hz, 2H) 3.35 (s, 3H) 3.55 (t, J=7.2Hz, 2H) 3.79 (s, 3H) 3.83 (s, 3H) 6.89 (d, J=2.0Hz, 1H) 6.95 (d, J=2.0Hz, 1H)
[0853] (129b) 3,4-dimethoxy-5-(2-methoxyethyl)benzaldehyde [0854] [Chemical Formula 335]

To a solution of 1.3 g of
5-bromo-l,2-dimethoxy-3-(2-methoxy-ethyl)benzene in 20 ml of THF there was added dropwise 2 ml of n-butyllithium (2.66 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -70°C for 30 minutes, 0.7 ml of N-formylmorpholine was added and the temperature was raised from -70°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (806 mg) as an oil. ^-NMR (CDCb) 5 2.97 (t, J=6.4Hz, 2H) 3.36 (s, 3H) 3.61 (t, J=6.8Hz,

2H) 3.91 (s, 3H) 3.92 (s, 3H) 7.33 (d, J=2.0Hz, 1H) 7.35 (d, J=2.0Hz,
1H), 9.86 (s, 1H)
[0855] (129c)
{2-[3,4-dimethoxy-5-(2-methoxyethyl)phenyl]-2-[4-(5-methyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester
[0856] [Chemical Formula 336]

The same procedure was carried out as in Examples (21d)-(21h), except that 3,4-dimethoxy-5-(2-methoxyethyl)benzaldehyde was used instead of the 8-methoxy-4H-benzo[l,3]dioxine-6-carbaldehyde in Example (2Id), to give the title compound. Mass spectrum (ESI)m/z: 513 (M+H)+ [0857] (129d)
4-({[3,4-dimethoxy-5-(2-methoxyethyl)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate

The same procedure was carried out as in Examples (21i)-(21j), except that
{2-[3,4-dimethoxy-5-(2-methoxyethyl)phenyl]-2-[4-(5-methyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester was used instead of the
{2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl

ester in Example (21 i), to give the title compound.
'H-NMR (de-DMSO) 5 1.73 (s, 3H) 2.73 (t, J=6.8Hz, 2H) 3.18 (s, 3H)
3.43 (t, J=6.8Hz, 2H) 3.66 (s, 3H) 3.74 (s, 3H) 5.28 (d, J=6.8Hz, 1H)
6.83 (d, J=8.8Hz, 2H) 6.97 (s, 1H) 7.08 (t, J=4.4Hz, 1H) 7.12 (s, 1H)
7.20 (d, J=6.8Hz, 1H) 7.55 (d, J=8.8Hz, 2H) 8.61 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 505 (M+H)+
[0858] (129e) (R) and
(S)-4-({[3,4-dimethoxy-5-(2-methoxyethyl)-phenyl]-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[0859] [Chemical Formula 337]

A SUMICHIRAL OA-2500 column was used for optical resolution of 63
mg of
4-({[3,4-dimethoxy-5-(methoxyethyl)phenyl]-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate, and the first eluting enantiomer (26.7 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 2.85 (t, J=6.8Hz, 2H) 3.28 (s, 3H) 3.55 (t, J=6.8Hz, 2H) 3.77 (s, 3H) 3.83 (s, 3H) 5.78 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.00 (d, J=1.6Hz, 1H) 7.09 (t, J=1.6Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 11 min
[0860] Example 130: (R) and
(S)-4-fff4-methoxv-8,9-dihvdro-5,7-dioxa-benzocvclohepten-2-vl)-(5-ox o-l-pyrimidin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vOmethyl]amino}ben zamidine acetate [0861] (130a)

2-bromo-4-methoxy-8,9-dihydro-5,7-dioxabenzocycloheptene [0862] [Chemical Formula 338]

After dissolving 3 g of 2-allyl-4-bromo-6-methoxyphenol in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50°C for 4 hours. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-aIlyl-4-bromo-6-methoxyphenoxy)triisopropylsilane. Ozone gas was blown into a solution of this compound in 140 ml of a dichloromethane:methanol = 1:1 mixed solvent for 40 minutes at -78°C. After blowing oxygen gas for 5 minutes to remove the dissolved ozone, 2 g of sodium borohydride was added. After stirring the mixture at room temperature for 2 hours, saturated aqueous ammonium chloride was added to the reaction mixture while cooling on ice. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(5-bromo-3-methoxy-2-triisopropylsilanyloxyphenyl)ethanol (3.808 g) as an oil.
After dissolving 1.6 g of this compound in 10 ml of THF, 5 ml of TBAF
(1.0 M, THF solution) was added and the mixture was stirred at room
temperature. Saturated aqueous ammonium chloride was added to the
reaction mixture, and extraction was performed with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give

4-bromo-2-(2-hydroxyethyl)-6-methoxyphenol as an oil.
To a solution of 898 mg of
4~bromo-2-(2-hydroxyethyl)-6-methoxyphenol in 10 ml of DMF there was added 1 g of sodium bistrimethylsilylamide while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 1 ml of bromochloromethane to the reaction mixture, it was stirred at 80°C for 20 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (420 mg) as an oil. 'H-NMR (CDC13) 5 2.96-2.99 (m, 2H) 3.78-3.82 (m, 2H) 3.84 (s, 3H) 5.04 (s, 2H) 6.89 (d, J=2.0Hz, 1H) 6.92 (d, J=2.0Hz, 1H) [0863] (130b)
4-methoxy-8,9-dihydro-5,7-dioxabenzocycloheptene-2-carbaldehyde [0864] [Chemical Formula 339]

To a solution of 420 mg of
2-bromo-4-methoxy-8,9-dihydro-5,7-dioxa-benzocycloheptene in 10 ml of THF there was added dropwise 0.7 ml of n-butyllithium (2.66 M, hexane solution) at -70°C under a nitrogen atmosphere. After stirring at -70°C for 10 minutes, 0.5 ml of N-formylmorpholine was added and the temperature was raised from -70°C to 0°C over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography (ethyl acetate-heptane) to give the title compound (235
mg) as an oil.
'H-NMR (CDCb) 8 3.11 (t, J=5.2Hz, 2H) 3.87-3.89 (m, 2H) 3.92 (s, 3H)
5.12 (s, 2H) 7.27 (d, J=2.0Hz, 1H) 7.33 (d, J=2.0Hz, 1H) 9.86 (s, 1H)
[0865] (130c) (R) and
(S)-4-{[(4-methoxy-8,9-dihydro-5,7-dioxa-benzocyclohepten-2-yl)-(5-ox
o-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}ben
zamidine acetate
[0866] [Chemical Formula 340]

The same procedure was carried out as in Examples (21d)-(21k), except
that
4-methoxy-8,9-dihydro-5,7-dioxa-benzocycloheptene-2-carbaldehyde
was used instead of the 8-methoxy-4H-benzo[l,3]dioxine-6-carbaldehyde
in Example (2Id), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 2.97 (t, J=4.0Hz, 2H) 3.77 (dd, J=3.6,
6.0Hz, 2H) 3.81 (s, 3H) 4.95 (s, 2H) 5.59 (s, 1H) 6.85 (d, J=8.8Hz, 2H)
6.98 (d, J=2.0Hz, 1H) 7.11 (d, J=2.0Hz, 1H) 7.31 (t, J=5.2Hz, 1H) 7.60
(d, J=8.8Hz, 2H) 8.76 (d, J=5.2Hz, 2H)
HPLC retention time: 13 min
[0867] Example 13Jj (R) and
(S)-4-(F(3-cvanomethvl-4-fluoro-5-methoxvphenyl)-(5-oxo-l-pyrimidin-
2-vl-4.5-dihydro-lH-[1.2.4]triazol-3-vl)methvl]amino}benzamidine
acetate
[0868] (131a)
4-fluoro-3-methoxy-5-triisopropylsilanyloxymethylbenzaldehyde
[0869] [Chemical Formula 341]


After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS
No. 128495-45-4] in 100 ml of DMF, 5 g of imidazole and 17 g of
t-butyl-chlorodiphenylsilane were added and the mixture was stirred
overnight at room temperature. Next, IN hydrochloric acid was added
to the reaction mixture, and extraction was performed with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil. To a solution of 20.4 g of this compound and 9.4 g of N,N,N',N',N"-pentamethyldiethylenetriamine in 60 ml of THF there was added dropwise 20 ml of n-butyllithium (2.66 M, hexane solution) at -78°C under a nitrogen atmosphere. After stirring for 15 minutes, 6.5 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 5-(t-butyl-diphenylsilanyloxymethyl)-2-fluoro-3-methoxy-benzaldehyde as an oil.
'H-NMR (CDC13) 5 1.10 (s, 9H) 3.86 (s, 3H) 4.75 (s, 2H) 7.23-7.27 (m, 2H) 7.35-7.45 (m, 6H) 7.64-7.66 (m, 4H) 10.33 (s, 1H) To a solution of this compound in 150 ml of an ethanoLTHF =1:1 mixed solvent there was added 2 g of sodium borohydride while cooling on ice. After stirring overnight at room temperature, IN hydrochloric acid was added to the reaction mixture while cooling on ice. The reaction

mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give [5-(t-butyl-diphenylsilanyloxymethyl)-2-fluoro-3-methoxyphenyl]methan ol (18.7 g) as an oil.
'H-NMR (CDCI3) 8 1.10 (s, 9H) 3.21 (s, 1H) 3.84 (s, 3H) 4.71 (s, 4H) 6.85 (d, J=4.8Hz, 1H) 6.94 (d, J=8.6Hz, 1H) 7.35-7.44 (m, 6H) 7.65-7.68 (m, 4H)
This compound was dissolved in 10 ml of DMF, and then 1 g of imidazole and 1 g of chlorotriisopropylsilane were added and the mixture was stirred at room temperature for 2 days. Next, IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After dissolving the residue in 200 ml of THF, 7.1 ml of
tetrabutylammonium hydroxide (40%, aqueous solution) was added and
the mixture was stirred at room temperature for 2 hours. Extraction was
performed with t-butyl methyl ether. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give
(4-fluoro-3-methoxy-5-triisopropylsilanyloxymethyl-phenyl)-methanol (2.435 g) as an oil.
After dissolving this compound in 30 ml of dichloromethane, there were added 2 g of MS3A, 1.3 g of N-methylmorpholine-N-oxide and 130 mg of tetrabutylammonium perruthenate in that order and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel chromatography (ethyl acetate-heptane) to give the title compound (2.103 g). [0870] (131b) {2-(4-fluoro-3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]

oxadiazol-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester
[0871] [Chemical Formula 342]

The same procedure was carried out as in Example (22b), except that
4-fluoro-3-methoxy-5-triisopropylsilanyloxymethylbenzaldehyde was
used instead of the
3,4-dimethoxy-5-triisopropylsilanyloxymethylbenzaldehyde, to give the
title compound.
Mass spectrum (ESI)m/z: 473 (M+H)+
[0872] (131c)
{2-(4-fluoro-3-cyanomethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)pheny]imino]-]-methylsulfanylethylidene}carbarnic acid
methyl ester
[0873] [Chemical Formula 343]

The same procedure was carried out as in Example (26a), except that
{2-(4-fluoro-3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[ 1,2,4]
oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester was used instead of the
{2-(3,4-dimethoxy-5-hydroxymethylphenyI)-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester, to give the title compound.
Mass spectrum (ESI)m/z: 482 (M+H)+
[0874] (13Id) (R) and
(S)-4-{[(3-cyanomethyl-4-fluoro-5-methoxyphenyl)-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine

acetate
[0875] [Chemical Formula 344]

The same procedure was carried out as in Examples (21i)-(21k), except that
{2-(4-fluoro-3-cyanomethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]ox
adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester was used instead of the
{2-(8-methoxy-4H-benzo[ 1,3]dioxin-6-yl)-2-[4-(5-methyl-[ 1,2,4]oxadiaz oI-3-yI)phenyIimino]-l-methylsulfanyIethylidene}carbamic acid methyl ester in Example (21i), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.88 (m, 5H) 5.62 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.19 (dd, J=2.0, 5.2Hz, 1H) 7.27 (t, J=4.8Hz, 1H) 7.33 (dd, J=2.0, 8.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 13 min
[0876] Example L32j (R) and
(S)-4-f{('3-ethoxv-4-methoxvphenyl')-fl-(3-fluoro-pvridin-2-vlV5-oxo-4. 5-dihvdro-lH41.2.41triazol-3-yl1methyl)amino}benzarnidine acetate [0877] [Chemical Formula 345]

The same procedure was carried out as m Example (30d), except that {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph

enylamino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (17e)) was used instead of the
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester, to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.38 (t, J=6.8Hz, 3H) 1.92 (s, 3H) 3.82 (s, 3H) 4.05
(q, J=6.8Hz, 2H) 5.60 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.96 (d, J=8.4Hz,
1H) 7.07 (dd, J=2.4, 8.4Hz, 1H) 7.12 (d, J=1.6Hz, 1H) 7.53 (quint,
J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 7.82 (dt, J=1.2, 8.4Hz, 1H) 8.37 (d,
J=4.4Hz, 1H)
HPLC retention time: 8 min
[0878] Example 133: (R) and
rS^^-dri-rS-fluoroDvridin^-vn-S-oxo^.S-dihvdro-lH-n^^ltriazol-S-
yl]-(8-methoxy-4H-benzo[l,3]dioxin-6-vOmethyl}amino)benzamidine
acetate
[0879] [Chemical Formula 346]

The same procedure was carried out as in Example (30d), except that
{2-(8-methoxy-4H-benzo[ 1,3]dioxin-6-yl)-2-[4-(5-methyl-[ 1,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester (Example (21h)) was used instead of the
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester, to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 6 1.88 (s, 3H) 3.81 (s, 3H) 4.85 (m, 2H) 5.23 (s, 2H)
5.56 (s, 1H) 6.80 (d, J=2.0Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.04 (d,

J=2.0Hz, 1H) 7.50-7.55 (m, 1H) 7.60 (d, J=8.8Hz, 2H) 7.81 (dt, 3=1.2, 8.4Hz, 1H) 8.37 (d, J=4.4Hz, 1H) HPLC retention time: 8 min
[0880] Example 134:
4-an-('3-bromopvridin-2-vn-5-oxo-4.5-dihvdro-lH-ri.2.41triazol-3-vll-( 2-fluoro-4,5-dimethoxyphenvl)methvUamino)benzamidine acetate [0881] [Chemical Formula 347]

The same procedure was carried out as in Examples (le)-(l g), except
that (3-bromopyridin-2-yl)hydrazine was used instead of the
2-hydrazinobenzoic acid hydrochloride in Example (le), to give the title
compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.77 (s, 3H) 3.82 (s, 3H) 5.91 (s, 1H)
6.85 (d, J=11.2Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.07 (d, J=7.2Hz, 1H) 7.43
(dd, J=4.8, 8.0Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.23 (dd, J=1.6, 8.0Hz, 1H)
8.52 (dd, J=1.6, 4.8Hz, 1H)
Mass spectrum (ESI)m/z: 542 (M+H)+
[0882] Example 135:
C2-{3-[(4-carbamimidovlphenvlamino)-C3-dimethylcarbamovlmethoxv-5-ethvl-2-fluorophenyl)methvl]-5-oxo-4.5-dihvdro-lH-n.2,4]triazol-l-vUp henvHcarbamic acid methyl ester trifluoroacetate [0883] (135a) 5-ethyl-2-fluorophenol [0884] [Chemical Formula 348]

A solution of 15.5 g of 4-ethylfluorobenzene and 14.6 g of N,N,N'N'-tetrarnethylethylenediamine in 500 ml of THF was cooled to -75°C under a nitrogen atmosphere, and then 126 ml of s-butyllithium

(0.99M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 28 ml of trimethyl borate, the reaction mixture was warmed to room temperature and 14.4 ml of acetic acid was added. After stirring for 30 minutes, the reaction mixture was cooled to 0°C, and then 28.4 ml of 30% aqueous hydrogen peroxide was added and the mixture was stirred at room temperature for 18 hours. Next, 500 ml of saturated aqueous sodium sulfite was added to the reaction mixture and extraction was performed with 1 liter of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (16.35 g) as a colorless liquid (boiling point: 76-80°C, 17 mmHg).
'H-NMR (CDCfe) 8 1.30 (t, J=7.7Hz, 3H) 2.57 (q, J=7.7Hz, 2H) 6.65 (ddd, J=8.5, 4.7, 2.1Hz, 1H) 6.83 (dd, J=8.5, 2.1Hz, 1H) 6.95 (dd, J=10.6, 8.5Hz, 1H)
[0885] (135b) t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane [0886] [Chemical Formula 349]

After adding 9.16 g of imidazole and 19.4 g of t-butyldimethylchlorosilane to a solution of 16.4 g of 5-ethyl-2-fluorophenol in 40 ml of DMF, the reaction mixture was stirred at room temperature for 18 hours. After then adding 500 ml of diethyl ether and 500 ml of water to the reaction mixture, the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (25.38 g) as a colorless liquid (boiling point: 133-135°C, 20 mmHg).

'H-NMR (CDCb) 6 0.19 (s, 6H) 1.01 (s, 9H) 1.38 (t, J=7.7Hz, 3H) 2.55 (q, J=7.7Hz, 2H) 6.67 (ddd, J=8.3, 4.3, 2.2Hz, 1H) 6.72 (dd, J=8.3, 2.2Hz, 1H) 6.94 (dd, J=10.8, 8.3Hz, 1H) [0887] (135c)
3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorobenzaldehyde [08881 [Chemical Formula 350]
A solution of 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane
and 7.5 g of N,N,N'N'-tetramethylethylenediamine in 250 ml of THF was
cooled to -75°C under a nitrogen atmosphere, and then 55.6 ml of
s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture
was stirred for 2 hours. After adding 7.74 ml of DMF and stirring at
-75°C for 1 hour, the temperature was allowed to rise to room
temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous
ammonium chloride were added to the reaction mixture, the organic layer
was washed twice with 500 ml of water and once with 500 ml of
saturated aqueous sodium chloride in that order, and the aqueous layer
was extracted with 100 ml of diethyl ether. The organic layers were
combined and dried over anhydrous magnesium sulfate, the desiccating
agent was filtered off, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (12.6 g) as a white solid.
'H-NMR (CDCb) 5 0.24 (s, 6H) 1.01 (s, 9H) 1.24 (t, J=7.7Hz, 3H) 2.60 (q, J=7.7Hz, 2H) 6.99 (dd, J=10.0, 2.2Hz, 1H) 7.25 (dd, J=4.8, 2.2Hz, 1H) 10.30 (s, 1H) [0889] (135d)
{2-[3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methy l-[l,2,4]oxadiazol-3-yl)phenylimino]-l-rnethylsulfanylethylidene} carbarn ic acid methyl ester [0890] [Chemical Formula 351]


The same procedure was carried out as in Examples (la)-(ld), except that
3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorobenzaldehyde was used
instead of the 2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to
give the title compound (0.76 g) as a light yellow oil.
'H-NMR (CDCI3) Two main isomers:
8 0.20 (s, 6H) 0.98 (s, 9H) 1.10 (t, J=7.8Hz, 3H) 2.49 (s, 3H) 2.50 (q,
J=7.8Hz, 2H) 2.64 (s, 3H) 3.63 (s, 3H) 6.55 (dd, J=5.6, 2.3Hz, 1H) 6.71
(d, J=8.3, 2.3Hz, 1H) 6.83 (d, J=8.3Hz, 2H) 7.88 (d, J=8.3Hz, 2H)
8 0.19 (s, 6H) 0.97 (s, 9H) 1.10 (t, J=7.8Hz, 3H) 2.36 (s, 3H) 2.50 (q,
J=7.8Hz, 2H) 2.68 (s, 3H) 3.57 (s, 3H) 6.43 (dd, J=5.6, 2.3Hz, 1H) 6.92
(d, J=8.3, 2.3Hz, 1H) 7.16 (d, J=8.3Hz, 2H) 8.04 (d, J=8.3Hz, 2H)
[0891] (I35e)
{2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[0892] [Chemical Formula 352]

To a solution of 0.76 g of
{2-[3-(t-butyldimethyIsilanyloxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methy l-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbam ic acid methyl ester in 30 ml of THF there was added 1.6 ml of TBAF (1.0 M, THF solution) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and dried over anhydrous

magnesium sulfate, the desiccating agent was filtered, and the filtrate
was concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate-heptane) to give the title
compound (0.41 g) as a white solid.
'H-NMR (CDCb) Two main isomers:
5 1.26 (t, J=7.8Hz, 3H) 2.46 (s, 3H) 2.48 (q, J=7.8Hz, 2H) 2.63 (s, 3H)
3.58 (s, 3H) 6.48 (dd, J=5.6, 2.1Hz, 1H) 6.81 (d, J=8.1, 2.1Hz, 1H) 6.82
(d, J=8.3Hz, 2H) 7.89 (d, J=8.3Hz, 2H)
8 1.24 (t, J=7.8Hz, 3H) 2.34 (s, 3H) 2.65 (q, J=7.8Hz, 2H) 2.66 (s, 3H)
3.58 (s, 3H) 7.02 (dd, J=8.2, 2.2Hz, 1H) 7.14 (d, J=8.3Hz, 2H) 7.16 (dd,
J=6.2, 2.2Hz, 1H) 8.03 (d, J=8.3Hz, 2H)
[0893] (135f)
{2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methy
l-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbam
ic acid methyl ester
[0894] [Chemical Formula 353]

After adding 0.163 g of potassium carbonate and 0.14 ml of 2-chloro-N,N-dimethylacetamide to a solution of 0.41 g of {2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the reaction mixture was stirred at room temperature for 60 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.41 g) as a light yellow solid.

'H-NMR (CDC13) TWO main isomers:
8 1.26 (t, J=7.8Hz, 3H) 2.46 (s, 3H) 2.48 (q, J=7.8Hz, 2H) 2.63 (s, 3H)
2.91 (s, 3H) 2.96 (s, 3H) 3.58 (s, 3H) 4.64 (s, 2H) 6.57 (dd, J=5.6, 2.1Hz,
1H) 6.82 (d, J=8.3Hz, 2H) 6.87 (dd, J=8.1, 2.1Hz, 1H) 7.88 (d, J=8.3Hz,
2H)
8 1.24 (t, J=7.8Hz, 3H) 2.34 (s, 3H) 2.65 (q, J=7.8Hz, 2H) 2.67 (s, 3H)
2.99 (s, 3H) 3.12 (s, 3H) 3.56 (s, 3H) 4.78 (s, 2H) 7.07 (dd, J=8.2, 2.2Hz,
1H) 7.14 (d, J=8.3Hz, 2H) 7.33 (dd, J=6.2, 2.2Hz, 1H) 8.04 (d, J=8.3Hz,
2H)
[0895] (135g)
2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-meth
yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,
2,4]triazol-l-yl)benzoic acid
[0896] [Chemical Formula 354]

The same procedure was carried out as in Example (2f), except that 0.409
g of
{2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methy
l-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbam
ic acid methyl ester and 0.160 g of 2-hydrazinobenzoic acid
hydrochloride were used instead of respectively the
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf
anylethylidene]carbamic acid methyl ester and
(l-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
'H-NMR (CD3OD) 8 1.17 (t, J=7.7Hz, 3H) 2.58 (q, J=7.7Hz, 2H) 2.59 (s, 3H) 2.95 (s, 3H) 3.07 (s, 3H) 4.89 (s, 2H) 5.93 (s, 1H) 6.81 (d, J=8.4Hz, 2H) 6.89 (dd, J=8.0, 2.2Hz, 1H) 6.98 (dd, J=5.5, 2.2Hz, 1H) 7.48 (td,

J=7.3, 1.5Hz, 1H) 7.49 (ddd, J=7.6, 1.5, 0.8Hz, 1H) 7.63 (ddd, J=7.6, 7.3, 1.8Hz, 1H) 7.79 (d, J=8.4Hz, 2H) 7.95 (ddd, J=7.3, 1.8, 0.8Hz, 1H) [0897] (135h)
[2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[ l,2,4]triazol-l-yl)phenyl]carbamic acid t-butyl ester [0898] [Chemical Formula 355]

A solution of 0.320 g of
2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l, 2,4]triazol-l-yl)benzoic acid, 0.098 ml of triethylamine and 0.151 ml of diphenylphosphorylazide in 10 ml of t-butanol was stirred under a nitrogen atmosphere at room temperature for 20 hours and then at 70°C for 36 hours. After adding 100 ml of ethyl acetate and 50 ml of water to the reaction mixture, the organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (0.135 g) as a white solid.
'H-NMR (CD3OD) 8 1.17 (t, J=7.7Hz, 3H) 1.48 (s, 9H) 2.59 (q, J=7.7Hz, 2H) 2.60 (s, 3H) 2.96 (s, 3H) 3.09 (s, 3H) 4.90 (s, 2H) 5.98 (s, 1H) 6.81 (d, J=8.4Hz, 2H) 6.90 (dd, J=8.3, 2.2Hz, 1H) 6.98 (dd, J=5.7, 2.2Hz, 1H) 7.18 (td, J=8.0, 1.7Hz, 1H) 7.35 (td, J=8.0, 1.7Hz, 1H) 7.40 (dd, J=8.0, 1.7Hz, 1H) 7.79 (d, J=8.4Hz, 2H) 7.79 (dd, J=8.0, 1.7Hz, 1H) [0899] (135i) 2-(3-{[l-(2-aminophenyl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[4-(

5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-ethyl-2-fluoroph
enoxy-N,N-dimethylacetamide
[0900] [Chemical Formula 356]

After adding 2 ml of trifluoroacetic acid to a solution of 0.135 g of [2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-met hyl-[l,2,4]oxadiazoI-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[ l,2,4]triazol-l-yl)phenyl]carbamic acid t-butyl ester in 10 ml of dichloromethane, the reaction mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. Next, 50 ml of ethyl acetate and 5 ml of 5% aqueous potassium carbonate were added to the residue, and the organic layer was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride in that order. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The title compound (0.100 g) was obtained as a white solid.
'H-NMR (CD3OD) 5 1.17 (t, J=7.7Hz, 3H) 2.58 (q, J=7.7Hz, 2H) 2.59 (s, 3H) 2.96 (s, 3H) 3.09 (s, 3H) 4.90 (s, 2H) 5.96 (s, 1H) 6.75 (td, J=7.8, 1.5Hz, 1H) 6.81 (d, J=8.5Hz, 2H) 6.87 (dd, J=7.8, 1.5Hz, 1H) 6.89 (dd, J=8.5, 2.2Hz, 1H) 6.98 (td, J=5.6, 2.2Hz, 1H) 7.13 (td, J=7.8, 1.5Hz, 1H) 7.22 (dd, J=7.8, 1.5Hz, 1H) 7.79 (d, J=8.5Hz, 2H)
[0901] (135j) (2-{3-
[4-(carbamimidoylphenylamino)-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)methyl]-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl}phenyl )carbamic acid methyl ester trifluoroacetate [0902] [Chemical Formula 357]


A solution of 36 mg of
2-(3- {[ 1 -(2-aminophenyl)-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-1 -yl]-[4-(
5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-ethy]-2-fluoroph
enoxy-N,N-dimethylacetamide in 6 ml of dichloromethane was cooled to
0°C, and then 12 jtxl of 2,4,6-collidine and 6 uJ of methyl chloroformate
were added and the reaction mixture was stirred at room temperature for
15 hours. The solvent was removed under reduced pressure, the residue
was dissolved in 2 ml of methanol, 2 ml of water and 2 ml of acetic acid,
50 mg of iron powder was added, and the mixture was heated at 60°C for
20 hours. After filtering the reaction mixture, it was purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (0.015 g) as a white solid.
'H-NMR (CD3OD) 5 1.18 (t, J=7.8Hz, 3H) 2.59 (q, J=7.8Hz, 2H) 2.98 (s, 3H) 3.10 (s, 3H) 3.69 (s, 3H) 4.91 (s, 2H) 6.03 (s, 1H) 6.87 (d, J=8.4Hz, 2H) 6.90 (dd, J=7.3, 1.2Hz, 1H) 6.93 (dd, J=6.3, 1.2Hz, 1H) 7.19 (td, J=8.2, 1.4Hz, 1H) 7.36 (td, J=8.2, 1.4Hz, 1H) 7.43 (dd, J=8.2, 1.4Hz, 1H) 7.65 (d, J=8.4Hz, 2H) 7.66 (dd, J=8.2, 1.4Hz, 1H)
[0903] Example 136j (R) and
rS'J^-rfn-^-aminopvridin^-vn-S-oxo^.S-dihvdro-lH-n^^ltriazol-S-
vl1-|'2-fluoro-3-(2-fluoroethoxv')-5-methoxvphenvnmethvUamino')benza
midine acetate
[0904] (136a)
{2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphen
yl]~l-methylsulfanylethylidene)carbamic acid methyl ester
[0905] [Chemical Formula 358]


The same procedure was carried out as in Examples (2a)-(2e), except that
2.16 g of 2-fluoro-3-(2-fluoroethoxy)-5-methoxybenzaldehyde was used
instead of the 2-fluoro-3,5-dimethoxybenzaldehyde in Example (2a), to
give the title compound as a white solid.
'H-NMR (CDCb) Two isomers:
5 2.34 and 2.47 (s, 3H) 3.61 and 3.64 (s, 3H) 3.67 and 3.82 (s, 3H) 4.14
and 4.20 (m, 1H) 4.25 and 4.31 (m, 1H) 4.64 and 4.71 (m, 1H) 4.76 and
4.83 (m, 1H) 6.20 and 6.99 (t, J=3.6Hz, 1H) 6.54 and 6.73 (dd, J=6.3,
3.6Hz, 1H) 6.82 and 7.09 (d, J=8.4Hz, 2H) 7.50 and 7.61 (d, J=8.4Hz,
2H)
[0906] (136b)
4-({[l-(3-aminopyridin-2-yI)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yI]-[
2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]methyl}amino)benzamidin
e trifluoroacetate
[0907] [Chemical Formula 359]

The same procedure was carried out as in Examples (2f)-(2h), except that
{2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphen
yl]-l-methylsulfanylethylidene}carbamic acid methyl ester and
(3-nitropyridin-2-yl)hydrazine [CAS No.15367-16-5] were used instead
of respectively the
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester in Example (2f) and (l-oxypyridin-2-yl)hydrazine in Example (2f), to give the title compound.

'H-NMR (CD3OD) 5 3.74 (s, 3H) 4.25 (m, 1H) 4.32 (m, 1H) 4.67 (m,
1H) 4.79 (m, 1H) 6.05 (s, 1H) 6.65 (dd, J=5.3, 2.1Hz, 1H) 6.69 (dd,
J=7.0, 2.1Hz, 1H) 6.88 (d, J=8.7Hz, 2H) 7.29 (dd, J=8.0, 5.9Hz, 1H) 7.41
(dd, J=8.0, 1.3Hz, 1H) 7.65 (d, J=8.7Hz, 2H) 7.84 (dd, J=5.9, 1.3Hz, 1H)
[0908] (136c) (R) and
(S)-4-( {[ 1 -(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-1 H-[ 1,2,4]triazol-3-yl]-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]methyl}amino)benza midine acetate [0909] [Chemical Formula 360]

A SUMICHIRAL OA-2500 column was used for optical resolution of 18
mg of
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[ 2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]methyl}amino)benzamidin e trifluoroacetate, and the first eluting enantiomer (5.9 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.72 (s, 3H) 4.23 (m, 1H) 4.30 (m, 1H) 4.67 (m, 1H) 4.79 (m, 1H) 5.97 (s, 1H) 6.63 (dd, J=7.1, 2.4Hz, 1H) 6.68 (dd, J=4.8, 2.4Hz, 1H) 6.85 (d, J=8.7Hz, 2H) 7.20 (dd, J=8.1, 4.7Hz, 1H) 7.32 (dd, 8.1, 1.2Hz, 1H) 7.61 (d, J=8.7Hz, 2H) 7.81 (dd, 4.7, 1.2Hz, 1H) HPLC retention time: 7 min
[0910] Example 137j (R) and
(S)-4-(fn-(3-aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-
yl]-(2-fluoro-3. 5-dimethoxvphenv0methvUamino)benzamidine acetate
[0911] (137a)
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(
2-fluoro-3, 5-dimethoxyphenyl)methyl}amino)benzamidine
trifluoroacetate
[0912] [Chemical Formula 361]


The same procedure was carried out as in Examples (2f)-(2h), except that
(3-nitropyridin-2-yl)hydrazine was used instead of the
(l-oxypyridin-2-yl)hydrazine in Example (2f), to give the title
compound.
'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.86 (s, 3H) 6.04 (s, 1H) 6.59 (dd,
J=5.2, 2.4Hz, 1H) 6.66 (dd, J=6.8, 2.4Hz, 1H) 6.87 (d, J=8.7Hz, 2H) 7.29
(dd, J=8.0, 5.6Hz, 1H) 7.41 (dd, J=8.0, 1.2Hz, 1H) 7.64 (d, J=8.7Hz, 2H)
7.84 (dd, J=5.6, 1.2Hz, 1H)
[0913] (137b) (R) and
(S)-4-({[l-(3-aminopyridin-2-y])-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-
yl]-(2-fluoro-3, 5-dimethoxyphenyl)methyl}amino)benzamidine
trifluoroacetate
[0914] [Chemical Formula 362]

A SUMICHIRAL OA-2500 column was used for optical resolution of 8
mg of
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(
2-fluoro-3,5-dimethoxyphenyl) methyl}amino)benzamidine
trifluoroacetate, and the first eluting enantiomer (2.8 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.86 (s, 3H) 6.04 (s, 1H) 6.59 (dd, J=5.2, 2.4Hz, 1H) 6.66 (dd, J=6.8, 2.4Hz, 1H) 6.87 (d, J=8.7Hz, 2H) 7.29 (dd, J=8.0, 5.6Hz, 1H) 7.41 (dd, J=8.0, 1.2Hz, 1H) 7.64 (d, J=8.7Hz, 2H)

7.84 (dd, J=5.6, 1.2Hz, 1H) HPLC retention time: 7 min
[0915] Example 138:
^dri-CS-aminopvridin^-vn-S-oxo-^S-dihvdro-lH-fl.Z^ltriazol-S-vll-C
2-fluoro-4, 5-dimethoxvphenvl)methvUamino)benzamidine
trifluoroacetate
[0916] (138a) 5-{(2-fluoro-4,
5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]me
thyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-lH-[l,2,4]triazol-3-one
[0917] [Chemical Formula 363]

The same procedure was carried out as in Example (2f), except that
(3-nitropyridin-2-yl)hydrazine and 182 mg of
{2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl
)phenyIimino]-l-methanesulfanyIethyIidene}carbamic acid methyl ester
(Example (Id)) were used instead of respectively the
(l-oxypyridin-2-yl)hydrazine and
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester, to give the title compound (104 mg).
'H-NMR (CD3OD) 5 2.59 (s, 3H) 3.81 (s, 3H) 3.84 (s, 3H) 5.93 (s, 1H) 6.83 (d, J=8.8Hz, 2H) 6.85 (d, J=10.4Hz, 1H) 7.07 (d, J=7.6Hz, 1H) 7.65 (dd, J=8.1, 4.5Hz, 1H) 7.80 (d, J=8.8Hz, 2H) 8.49 (dd, J=8.1, 1.3Hz, 1H) 8.77 (dd, J=4.5, 1.3Hz, 1H) [0918] (138b)
4-({[l-(3-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(
2-fluoro-4, 5-dimethoxyphenyl)methyl} amino)benzamidine
trifluoroacetate

[0919] [Chemical Formula 364]

The same procedure was carried out as in Example (lg), except that 104
mg of 5-{(2-fluoro-4,
5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]me
thyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-lH-[l,2,4]triazol-3-one was
used instead of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyI)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid, to give the title compound (34 mg).
'H-NMR (CD3OD) 8 3.73 (s, 3H) 3.81 (s, 3H) 5.98 (s, 1H) 6.86 (d, J=l 1.4Hz, 1H) 6.87 (d, J=8.6Hz, 2H) 7.05 (d, J=7.8Hz, 1H) 7.60 (br.s, 1H) 7.83 (br.s, 1H) 7.64 (d, J=8.6Hz, 2H) 7.85 (br.s, 1H) 8.38 (br.s, 2H) 8.79 (br.s, 2H)
[0920] Example 139:
4-f(n-f2-aminophenvn-5-oxo-4.5-dihvdro-lH-ri.2.41triazol-3-vn-r3-f2-
dimethvlaminoethoxv)-5-ethvl-2-fluorophenyl]methvUamino)benzamidin
e bistrifluoroacetate
[0921] (139a)
{2-[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methyl-[
l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester
[0922] [Chemical Formula 365]

The same procedure was carried out as in Example (135f), except that

(2-chloroethyl)dimethylamine hydrochloride was used instead of the
2-chloro-N,N-dimethylacetamide, to give the title compound.
'H-NMR (CDCI3) Two isomers:
5 1.08 (t, J=7.8Hz, 3H) 2.32 (s, 6H) 2.38 (s, 3H) 2.49 (q, J=7.8Hz, 2H)
2.61 (s, 3H) 2.70 (d, J=5.5Hz, 2H) 3.59 (s, 3H) 4.02 (d, J=5.5Hz, 2H)
6.46 (dd, J=5.5, 2.2Hz, 1H) 6.75 (dd, J=8.1, 2.2Hz, 1H) 6.81 (d, J=8.6Hz,
2H) 7.86 (d, J=8.6Hz, 2H)
5 1.23 (t, J=7.8Hz, 3H) 2.34 (s, 3H) 2.58 (s, 6H) 2.63 (q, J=7.8Hz, 2H)
2.66 (s, 3H) 2.79 (d, J=5.5Hz, 2H) 3.56 (s, 3H) 4.14 (d, J=5.5Hz, 2H)
6.96 (dd, J=8.1, 2.2Hz, 1H) 7.12 (d, J=8.6Hz, 2H) 7.28 (dd, J=5.5, 2.2Hz,
1H) 8.01 (d, J=8.6Hz, 2H)
[0923] (139b)
2-(3-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-methyl-
[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4
]triazol-l-yl)benzoic acid trifluoroacetate
[0924] [Chemical Formula 366]
The same procedure was carried out as in Example (2f), except that
2-hydrazinobenzoic acid hydrochloride and 505 mg of
{2-[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methyl-[
l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester were used respectively instead of
(l-oxypyridin-2-yl)hydrazine and
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester, to give the title compound (433 mg).
'H-NMR (CD3OD) 5 1.19 (t, J=7.7Hz, 3H) 2.60 (s, 3H) 2.62 (q, J=7.7Hz, 2H) 3.00 (s, 6H) 3.62 (t, J=5.8Hz, 2H) 4.43 (t, J=5.8Hz, 2H) 5.95 (s, 1H) 6.82 (d, J=8.8Hz, 2H) 7.03 (dd, J=8.0, 1.5Hz, 1H) 7.07 (dd, J=5.7, 1.5Hz,

1H) 7.48 (dd, J=7.3, 1.0Hz, 1H) 7.50 (td, J=7.3, 1.0Hz, 1H) 7.64 (td, J=7.3, 1.0Hz, 1H) 7.79 (d, J=8.8Hz, 2H) 7.95 (dd, J=7.3, 1.0Hz, 1H) [0925] (139c)
2-(2-aminophenyl)-5-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophen yl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)-phenylamino]-methyl}-2,4-dihyd ro-1 H-[ 1,2,4]triazol-3-one trifluoroacetate [0926] [Chemical Formula 367]

The same procedure was carried out as in Examples (135h)-(135i),
except that
2-(3-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4 ]triazol-l-yl)benzoic acid was used instead of the 2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4] triazol-l-yl)benzoic acid in Example (135h), to give the title compound. 'H-NMR (CD3OD) 5 1.20 (t, J=7.5Hz, 3H) 2.60 (s, 3H) 2.63 (q, J=7.5Hz, 2H) 3.00 (s, 6H) 3.62 (t, J=5.2Hz, 2H) 4.43 (t, J=5.2Hz, 2H) 5.99 (s, 1H) 6.81 (d, J=8.8Hz, 2H) 6.82 (t, J=7.5Hz, 1H) 6.95 (d, J=8.3Hz, 1H) 7.02-7.07 (m, 2H) 7.18 (t, J=7.5Hz, 1H) 7.25 (d, J=7.5Hz, 1H) 7.78 (d, J=8.8Hz, 2H) [0927] (139d)
4-({[l-(2-aminophenyl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]methyl}amino)benzamidin e bistrifluoroacetate [0928] [Chemical Formula 368]


The same procedure was carried out as in Example (lg), except that 13.2
mg of
2-(2-aminophenyl)-5-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophen yl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro -lH-[l,2,4]triazol-3-one trifluoroacetate was used instead of the 2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid, to give 4.7 mg of the title compound as a colorless oil. 'H-NMR (CD3OD) 8 1.20 (t, J=7.8Hz, 3H) 2.63 (q, J=7.8Hz, 2H) 3.01 (s, 6H) 3.64 (t, J=5.6Hz, 2H) 4.44 (t, J=5.6Hz, 2H) 6.05 (s, 1H) 6.88 (d, J=8.7Hz, 2H) 6.93 (t, J=7.5Hz, 1H) 7.04 (d, J=7.5Hz, 1H) 7.05 (dd, J=5.4, 2.2Hz, 1H) 7.07 (dd, J=7.8, 2.2Hz, 1H) 7.22 (t, J=7.5Hz, 1H) 7.29 (d, J=7.5Hz, 1H) 7.65 (d, J=8.7Hz, 2H)
[0929] Example 140:
4-({[3-(2-dimethvlaminoethoxv)-5-ethvl-2-fluorophenyl]-(5-oxo-l-pyridi n-2-vl-4.5-dihydro-lH-n.2.41triazol-3-vl)methvUamino)benzamidine b i strifl uoroacetate [0930] (140a)
5-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-methyl-[l, 2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyridin-2-yl-2,4-dihydro-lH-[ 1,2,4]triazol-3-one trifluoroacetate [0931] [Chemical Formula 369]

The same procedure was carried out as in Example (2f), except that

(pyridin-2-yl)hydrazine and 30 mg of
2-[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methyl-[l
,2,4]oxadiazol-3-y])phenylimino]-l-methylsulfanylethylidene}carbamic
acid methyl ester (Example (139a)) were used instead of respectively
(l-oxypyridin-2-yl)hydrazine and
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf
anylethylidene]carbamic acid methyl ester, to give the title compound
(20 mg) as a white solid.
'H-NMR (CD3OD) 5 1.19 (t, J=7.7Hz, 3H) 2.59 (s, 3H) 2.61 (q, J=7.7Hz,
2H) 3.01 (s, 6H) 3.63 (d, J=5.1Hz, 2H) 4.42 (d, J=5.1Hz, 2H) 5.98 (s,
1H) 6.81 (d, J=8.8Hz, 2H) 7.02 (dd, J=7.7, 2.1Hz, 1H) 7.06 (dd, J=6.5,
2.1Hz, 1H) 7.31 (dd, J=7.9, 5.1Hz, 1H) 7.78 (d, J=8.8Hz, 2H) 7.95 (t,
J=7.9Hz, 1H) 8.06 (d, J=7.9Hz, 1H) 8.42 (d, J=5.1Hz, 1H)
[0932] (140b)
4-({[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-(5-oxo-l-pyridi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
bistrifluoroacetate
[0933] [Chemical Formula 370]

The same procedure was carried out as in Example (lg), except that 20
mg of
5-{[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-methyl-[l,
2,4]oxadiazol-3-yl)phenylamino]methyI}-2-pyridin-2-yl-2,4-dihydro-lH-
[l,2,4]triazol-3-one trifluoroacetate was used instead of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic
acid, to give the title compound (6.5 mg) as a colorless oil.
1 H-NMR (CD3OD) 8 1.22 (t, J=7.7Hz, 3H) 2.65 (q, J=7.7Hz, 2H) 3.01 (s,
6H) 3.63 (d, J=5.3Hz, 2H) 4.44 (d, J=5.3Hz, 2H) 6.01 (s, 1H) 6.88 (d,

J=8.8Hz, 2H) 7.05 (dd, J=6.0, 2.1Hz, 1H) 7.07 (dd, J=7.6, 2.1Hz, 1H) 7.31 (dd, J=7.6, 5.0Hz, 1H) 7.65 (d, J=8.8Hz, 2H) 7.94 (t, J=7.6Hz, 1H) 8.05 (d, J=7.6Hz, 1H) 8.43 (d, J=5.0Hz, 1H)
[0934] Example 141:
4-f{[3-(2-dimethvlamino-l-methylethoxy)-5-ethyl-2-fluorophenyr)-f5-ox o-1 -pyridin-2-yl-4.5-dihydro-1 H-fl.2.4]triazol-3-yl)methvl }amino)benza midine bistrifluoroacetate [0935] (141a)
{2-[3-(2-dimethylamino-l-methylethoxy)-5-ethyl-2-fluorophenyl]-2-[4-( 5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene }carbamic acid methyl ester [0936] [Chemical Formula 371]

The same procedure was carried out as in Example (135f), except that
(2-chloropropyl)dimethylamine hydrochloride was used instead of the
2-chloro-N,N-dimethylacetamide, to give the title compound (41 mg) as
a light yellow oil.
'H-NMR (CDCb) Two isomers:
5 1.17 (t, J=7.6Hz, 3H) 1.23 (d, J=6.3Hz, 3H) 2.24 (s, 6H) 2.30-2.61 (m,
2H) 2.46 (s, 3H) 2.47 (q, J=7.6Hz, 2H) 2.61 (s, 3H) 3.59 (s, 3H) 4.51
(sext, J=6.3Hz, 1H) 6.52 (dd, J=5.1, 2.1Hz, 1H) 6.82 (d, J=8.8Hz, 2H)
6.83 (dd, J=7.6, 2.1Hz, 1H) 7.87 (d, J=8.8Hz, 2H)
5 1.24 (t, J=7.6Hz, 3H) 1.31 (d, J=6.3Hz, 3H) 2.30-2.61 (m, 2H) 2.31 (s,
3H) 2.33 (s, 6H) 2.64 (q, J=7.6Hz, 2H) 2.65 (s, 3H) 3.55 (s, 3H) 4.32
(sext, J=6.3Hz, 1H) 7.02 (dd, J=7.6, 2.1Hz, 1H) 7.15 (d, J=8.8Hz, 2H)
7.29 (dd, J=5.1, 2.1Hz, 1H) 8.02 (d, J=8.8Hz, 2H)
[0937] (141b)
5-{[3-(2-dimethylamino-l-methylethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-
methyl-[l,2,4]oxadiazol-3-yl)-phenylamino]methyl}-2-pyridin-2-yl-2,4-d
ihydro-1 H-[ 1,2,4]triazol-3-one trifluoroacetate

T09381 rChemical Formula 372]
The same procedure was carried out as in Example (2f), except that
(pyridin-2-yl)hydrazine and 26 mg of
{2-[3-(2-dimethylamino-l-methylethoxy)-5-ethyl-2-fluorophenyl]-2-[4-(
5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene
}carbamic acid methyl ester were used instead of respectively the
(l-oxypyridin-2-yl)hydrazine and
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf anylethylidene]carbamic acid methyl ester, to give the title compound (18 mg) as a white solid. 'H-NMR (CD3OD) Two isomers:
5 1.20 and 1.21 (t, J=7.8Hz, 3H) 1.31 and 1.32 (d, J=6.4Hz, 3H) 2.60 (s, 3H) 2.63 (q, J=7.8Hz, 2H) 3.00 (s, 6H) 3.40 (dd, J=13.7, 3.1Hz, 1H) 3.53 (dd, J=13.7, 10.0Hz, 1H) 4.94 (m, 1H) 5.98 and 5.99 (s, 1H) 6.81 and 6.82 (d, J=8.8Hz, 2H) 7.01 (d, J=7.6Hz, 1H) 7.03 (d, J=5.5Hz, 1H) 7.31 (ddd, J=7.7, 5.3, 0.8Hz, 1H) 7.79 (d, J=8.8Hz, 2H) 7.95 (td, J=7.7, 1.3Hz, 1H) 8.06 (dd, J=7.7, 0.8Hz, 1H) 8.44 (dd, J=5.3, 1.3Hz, 1H) [0939] (141c)
4-({[3-(2-dimethylamino-l-methylethoxy)-5-ethyl-2-fluorophenyl]-(5-ox o-l-pyridin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benza midine bistrifluoroacetate [0940] [Chemical Formula 373]

The same procedure was carried out as in Example (lg), except that 15.2

mg of
5-{[3-(2-dimethylamino-l-methylethoxy)-5-ethyl-2-fluorophenyl]-[4-(5-
methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyridin-2-yI-2,4-di
hydro-lH-[l,2,4]triazol-3-one trifluoroacetate was used instead of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-rnethyl-[l,2,4]oxadiazol-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic
acid, to give the title compound (8.18 mg) as a colorless oil.
'H-NMR (CD3OD) Two isomers:
8 1.20 and 1.21 (t, J=7.8Hz, 3H) 1.31 and 1.32 (d, J=6.4Hz, 3H) 2.64 and
2.65 (q, J=7.8Hz, 2H) 3.00 (s, 6H) 3.42 (dd, J=13.6, 2.4Hz, 1H) 3.54 (dd,
J=13.6, 10.2Hz, 1H) 4.94 (m, 1H) 6.02 and 6.03 (s, 1H) 6.88 and 6.89 (d,
J=8.8Hz, 2H) 7.01-7.04 (m, 2H) 7.32 (ddd, J=7.4, 5.2, 1.0Hz, 1H) 7.65
(d, J=8.8Hz, 2H) 7.95 (td, J=7.4, 1.3Hz, 1H) 8.05 (dd, J=7.4, 1.0Hz, 1H)
8.44 (dd, J=5.2, 1.3Hz, 1H)
[0941] Example 142:
2-(3{(4-carbamimidoyl-phenvlamino)-[3-(3-dimethvlamino-2.2-dimethvl propoxv)-5-ethvl-2-fiuorophenyl]methyU-5-oxo-4,5-dihydro-lH-[1.2.4]t riazol-1-yUbenzoic acid bistrifluoroacetate [0942] (142a)
{2-[3-(3-dimethylamino-2,2-dimethylpropoxy)-5-ethyl-2-fluorophenyl]-2 -[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyli dene}carbamic acid methyl ester [0943] [Chemical Formula 374]

The same procedure was carried out as in Example (135f), except that (3-chloro-2,2-dimethylpropyl)dimethylamine was used instead of the 2-chloro-N,N-dimethylacetamide , to give the title compound. 1 H-NMR (CDCI3) 8 0.94 (s, 6H) 1.07 (t, J=7.8Hz, 3H) 2.27 (s, 6H) 2.29 (s, 2H) 2.34 (s, 3H) 2.55 (q, J=7.8Hz, 2H) 2.63 (s, 3H) 3.57 (s, 3H) 3.75 (s, 2H) 6.43 (dd, J=5.4 1 8Hz 1m 6.76 Cdd. J=8.0. 1.8Hz, 1H) 6.82 (d,

J=8.9Hz, 2H) 7.87 (d, J=8.9Hz, 2H)
[0944] (142b)
2-(3-{[3-(3-dimethylamino-2,2-dimethylpropoxy-5-ethyl-2-fluorophenyl)
-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dih
ydro-lH-[l,2,4]triazol-l-yl)benzoic acid trifluoroacetate
[0945] [Chemical Formula 375]

The same procedure was carried out as in Example (2f), except that
2-hydrazinobenzoic acid hydrochloride and 35 mg of
{2-[3-(3-dimethylamino-2,2-dimethylpropoxy)-5-ethyl-2-fluorophenyl]-2
-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyli
denejcarbamic acid methyl ester were used instead of respectively the
(l-oxypyridin-2-yl)hydrazine and
[2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-l-methylsulf
anylethylidene]carbamic acid methyl ester, to give the title compound
(33 mg) as a colorless oil.
'H-NMR (CD3OD) 5 1.20 (t, J=7.8Hz, 3H) 1.24 (s, 3H) 1.25 (s, 3H) 2.60
(s, 3H) 2.63 (q, J=7.8Hz, 2H) 2.99 (s, 6H) 3.35 (s, 2H) 4.00 (s, 2H) 5.95
(s, 1H) 6.81 (d, J=9.0Hz, 2H) 7.00 (d, J=7.5Hz, 1H) 7.02 (d, J=5.0Hz,
1H) 7.48 (d, J=7.6Hz, 1H) 7.49 (t, J=7.6Hz, 1H) 7.63 (td, J=7.6, 1.2Hz,
1H) 7.89 (d, J=9.0Hz, 2H) 7.94 (dd, J=7.6, 1.2Hz, 1H)
[0946] (142c)
2-(3{(4-carbamimidoylphenylamino)-[3-(3-dimethylamino-2,2-dimethylp
ropoxy)-5-ethyl-2-fluorophenyl]methyI}-5-oxo-4,5-dihydro-lH-[l,2,4]tri
azol-l-yl}benzoic acid bistrifluoroacetate
[0947] [Chemical Formula 376]


The same procedure was carried out as in Example (lg), except that 33
mg of
(3-{[3-(3-dimethylamino-2,2-dimethylpropoxy-5-ethyl-2-fluorophenyl)-[
4-(5-methyl-[l,2,4]oxadiazol-3-yI)phenylamino]methyl}-5-oxo-4,5-dihyd
ro-lH-[l,2,4]triazol-l-yl)benzoic acid trifluoroacetate was used instead
of the
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid, to give the title compound (12 mg) as a white oil. 'H-NMR (CD3OD) 5 1.20 (t, J=7.8Hz, 3H) 1.22 (s, 3H) 1.24 (s, 3H) 2.61 (q, J=7.8Hz, 2H) 2.97 (s, 6H) 3.30 (s, 2H) 3.96 (s, 2H) 5.97 (s, 1H) 6.85 (d, J=8.7Hz, 2H) 6.98 (d, J=5.0Hz, 1H) 7.01 (d, J=7.3Hz, 1H) 7.45 (d, J=7.6Hz, 1H) 7.48 (t, J=7.6Hz, 1H) 7.62 (t, J=7.6Hz, 1H) 7.63 (d, J=8.7Hz, 2H) 7.93 (d, J=7.6Hz, 1H)
[0948] Example H3j (R) and
(S)-2-fluoro-4-{[(2-fluoro-4.5 {2-[4-cyano-3-fluorophenylimino]-2-(2-fluoro-4,5-dimethoxyphenyl)-l-methylsulfanylethylidene}carbamic acid methyl ester [0950] [Chemical Formula 377]


The same procedure was carried out as in Example (37a), except that
2-fluoro-4,5-dimethoxybenzaldehyde was used instead of
3,4-dimethoxybenzaldehyde, to give the title compound.
'H-NMR (CDCI3) 5 2.36 (s, 3H) 3.63 (s, 3H) 3.92 (s, 3H) 3.94 (s, 3H)
6.60 (m, 1H) 6.62 (d, J=12.4Hz, 1H) 6.88 (d, J=8.8Hz, 1H) 7.38 (d,
J=6.8Hz, 1H) 7.54 (t, J=7.2Hz, 1H)
Mass spectrum (ESI)m/z: 434 (M+H)+
[0951] (143b)
2-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzonitrile
[0952] [Chemical Formula 378]

The same procedure was carried out as in Example (17f), except that
{2-[4-cyano-3-fluorophenylimino]-2-(2-fluoro-4,5-dimethoxyphenyl)-l-
methylsulfanylethylidene}carbamic acid methyl ester was used instead of
the
{2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enyIimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give the title compound.
'H-NMR (CD3OD) 5 3.77 (s, 3H) 3.84 (s, 3H) 5.91 (s, 1H) 6.57 (dd,
J=12.4, 2.0Hz, 1H) 6.63 (dd, J=8.4, 2.0Hz, 1H) 6.87 (d, J=11.6Hz, 1H)
7.00 (d, J=7.2Hz, 1H) 7.37 (t, J=4.8Hz, 1H) 7.42 (dd, J=8.8, 7.6Hz, 1H)
8.79 (d, J=4.8Hz, 2H)
[0953] (143c) (R) and
(S)-2-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-y
l-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate
[0954] [Chemical Formula 379]


The same procedure was carried out as in Examples (2g)-(2h), except
that
[2-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyI)-(5-oxo-l-pyrimidin-2-yI-4
,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzonitrile and 0.1%
acetic acid were used instead of respectively the
4-( {(2-fluoro-3,5 -dimethoxyphenyl)-[5-oxo-1 -(1 -oxypyridin-2-yl)-4,5 -di
hydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzonitrile in Example (2g)
and the 0.1% trifluoroacetic acid in Example (2h), to give
2-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyI)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
'H-NMR (CD3OD) 5 3.67 (s, 3H) 3.73 (s, 3H) 5.78 (s, 1H) 6.50 (dd,
J=14.4, 2.4Hz, 1H) 6.61 (dd, J=8.8, 2.4Hz, 1H) 6.75 (d, J=11.6Hz, 1H)
7.01 (d, J=6.8Hz, 1H) 7.22 (t, J=4.8Hz, 1H) 7.37 (t, J=8.4Hz, 1H) 8.68
(d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 483 (M+H)+
A 3.5 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (1.0
mg) of the title compound was obtained.
HPLC retention time: 15 min
[0955] Example L44j (E) and
(S)-4-{[(4-cvanomethoxy-3-methoxvphenvl)-(5-oxo-l-pvridazin-3-vl-4,5 -dihydro-lH41.2.4]triazol-3-vl)methvl]amino}benzamidine acetate [0956] [Chemical Formula 380]


The same procedure was carried out as in Examples (119a)-(l 19b),
except that
{2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsu]fanylethylidene}carbamic acid methyl ester (Example (16a)) was used instead of the {2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (119a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.84 (s, 3H) 4.91 (s, 2H) 5.65 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.06 (d, J=8.4Hz, 1H) 7.13 (dd, J=8.4, 2.0Hz, 1H) 7.28 (d, J=2.0Hz, IH) 7.60 (d, J=8.8Hz, 2H) 7.75 (dd, J=9.2, 4.8Hz, 1H) 8.53 (dd, J=9.2, 1.2Hz, IH) 9.01 (dd, J=4.8, 1.2Hz, IH) HPLC retention time: 12 min
[0957] Example L45j (R) and
(S)-4-{f(2-fluoro-3.5-dimethoxvphenvl)-(5-oxo-l-pvridazin-3-vl-4.5-dih vdro-1 H-f 1.2,4"jtriazol-3-vDmethyl]amino}benzamidine acetate [0958] [Chemical Formula 381]

The same procedure was carried out as in Examples (3e)-(3g), except that methyl iodide and 3-hydrazinopyridazine hydrochloride were used instead of respectively the l-fluoro-2-iodoethane in Example (3e) and the

2-hydrazinopyrimidine in Example (3f), to give
4-{[(2-fluoro-3,5-dimethoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro
-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
'H-NMR (CD3OD) 6 1.93 (s, 3H) 3.71 (s, 3H) 3.84 (s, 3H) 5.97 (s, 1H)
6.59-6.64 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.61 (d, J=8.8Hz, 2H) 7.76 (dd,
J=8.8, 4.8Hz, 1H) 8.50 (dd, J=8.8, 1.2Hz, 1H) 9.01 (dd, J=4.8, 1.2Hz,
1H)
Mass spectrum (ESI)m/z: 465 (M+H)+
A 5.5 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (2.4
mg) of the title compound was obtained.
HPLC retention time: 14 min
[0959] Example 146j (R) and
(^M-{r(3-cvanomethvl-4-fluoro-5-methoxvphenvD-(5-oxo-l-pyridazin-
3-vl-4,5-dihvdro-lH-[1.2,4]triazol-3-yOmethyl]amino}benzamidine
acetate
[09601 [Chemical Formula 3821
The same procedure was carried out as in Example (119a), except that {2-(4-fluoro-3-cyanomethyl-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]ox adiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (131c)) was used instead of the {2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to give
4-{[(3-cyanomethyl-4-fluoro-5-methoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate. 'H-NMR (CD3OD) 5 1.94 (s, 3H) 3.85 (s, 3H) 3.86 (s, 2H) 5.72 (s, 1H)

6.87 (d, J=8.8Hz, 2H) 7.20 (dd, J=6.0, 2.0Hz, 1H) 7.33 (dd, J=7.6, 2.0Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 7.77 (dd, J=9.2, 4.8Hz, 1H) 8.52 (dd, J=9.2, 1.6Hz, 1H) 9.03 (dd, J=4.8, 1.6Hz, 1H) Mass spectrum (ESI)m/z: 474 (M+H)+
A 12 mg portion of this compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (4.5 mg) of the title compound was obtained. HPLC retention time: 10 min
[0961] Example 147:
4-{[(9-methoxv-3.4-dihvdro-2H-benzo[biri.41dioxepin-7-vl")-(5-oxo-l-p
yridazin-3-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvnamino}benzami
dine acetate
[0962] [Chemical Formula 383]

The same procedure was carried out as in Example (119a), except that {2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb amic acid methyl ester (Example (30c)) was used instead of the {2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylimino]-l-methylsulfanyl-ethylidene}carbamic acid methyl ester, to give the title compound.
'H-NMR (CD3OD) 8 1.94 (s, 3H) 2.13 (m, 2H) 3.79 (s, 3H) 4.11 (m, 4H) 5.61 (s, 1H) 6.81 (d, J=2.0Hz, 1H) 6.87 (d, J=8.8Hz, 2H) 6.91 (d, J=2.0Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 7.77 (dd, J=9.2, 5.2Hz, 1H) 8.49 (dd, J=9.2, 1.6Hz, 1H) 9.03 (dd, J=5.2, 1.6Hz, 1H) Mass spectrum (ESI)m/z: 489 (M+H)+
[0963] Example 148: (R) and
(S)-{[(3-cvanomethoxv-2-fluoro-5-methoxvphenvl)-(5-oxo-l-pyridazin-3

-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methyl]amino}benzamidine
acetate
[0964] [Chemical Formula 384]

The same procedure was carried out as in Example (16a), except that
{2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yI)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester (Example (3d)) was used instead of the
{2-(4-hydroxy-3-methoxyp'henyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give
{2-(3-cyanomethoxy-2-fluoro-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]o
xadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester.
The same procedure was carried out as in Example (119a), except that
this compound was used instead of the
{2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl
)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give
{[(3-cyanomethoxy-2-fluoro-5-methoxyphenyl)-(5-oxo-l-pyridazin-3-yl-
4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.73 (s, 3H) 5.05 (s, 2H) 6.02 (s, 1H)
6.76-6.79 (m, 2H) 6.87 (d, J=9.2Hz, 2H) 7.63 (d, J=9.2Hz, 2H) 7.77 (dd,
J=9.2, 4.8Hz, 1H) 8.47 (dd, J=9.2, 1.6Hz, 1H) 9.03 (dd, J=4.8, 1.6Hz,
1H)
Mass spectrum (ESI)m/z: 490 (M+H)+
A 14 mg portion of this compound was optically resolved using a

SUMICHIRAL OA-2500 column, and the first eluting enantiomer (5.1 mg) of the title compound was obtained. HPLC retention time: 10 min
[0965] Example 149j 0t) and
(S)-4-{[(3,4-dimethoxvphenyl)-(5-oxo-l-pyridazin-3-vl-4.,5-dihvdro-lH-[ l,2.41triazol-3-yl)methvllamino}benzamidine acetate [0966] [Chemical Formula 385]

The same procedure was carried out as in Example (119a), except that
(2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli
mino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example
(36d)) was used instead of the
{2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl
)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give
4-{[(3,4-dimethoxyphenyl)-(5-oxo-l-pyridazin-3-yl-4,5-dihydro-lH-[l,2,
4]triazol-3-yl)methyl]amino}benzamidine acetate.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.79 (s, 3H) 3.80 (s, 3H) 5.65 (s, 1H)
6.87 (d, J=9.2Hz, 2H) 6.92 (d, J=8.4Hz, 1H) 7.08 (dd, J=8.4, 2.0Hz, 1H)
7.16 (d, J=2.0Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 7.76 (dd, J=9.2, 4.8Hz, 1H)
8.47 (dd, J=9.2, 1.6Hz, 1H) 9.03 (dd, J=4.8, 1.6Hz, 1H)
Mass spectrum (ESI)m/z: 447 (M+H)+
A 13 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (2.7
mg) of the title compound was obtained.
HPLC retention time: 14 min
[0967] Example 15pj (R) and
(S)-4-f[f8-methoxy-4H-benzofl,3]dioxin-6-yl)-(5-oxo-l-pvridazin-3-yl-

4.5-dihydro-lH-[1.2.4]triazol-3-vl)methyllaminolbenzamidine acetate [0968] [Chemical Formula 386]

The same procedure was carried out as in Examples (119a)-(119b),
except that
{2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid methyl ester (Example (21 h)) was used instead of the (2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (119a), to give the first eluting enantiomer of the title compound.
JH-NMR (CD3OD) 8 1.92 (s, 3H) 3.81 (s, 3H) 4.84 (d, J=2.4Hz, 2H) 5.21 (s, 2H) 5.54 (s, 1H) 6.82-6.90 (m, 3H) 7.06 (d, J=2.0Hz, 1H) 7.58 (d, J=9.2Hz, 2H) 7.73 (dd, J=9.2, 4.8Hz, 1H) 8.55 (dd, J=9.2, 1.2Hz, 1H) 8.98 (dd, J=4.8, 1.2Hz, 1H) HPLC retention time: 16 min
[0969] Example 15Jj (R) and
(S>-4-([f2-fluoro-3-(2-fluoroethoxv)-5-methoxvphenvl>-(5-oxo-l-pvridaz
in-3-yl-4,5-dihvdro-lH-[1.2,4]triazol-3-vnmethvl]aminolbenzamidine
acetate
[0970] [Chemical Formula 387]


The same procedure was carried out as in Examples (119a)-(l 19b),
except that
{2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (3e)) was used instead of the {2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (119a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.94 (s, 3H) 3.70 (s, 3H) 4.22-4.29 (m, 2H) 4.66-4.77 (m, 2H) 6.00 (s, 1H) 6.62-6.67 (m, 2H) 6.86 (d, J=8.0Hz, 2H) 7.61 (d, J=8.0Hz, 2H) 7.76 (dd, J=8.8, 4.0Hz, 1H) 8.47 (d, J=8.8Hz, 1H) 9.03 (d, J=4.0Hz, 1H) (data for racemic mixture) HPLC retention time: 13 min
[0971] Example 152: (R) and
(S)-3-{3-[(4-carbamimidovlphenvlamino)-(8-methoxv-4H-benzo|"1.31dio
xin-6-vl)methvll-5-oxo-4.5-dihvdron.2.41triazol-l-yl|thiophene-2-carbo
xvlic acid methyl ester acetate
(152a)
3-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiophene-2-carboxyli
c acid methyl ester acetate
[0972] [Chemical Formula 388]

After adding 32 mg of 3-hydrazinothiophene-2-carboxylic acid methyl
ester [CAS No.75681-13-9] and 0.030 ml of triethylamine to a solution
of 90 mg of
{2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz

ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester (Example (21 h)) in 1 ml of DMF, the mixture was stirred at 85°C
for 20 hours under a nitrogen atmosphere. The reaction mixture was
concentrated, and the residue was dissolved in 0.8 ml of methanol, 0.8 ml
of THF and 0.1 ml of acetic acid. After adding 100 mg of sodium
cyanotrihydroborate to the solution, the mixture was stirred at room
temperature for 18 hours and 30 minutes. The reaction mixture was
crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product.
To a solution of the obtained crude product in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred at 65°C for 16 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give 27.99 mg of the title
compound as a white solid.
!H-NMR (CD3OD) 5 1.93 (s, 3H) 3.75 (s, 3H) 3.83 (s, 3H) 4.86 (s, 2H)
5.24 (s, 2H) 5.61 (s, 1H) 6.81 (d, J=1.6Hz, 1H) 6.87 (d, J=8.8Hz, 2H)
7.03 (d, J=1.6Hz, 1H) 7.20 (d, J=4.8Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 7.76
(d, J=4.8Hz, 1H)
Mass spectrum (ESI)m/z: 537 (M+H)+
[0973] (152b) (R) and
(S)-3-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dio
xin-6-yI)methyI]-5-oxo-4,5-dihydrofl,2,4]triazoI-l-yl}thiophene-2-carbo
xylic acid methyl ester acetate
[0974] [Chemical Formula 389]

A SUMICHIRAL OA-2500 column was used for optical resolution of
27.99mg of
3-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiophene-2-carboxyli
c acid methyl ester acetate, and the first eluting enantiomer (10.25 mg) of
the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.75 (s, 3H) 3.84 (s, 3H) 4.87 (s, 2H)
5.24 (s, 2H) 5.58 (s, 1H) 6.81 (d, J=1.2Hz, 1H) 6.86 (d, J=8.8Hz, 2H)
7.03 (br.s, 1H) 7.20 (d, J=5.6Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 7.76 (d,
J=5.2Hz, 1H)
HPLC retention time: 9 min (Column name: SUMICHIRAL OA-2500, 30
mm(p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 20 ml/min)
[0975] Example 153: (R) and
(S)-4-(ff2-fluoro-3-(2-hvdroxvethoxv')-5-methoxvphenvll-(5-oxo-l-pvri
midin-2-yl-4,5-dihvdro-lH-[1.2.4]triazol-3-yl)methyl}amino)benzamidin
e acetate
[0976] (153a)
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[0977] [Chemical Formula 390]

After adding 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 80 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl

ester (Example (3d)) in 1 ml of DMF, the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 69 mg of a yellow oil. To a solution of the obtained 69 mg of yellow oil in 1 ml of DMF there were added 13 mg of 2-hydrazinopyrimidine and 0.016 ml of triethylamine, and the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1 ml of methanol, 1 ml of THF and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product.
To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 60°C for 2 days under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (13.89
mg).
'H-NMR (CD3OD) 5 1.94 (s, 3H) 3.71 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.10
(t, J=4.8Hz, 2H) 5.99 (s, 1H) 6.55-6.72 (m, 2H) 6.86 (d, J=8.8Hz, 2H)
7.34 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H).
Mass spectrum (ESI)m/z: 495 (M+H)+
[0978] (153b) (R) and
(S)-4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidin
e acetate
[0979] [Chemical Formula 391]


A SUMICHIRAL OA-2500 column was used for optical resolution of
13.89 mg of
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyI]-(5-oxo-l-pyrimidi n-2-yI-4,5-dihydro-lH-[l,2,4]triazol-3-yI)methyl}amino)benzamidine acetate, and the first eluting enantiomer (5.89 mg) of the title compound was obtained as a white solid.
"H-NMR (CD3OD) 8 1.91 (s, 3H) 3.71 (s, 3H) 3.82-3.94 (m, 2H) 4.02-4.16 (m, 2H) 5.95 (s, 1H) 6.57-6.70 (m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.30 (t, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=5.2Hz, 2H). HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[0980] Example 154: (R) and
(S)-4-({(2-fluoro-3.5-dimethoxvphenvl)-[5-oxo-l-(3-oxo-3.4-dihydropyr
azin-2-vl)1-4,5-dihvdro-lH-[1.2.41triazol-3-yl1methvUamino)benzamidin
e acetate
[0981] (154a) (3-t-butoxypyrazin-2-yl)hydrazine
[0982] [Chemical Formula 392]

To a solution of 5.64 g of diisopropylamine in 100 ml of THF there was added 21.1 ml of n-butyllithium (2.55M, n-hexane solution) at -75°C under a nitrogen atmosphere, and after stirring the mixture for 30 minutes, a solution of 6.78 g of 3-t-butoxypyrazine [CAS

No.70090-30-1] in 30 ml of THF was added dropwise. After stirring at the same temperature for 4 hours, a solution of 17.9 g of iodine in 100 ml of THF was added dropwise and the mixture was stirred overnight at room temperature. Next, 800 ml of saturated aqueous sodium sulfite and 800 ml of ethyl acetate were added, and the organic layer was washed with 300 ml of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give 2-t-butoxy-3-iodopyrazine (0.77 g) as a yellow oil. This compound was dissolved in 10 ml of THF, and then 1 ml of hydrazine monohydrate was added and the mixture was heated to reflux for 5 days. Next, 200 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.28 g) as a gold-colored solid. 'H-NMR (CDC13) 5 1.59 (s, 9H) 3.87 (br.s, 2H) 6.22 (br.s, 1H) 7.33 (d, J=3.3Hz, 1H) 7.56 (d, J=3.3Hz, 1H) [0983] (154b)
3-(3-{(2-fluoro-3,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl} -5-0X0-4,5-dihydro-1 H-[ 1,2,4]triazol-1 -yl)-1 H-py razin-2-one [0984] [Chemical Formula 393]

After adding 2 ml of trifluoroacetic acid to a solution of 139 mg of (3-t-butoxypyrazin-2-yl)hydrazine in 2 ml of dichloromethane, the

mixture was stirred at room temperature for 2 hours. Next, 50 ml of
toluene was added, the mixture was concentrated under reduced pressure,
and then 50 ml of methanol was added and the mixture was concentrated
under reduced pressure. The residue was dissolved in 20 ml of DMF.
The same procedure was carried out as in Examples (3e)-(3f), except that
methyl iodide and the aforementioned 4 ml DMF solution were used
instead of respectively the l-fluoro-2-iodoethane in Example (3e) and the
2-hydrazinopyrimidine in Example (3f), to give the title compound (34
mg) as a yellow solid.
'H-NMR (CD3OD) 5 2.59 (s, 3H) 3.73 (s, 3H) 3.85 (s, 3H) 5.94 (s, 1H)
6.61 (s, 1H) 6.63 (s, 1H) 6.79 (d, J=9.1Hz, 2H) 7.38 (d, J=3.6Hz, 1H)
7.50 (d, J=3.6Hz, 1H) 7.78 (d, J=9.1Hz, 2H)
[0985] (154c) (R) and
(S)-4-({(2-fluoro-3,5-dimethoxyphenyl)-[5-oxo-l-(3-oxo-3,4-dihydropyr
azin-2-yl)]-4,5-dihydro-lH-[l,2,4]triazoI-3-yl]methyl}amino)benzamidin
e acetate
[0986] [Chemical Formula 394]

The same procedure was carried out as in Examples (3g)-(3h), except
that
3-(3-{(2-fluoro-3,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylamino]-methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)-lH-p
yrazin-2-one was used instead of the
5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2,4]o
xadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[ 1,2,4]
triazol-3-one in Example (3g), to give the first eluting enantiomer of the
title compound as a white solid.
'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.72 (s, 3H) 3.85 (s, 3H) 5.92 (s, 1H)
6.59-6.64 (m, 2H) 6.83 (d, J=8.8Hz, 2H) 7.50 (br.s, 1H) 7.61 (d,

J=8.8Hz, 2H) 7.70 (br.s, 1H)
[0987] Example L55j (Rj and
(^)-3-(3-f(4-carbamimidoylphenvlaminoW3.4-dimethoxyphenyDmethyl]
-5-0X0-4.5-dihydro[1.2.4]triazol-l-vl}thiophene-2-carboxylic acid
acetate
[0988] [Chemical Formula 395]

After adding 30 mg of 3-hydrazinothiophene-2-carboxylic acid methyl
ester and 25 ul of triethylamine to a solution of 80 mg of
{2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli
mino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example
(36d)) in 3 ml of DMF, the mixture was stirred at 85°C for 18 hours
under a nitrogen atmosphere. The reaction mixture was concentrated,
and the residue was dissolved in 2 ml of methanol and 2 ml of THF.
After adding 35 yd of acetic acid and 56 mg of sodium
cyanotrihydroborate to the solution, the mixture was stirred at room
temperature for 15 hours. Next, 2 ml of an aqueous IN sodium
hydroxide solution was added to the reaction mixture, and stirring was
continued at room temperature for 2 hours. After adding 2 ml of IN
hydrochloric acid to the reaction mixture, extraction was performed with
ethyl acetate. The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give 70 mg of
3-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyla mino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene-2-carboxy lie acid.

To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 70 mg of iron powder, and the
mixture was stirred at 60°C for 16 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 40 mg of
3-{3-[(4-carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl]-5-o
xo-4,5-dihydro[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
trifluoroacetate.
Mass spectrum (ESI)m/z: 495 (M+H)+
40 mg of this compound was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (17.25 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.83 (s, 3H) 3.85 (s, 3H) 5.55 (s, 1H)
6.87 (d, J=8.8Hz, 2H) 6.98 (d, J=8.4Hz, 1H) 7.07-7.09 (m, 2H) 7.15 (d,
J=2.0Hz, 1H) 7.43 (d, J=5.2Hz, 1H) 7.62 (d, J=8.8Hz, 2H)
HPLC retention time: 19 min (Column name: SUMICHIRAL OA-2500,
30 mmcp * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[0989] Example L56j (R) and
(S>-4- (\( 9-methoxv-3.4-dihvdro-2H-benzorb1 \ 1,41dioxepin-7-vn-(5 -oxo-
l-pvrimidin-2-vl-4.5-dihvdro-lH-[l,2.4"|triazol-3-yl)methvl]amino}benza
midine acetate
[0990] [Chemical Formula 396]

The same procedure was carried out as in Example (30d), except that
2-hydrazinopyrimidine was used instead of the

(3-fluoropyridin-2-yl)hydrazine, to give the first eluting enantiomer of
the title compound.
'H-NMR (CD3OD) 5 1.93 (s, 3H) 2.12-2.19 (m, 2H) 3.81 (s, 3H)
4.10-4.15 (m, 4H) 5.54 (s, 1H) 6.80 (d, J=1.6Hz, 1H) 6.85 (d, J=8.8Hz,
2H) 6.90 (d, J=2.4Hz, 1H) 7.31 (t, J=5.2Hz, 1H) 7.60 (d, J=9.2Hz, 2H)
8.77 (d, J=5.2Hz, 2H)
Mass spectrum (ESI)m/z: 489 (M+H)+ (data for racemic mixture)
HPLC retention time: 15 min
[0991] Example 157:
5-{34(4-carbamimidoylphenvlaminoVf2-fluoro-4.5-dimethoxvphenvOme
thyl]-5-oxo-4,5-dihydro-[1.2.4]triazol-l-vl}-lH-pvrazole-4-carboxvlic
acid acetate
(157a) 3-(N'-t-butoxycarbonylhydrazino)-lH-pyrazole-4-carboxylic acid
ethyl ester
[0992] [Chemical Formula 397]

After adding 10 ml of an aqueous solution containing 6.66 g.of sodium nitrite and 100 ml of a 35% hydrochloric acid solution containing 64.3 g of stannous chloride dihydrate in that order to 65 ml of a 35% hydrochloric acid solution containing 15.7 g of 3-amino-lH-pyrazole-4-carboxylic acid ethyl ester while cooling on ice, the mixture was stirred for 2 hours. The precipitate was filtered off and dissolved in 150 ml of water. After then adding 300 ml of dichloromethane, the mixture was adjusted to alkalinity with potassium carbonate, and then 33.1 g of di-t-butyl dicarbonate was added and the mixture was stirred for 60 hours at room temperature. The solution was separated, the aqueous solution was extracted twice with 200 ml of dichloromethane, and the organic layers were combined and dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (heptane-ethyl acetate)
to give the title compound (4.35 g) as a white solid.
'H-NMR (CDCI3) 5 1.34 (t, J=7.3Hz, 3H) 1.43 (s, 9H) 1.67 (br.s, 2H)
4.29 (q, J=7.3Hz, 2H) 6.92 (br.s, 1H) 7.79 (s, 1H)
[0993] (157b) 3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester
bishydrochloride
[0994] [Chemical Formula 398]

After adding 25 ml of trifluoroacetic acid to a solution of 3.30 g of 3-(N'-t-butoxycarbonylhydrazino)-lH-pyrazole-4-carboxylic acid ethyl ester in 50 ml of dichloromethane, the mixture was stirred for 2 hours at room temperature. Next, 100 ml of toluene was added and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of methanol, and after adding a 4N solution containing hydrochloric acid in ethyl acetate until the solution reached acidic, the solvent was removed under reduced pressure. The residue was treated with 50 ml of t-butyl methyl ether, and the solid was filtered off and dried under reduced pressure to give the title compound (3.30 g) as a white solid.
'H-NMR (de-DMSO) 5 1.25 (t, J=7.3Hz, 3H) 4.19 (q, J=7.3Hz, 2H) 8.18 (br.s, 1H) 8.23 (s, 1H) 9.90 (br.s, 4H) 12.55 (br.s, 1H) [0995] (157c)
5-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-lH-pyrazo le-4-carboxylic acid ethyl ester [0996] [Chemical Formula 399]


A solution of 0.140 g of 3-hydrazino-lH-pyrazole-4-carboxylic acid
ethyl ester, 0.236 g of
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example Id) and 0.209 ml of triethylamine in 6 ml of DMF was heated at 85°C for 15 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in 7 ml of methanol, and then 0.251 g of sodium cyanotrihydroborate, 0.086 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (0.152 g) as a light green solid.
'H-NMR (CD3OD) 5 1.16 (t, J=7.4Hz, 3H) 2.58 (s, 3H) 3.78 (s, 3H) 3.82 (s, 3H) 4.11-4.18 (m, 2H) 5.94 (s, 1H) 6.82 (d, J=9.0Hz, 2H) 6.85 (d, J=8.2Hz, 1H) 7.10 (d, J=5.9Hz, 1H) 7.79 (d, J=9.0Hz, 2H) 8.24 (s, 1H) [0997] (157d)
5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic acid ethyl ester acetate [0998] [Chemical Formula 400]


To a solution of 0.152 g of
5-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-lH-pyrazo
le-4-carboxylic acid ethyl ester in 15 ml of a methanobwatenacetic acid
= 1:1:1 mixed solvent there was added 0.150 g of iron powder, and the
mixture was heated and stirred at 60°C for 20 hours. After filtering the
reaction mixture, it was purified by reverse-phase high performance
liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give
0.091 g of the title compound.
'H-NMR (CD3OD) 5 1.19 (t, J=7.4Hz, 3H) 1.97 (s, 3H) 3.80 (s, 3H) 3.84
(s, 3H) 4.17 (m, 2H) 5.93 (s, 1H) 6.87 (d, J=8.7Hz, 2H) 6.88 (d,
J=10.3Hz, 1H) 7.08 (d, J=6.9Hz, 1H) 7.63 (d, J=8.7Hz, 2H) 8.25 (s, 1H)
[0999] (157e)
5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic
acid acetate
[ 1000] [Chemical Formula 401 ]


After adding 0.056 ml of triethylamine, 0.0015 g of
4-dimethylaminopyridine and 71 mg of di-t-butyl dicarbonate to a
solution of 0.068 g of
5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)rae thyl]-5-oxo-4,5-dihydro-[ 1,2,4]triazol-1 -yl} -1 H-pyrazole-4-carboxylic acid ethyl ester acetate in 4 ml of acetonitrile, the mixture was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and then 1 ml of methanol and 1 ml of a 5N aqueous solution of sodium hydroxide were added and the mixture was further stirred at room temperature for 6 hours. Next, 2 ml of acetic acid, 1 ml of water and 1 ml of methanol were added to the reaction mixture, which was then stirred and heated at 50°C for 15 hours. After cooling, purification was performed by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 0.034 g of the title compound.
'H-NMR (CD3OD) 5 1.98 (s, 3H) 3.79 (s, 3H) 3.83 (s, 3H) 5.94 (s, 1H) 6.86 (d, J=10.6Hz, 1H) 6.86 (d, J=9.1Hz, 2H) 7.04 (d, J=6.8Hz, 1H) 7.64 (d, J=9.1Hz, 2H) 8.23 (s, 1H)
[1001] Example H8j 4-(UK) and
fS)-[3-f3-hvdroxvpropoxv)-5-methoxvphenvn-f5-oxo-l-pvrimidin-2-yl-4 .5-dihvdro-lH-n.2.41triazol-3-vnmethvl)amino)benzamidine acetate [1002] [Chemical Formula 402]

After adding 200 mg of potassium carbonate and 0.1 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 100 mg of {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example 4c) in 1 ml of DMF, the mixture was stirred at room

temperature for 17 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried through PRESEP™. The filtrate was concentrated to give a yellow oil (123 mg).
To a solution of the obtained 123 mg of yellow oil in 1 ml of DMF there
were added 22 mg of 2-hydrazinopyrimidine and 0.028 ml of
triethylamine, and the mixture was stirred at 85°C for 12 hours under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid.
After adding 100 mg of sodium cyanotrihydroborate to the solution, the
mixture was stirred at room temperature for 3 days. The reaction
mixture was crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product of
5-({3-[3-(t-butyldimethylsilanyloxy)propoxy]-5-methoxyphenyl}-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl)-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one.
To a solution of the obtained crude product in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred at 60°C for 18 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-({[3-(3-hydroxypropoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidin-2-yl-4 ,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate. Mass spectrum (ESI)m/z: 491 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (7.65 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.23-3.37 (m, 2H) 3.63-3.81 (m, 5H) 4.04 (t, J=6.0Hz, 2H) 5.60 (s, 1H) 6.45 (s, 1H) 6.72 (s, 2H) 6.86 (d, J=8.4Hz, 2H) 7.34 (t, J=4.4Hz, 1H) 7.60 (d, J=8.4Hz, 2H) 8.78 (d,

J=4.4Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30 mm(p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1003] Example 159j 4-(i(K) and
fS)-r3-C2-hvdroxvethoxv)-4.5-dimethoxvphenvll-(5-oxo-l-pyrimidin-2-vl -4J-dihvdro-lH-[1.2.4]triazol-3-vDmethvUamino)benzamidine acetate [1004] (159a)
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [1005] [Chemical Formula 403]

To a solution of 3.2 g of 3-hydroxy-4,5-dimethoxybenzaldehyde in 50 ml
of DMF there were added 1.49 g of imidazole and 4.5 ml of
chlorotriisopropylsilane. The mixture was stirred at room temperature
for 21 hours and 30 minutes. Water was added to the reaction mixture
and extraction was performed with ethyl acetate. The organic layer was
washed with ice-cooled IN hydrochloric acid, water, saturated aqueous
sodium hydrogencarbonate, water and saturated brine in that order, and
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
3,4-dimethoxy-5-triisopropylsilanyloxybenzaldehyde (6.08 g) as a light yellow oil.
To a solution of the obtained 6.08 g of light yellow oil in 200 ml of
dichloromethane there were added 3.14 g of
4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 6 g of MS3A, 1.12 g of

Yb(OTf)3 and 4.5 ml of trimethylsilyl cyanide under a nitrogen
atmosphere, and the mixture was stirred at room temperature for 15 hours
and 30 minutes. The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was crudely purified
by NH silica gel column chromatography (ethyl acetate) to give a crude
product of
(3,4-dimethoxy-5-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[l,2,4]oxa diazol-3-yl)phenylamino]acetonitrile.
To a solution of the obtained crude product in 225 ml of a methanohTHF
= 2:1 mixed solvent there was added 40 ml of a 20% aqueous solution of
ammonium sulfide, and the mixture was stirred at room temperature for 7
hours. Water was added to the reaction mixture and extraction was
performed with ethyl acetate. The organic layer was washed with water
and saturated brine in that order and dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was crudely purified
by silica gel column chromatography (heptane-ethyl acetate) to give a
crude product of
2-(3,4-dimethoxy-5-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4] oxadiazol-3-yl)phenylamino]thioacetamide.
To a solution of the obtained crude product in 70 ml of dichloromethane there was added 2.2 g of Me30+BF4", and the mixture was stirred at room temperature for 16 hours and 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 100 ml of toluene there were added 4.6 ml of 2,4,6-collidine and 2.3 ml of methyl chloroformate, and the mixture was stirred at 80°C for 19 hours under a nitrogen atmosphere. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled IN

hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate,
water and saturated brine in that order and dried over anhydrous sodium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was crudely purified
by silica gel column chromatography (heptane-ethyl acetate) to give
{2-(3,4-dimethoxy-5-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylamino]-l-methylsulfanylethylidene}carbamic acid
methyl ester (2.53 g) as a yellow oil.
To a solution of 2.53 g of the obtained yellow oil in 20 ml of THF there
was added 4.2 ml of TBAF (1.0 M, THF solution), and the mixture was
stirred at 0°C for 2 hours. Saturated aqueous ammonium chloride was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was washed with water and saturated brine in
that order and dried over anhydrous sodium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (heptane-ethyl acetate) to give the title compound (1.22
g) as a yellow solid.
'H-NMR (CDC13) Main isomer:
6 2.32 (s, 3H) 2.65 (s, 3H) 3.65 (s, 3H) 3.93 (s, 3H) 3.97 (s, 3H) 5.82 (s,
1H) 7.00 (d, J=2.0Hz, 1H) 7.14 (d, J=8.8Hz, 2H) 7.19 (d, J=2.0Hz, 1H)
8.00 (d, J=8.8Hz, 2H)
[1006] (159b) 4-({(R) and
(S)-[3-(2-hydroxyethoxy)-4,5-dimethoxyphenyl]-(5-oxo-l-pyrimidin-2-yl
-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate
[1007] [Chemical Formula 404]

After adding 300 mg of potassium carbonate and 0.1 ml of

2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 100 mg of
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
in 1 ml of DMF, the mixture was stirred at room temperature for 20
hours. Water was added to the reaction mixture and extraction was
performed with ethyl acetate. The organic layer was washed with water
and saturated brine in that order, and dried through PRESEP™. The
filtrate was concentrated, and the residue was purified by silica gel
column chromatography (ethyl acetate-heptane) to give
(2-{3,4-dimethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(
5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]-l-methylsulfanylethyliden
e)carbamic acid methyl ester (80 mg) as a yellow oil.
To a solution of the obtained 80 mg of yellow oil in 1 ml of DMF there
were added 15 mg of 2-hydrazinopyrimidine and 0.019 ml of
triethylamine, and the mixture was stirred at 85°C for 12 hours under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid.
After adding 100 mg of sodium cyanotrihydroborate to the solution, the
mixture was stirred at room temperature for 3 days. The reaction
mixture was crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product of
5-({3,4-dimethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyI)-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one.
To a solution of the obtained crude product in 3 ml of a
methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100
mg of iron powder, and the mixture was stirred at 60°C for 18 hours
under a nitrogen atmosphere. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-({[3-(2-hydroxyethoxy)-4,5-dimethoxyphenyl]-(5-oxo-l-pyrimidin-2-y l-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine acetate.

Mass spectrum (ESI)m/z: 507 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (7.23 mg) of the title compound
was obtained as a light yellow solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.77 (s, 3H) 3.82 (s, 3H) 3.84 (t,
J=4.8Hz, 2H) 3.97-4.12 (m, 2H) 5.60 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.90
(s,2H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30
mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 40 ml/min)
[1008] Example L60j 4-lUR) and
(SW5-ethoxv-6-methoxvpvridin-3-ylW5-oxo-l-pvrimidin-2-yl-4.5-dihvd ro-lH-n.2.41triazol-3-vDmethvnamino)benzamidine acetate [1009] (160a)
{2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [1010] [Chemical Formula 405]

After adding 7.5 g of potassium carbonate and 6 ml of ethyl iodide to a solution of 3.9 g of 2-chloropyridin-3-ol in 60 ml of DMF, the mixture was stirred at 80°C for 1 hour and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous magnesium sulfate The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After adding a 28% sodium methoxide-methanol solution to the residue and stirring at 80°C for 3 hours, the mixture was further stirred at 100°C

for 3 hours. Water was added to the reaction mixture and extraction
was performed with ethyl acetate. The organic layer was washed with
water and saturated brine in that order and then dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (heptane-ethyl acetate) to
give 3-ethoxy-2-methoxypyridine (4.1 g) as a colorless oil.
To a solution of 4.1 g of the obtained colorless oil and 4.25 g of sodium
acetate in 40 ml of acetic acid there was added a solution of 2.83 ml of
bromine in 10 ml of acetic acid at 10°C. The reaction mixture was
stirred at 10°C for 1 hour, and then at room temperature for 3 hours.
The reaction mixture was poured into ice water and neutralized with an
aqueous 5N sodium hydroxide solution. It was then extracted with ethyl
acetate. The organic layer was washed with water and saturated brine in
that order and then dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (heptane-ethyl acetate) to give
5-bromo-3-ethoxy-2-methoxypyridine (5.28 g) as a light yellow oil. To a solution of the 5.28 g of light yellow oil in 80 ml of THF there was added dropwise 9.07 ml of n-butyllithium (2.64 M, hexane solution) at -78°C over a period of 20 minutes. After stirring at -78°C for 3 hours, 4.59 ml of N-formylmorpholine was added. After further stirring at -78°C for 20 minutes, the temperature was slowly allowed to rise to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give 5-ethoxy-6-methoxypyridine-3-carbaldehyde (2.23 g) as a light yellow oil. After adding 533 mg of 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine,

1.5 g of MS3A and 171 mg of Yb(OTf)3 to a solution of 500 mg of the obtained light yellow oil in 10 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours, and then 0.69 ml of trimethylsilyl cyanide was added and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 20 ml of a methanol:THF = 3:1 mixed solvent there was added 20 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture and filtration was performed to give
2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]thioacetamide (1.06 g) as a white solid. To a solution of the obtained 1.06 g of white solid in 20 ml of acetonitrile there was added 431 mg of Me30+BF4", and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 20 ml of ethyl acetate there was added 2.5 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 20 ml of toluene there were added 1.22 ml of 2,4,6-collidine and 0.61 ml of methyl chloroformate, and the mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. Ice-cooled IN hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was

purified by silica gel column chromatography (heptane-ethyl acetate) to
give the title compound (750 mg) as a yellow solid.
Mass spectrum (ESI)m/z: 470 (M+H)+
[1011] (160b) 4-{[(R) and
(S)-(5-ethoxy-6-methoxypyridin-3-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihyd
ro-lH-[l,2,4]triazol-3-yl)methyl]amino}berizamidine acetate
[1012] [Chemical Formula 406]

After adding 23.5 mg of 2-hydrazinopyrimidine and 0.030 ml of
triethylamine to a solution of 100 mg of
{2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
in 1 ml of DMF, the mixture was stirred at 85°C for 21 hours under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was dissolved in 2.0 ml of methanol and 0.1 ml of acetic acid.
After adding 100 mg of sodium cyanotrihydroborate to the solution, the
mixture was stirred at room temperature for 23 hours. The reaction
mixture was crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product of
5-{(5-ethoxy-6-methoxypyridin-3-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one
To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 60°C for 11 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction

mixture, it was purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give
4-{[(5-ethoxy-6-methoxypyridin-3-yl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihy
dro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
Mass spectrum (ESI)m/z: 462 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (5.37 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 1.33 (t, J=5.8Hz, 3H) 1.92 (s, 3H) 3.91 (s, 3H) 3.99
(q, J=5.8Hz, 2H) 5.69 (s, 1H) 6.88 (d, J=8.4Hz, 2H) 7.30 (d, J=4.8Hz,
1H) 7.38 (s, 1H) 7.60 (d, J=8.4Hz, 2H) 7.83 (s, 1H) 8.76 (d, J=4.8Hz,
2H)
HPLC retention time: 12 min (Column name: SUMICHIRAL OA-2500,
30 mmq> * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1013] Example \_6U (R) and
(S)-4-{[(4-fluoro-7-methoxy-23-dihydrobenzofuran-5-yn-(5-oxo-l-pvri
midin-2-yl-4,5-dihvdro-lH-[1.2.4]triazol-3-yl)methvl]amino)benzamidin
e acetate
[1014] (161a)
4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde
[1015] [Chemical Formula 407]

To a suspension of 50 g of methyltriphenylphosphonium bromide in 300 ml of toluene there was added dropwise 45 ml of n-butyllithium (2.55 M, hexane solution) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and allowed to stand. Next, 150 ml of the supernatant was added to a solution of 5 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No.457628-15-8] in

90 ml of toluene. The mixture was stirred at room temperature for 1
hour, IN hydrochloric acid was added to the reaction mixture, and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate and filtered, and the filtrate was
concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
3-fluoro-6-methoxy-2-vinylphenol (4.33 g).
After dissolving 4.33 g of this compound in 20 ml of DMF, there were
added 3 g of imidazole and 5.5 g of chlorotriisopropylsilane, and the
mixture was stirred overnight at 50°C. Ethyl acetate was added to the
reaction mixture, and washing was performed with water. The organic
layer was dried over anhydrous magnesium sulfate. The desiccating
agent was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
(3-fluoro-6-methoxy-2-vinylphenoxy)triisopropylsilane (3.35 g). After dissolving 3.35 g of this compound in 20 ml of THF, there was added dropwise 10 ml of borane-tetrahydrofuran complex (1M, THF solution) while cooling on ice. The mixture was stirred overnight at room temperature, and then 10 ml of saturated aqueous sodium hydrogencarbonate and 10 ml of 30% aqueous hydrogen peroxide were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated.
The residue was dissolved in 20 ml of THF, and then 20 ml of TBAF (1M, THF solution) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and washing was performed with water. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3-fluoro-2-(2-hydroxyethyl)-6-methoxyphenol

(1.01 g).
After dissolving 1.01 g of this compound in 20 ml of THF, 2.1 g of
triphenylphosphine was added and the mixture was cooled to -70°C.
Next, 1.6 ml of diisopropylazodicarboxylate was added and the mixture
was stirred overnight at room temperature. The reaction mixture was
concentrated, and the residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
4-fluoro-7-methoxy-2,3-dihydrobenzofuran (802 mg). To a solution of 665 mg of this compound and 740 mg of N,N,N',N',N"-pentamethyldiethylenetriamine in 15 ml of THF there was added dropwise 1.66 ml of n-butyllithium (2.55 M, hexane solution) at -74°C. After stirring at -70°C for 1 hour, 0.5 ml of N-formylmorpholine was added. The temperature of the reaction mixture was slowly allowed to rise to 6°C. Next, IN hydrochloric acid was added to the reaction mixture while cooling on ice, and then it was extracted with a mixture of hexane and t-butyl methyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (321 mg) as an oil.
'H-NMR (CDC13) 5 3.34 (t, J=8.8Hz, 2H) 3.89 (s, 3H) 4.82 (t, J=8.8Hz, 2H) 7.24 (d, J=5.6Hz, 1H) 10.18 (s, 1H) [1016] (161b)
[2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester [1017] [Chemical Formula 408]

After adding 966 mg of 4-aminobenzonitrile, 1 g of MS3A, 507 mg of Yb(OTf>3 and 2 ml of trimethylsilyl cyanide to a solution of 1.6 g of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde in 25 ml of

THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure.
To a solution of the residue in 30 ml of an ethanohTHF = 2:1 mixed solvent there was added 10 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-(4-cyanophenylamino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5 -yl)thioacetamide.
To a solution of this compound in 10 ml of acetonitrile there was added 1 g of Me30+BF4% and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 30 ml of ethyl acetate there was added 1.5 g of manganese dioxide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
After then adding 4 ml of 2,4,6-collidine and 2 ml of methyl chloroformate to a solution of the residue in 50 ml of toluene, the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, 0.5 N hydrochloric acid was added and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was

purified by silica gel column chromatography (ethyl acetate-heptane) to
give the title compound (1.68 g, isomeric mixture) as a light yellow
solid.
'H-NMR (CDCb) Two main isomers:
5 2.33 (s, 3H) 3.31 (t, J=8.8Hz, 2H) 3.63 (s, 3H) 3.90 (s, 3H) 4.79 (t,
J=8.8Hz, 2H) 6.82 (d, J=7.2Hz, 1H) 7.07 (d, J=8.0Hz, 2H) 7.59 (d,
J=8.0Hz, 2H)
5 2.48 (s, 3H) 3.17 (t, J=7.6Hz, 2H) 3.61 (s, 3H) 3.69 (s, 3H) 4.70 (t,
J=7.6Hz, 2H) 6.43 (d, J=5.6Hz, 1H) 7.33 (d, J=5.6Hz, 2H) 7.51 (d,
J=8.8Hz, 2H)
[1018] (161c) (R) and
(S)-4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidm
e acetate
[1019] [Chemical Formula 409]

After adding 144 mg of 2-hydrazinopyrimidine and 900 u.1 of
triethylamine to a solution of 624 mg of
[2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester in 12 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6.6 ml of a methanohacetic acid = 10:1 mixed solvent. After adding 1 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off

and the filtrate was concentrated under reduced pressure. The residue
was purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzonitrile
(414 mg) as a light yellow solid.
To a solution of 414 mg of this compound in 9 ml of pyridine there were
added 1.2 ml of triethylamine and 9 ml of a 20% aqueous solution of
ammonium sulfide, and the mixture was stirred overnight at 60°C under a
nitrogen atmosphere. The reaction mixture was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give
4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}thiobenzamide
(207 mg) as a light yellow solid.
To a suspension of 207 mg of this compound in 10 ml of acetonitrile
there was added 68.2 mg of Me30+BF4", and the mixture was stirred at
room temperature for 15 minutes. After adding 5 ml of isopropanol and
0.1 ml of 1,1,3,3-tetramethyldisilazane to the reaction mixture, it was
stirred at 60°C for 36 hours. The reaction mixture was concentrated,
and the residue was purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give
4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-1 H-[ 1,2,4]triazol-3-yl)methyl]amino } benzamidine
acetate (173 mg).
A SUMICHIRAL OA-2500 column was used for optical resolution of 173
mg of this compound, and the first eluting enantiomer (71 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.27 (t, J=8.8Hz, 2H) 3.76 (s, 3H) 4.66
(t, J=8.8Hz, 2H) 5.88 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.97 (d, J=5.6Hz,
1H) 7.31 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 28 min
[1020] Example 162j (R) and

(S)-4-{3-[(4-carbamimidoylphenvlamino)-f2-fluoro-4.5-dimethoxvphenvl )methvll-5-oxo-4.5-dihvdro[1.2.41triazol-l-vUthiazole-5-carboxvlic acid [1021] (162a) 4-amino-2-methanesulfonylthiazole-5-carboxylic acid methyl ester [1022] [Chemical Formula 410]

After adding 45.2 g of 4-amino-2-methylsulfanylthiazole-5-carboxylic acid methyl ester [CAS No.60093-05-2] to 2 liters of a watenmethanol = 1:1 mixed solvent at room temperature, 408 g of Oxone™ was added in small portions over a period of 30 minutes with stirring. The mixture was stirred at room temperature for 24 hours, and then poured into a mixture of 10 liters of ethyl acetate and 10 liters of water. After washing the organic layer with 5 liters of saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (37.6 g) as a white solid. 'H-NMR (CDC13) 8 3.29 (s, 3H) 3.90 (s, 3H) 6.00 (br.s, 2H) [1023] (162b) 4-aminothiazole-5-carboxylic acid methyl ester [1024] [Chemical Formula 411]

To a solution of 37.6 g of
4-amino-2-methanesulfonylthiazole-5-carboxylic acid methyl ester in 1 liter of a methanol:THF =1:1 mixed solvent at room temperature there was added 15 g of sodium borohydride in small portions over a period of 10 hours. The reaction mixture was stirred at room temperature for 40 hours, and then poured into a mixture of 6 liters of ethyl acetate and 3 liters of water. The organic layer was washed with 3 liters of water and 3 liters of saturated brine, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (15.3 g) as a light yellow solid. 'H-NMR (CDCb) 5 3.85 (s, 3H) 5.87 (br.s, 2H) 8.54 (s, 1H) [1025] (162c) 4-hydrazinothiazole-5-carboxylic acid methyl ester [1026] [Chemical Formula 412]

To a solution of 4-aminothiazole-5-carboxylic acid methyl ester (15.3 g) in concentrated hydrochloric acid (90 ml) there was added dropwise an aqueous solution (10 ml) containing sodium nitrite (7.32 g) at 0-10°C. The mixture was then stirred at 0°C for 30 minutes. To this mixture there was added dropwise a concentrated hydrochloric acid solution (100 ml) containing stannous chloride (73.2 g) at 0-10°C, and the mixture was stirred at the same temperature for 2 hours. The mixture was filtered, and the filtrate was carefully added to a suspension of potassium carbonate and celite in ethyl acetate (3 liters) with stirring, with regular addition of potassium carbonate to prevent solution acidic. After adding the filtered substance to a solution of this mixture in ethyl acetate, it was rendered basic with a 5N aqueous sodium hydroxide solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A) was separated off. The remaining suspension was filtered through celite and the filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (500 ml) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layer, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off

and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl
acetate-methanol) to give the title compound (11.6 g) as a light yellow
solid.
'H-NMR (CDCI3) 8 3.83 (s, 3H) 4.14 (br.s, 2H) 7.55 (br.s, 1H) 8.61 (s,
1H)
[1027] (162d) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl
)methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
[1028] [Chemical Formula 413]

After adding 115 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester and 93 u.1 of triethylamine to a solution of 315 mg of [2-(2-fluoro-3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example Id) in 50 ml of DMF, the mixture was stirred at 85°C for 24 hours under a nitrogen atmosphere. The reaction mixture was then concentrated.
The residue was dissolved in 5 ml of THF, and then 534 ul of 5N aqueous sodium hydroxide was added and the mixture was stirred at room temperature for 14 hours. After adding 10 ml of water and 700 u.1 of 5N hydrochloric acid to the reaction mixture, it was extracted with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 9 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 300 mg of iron powder, and the mixture was stirred at 60°C for 20 hours under a nitrogen atmosphere.

After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 150 mg of
4-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
trifluoroacetate.
Mass spectrum (ESI)m/z: 514 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (50 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 3.78 (s, 3H) 3.83 (s, 3H) 5.91 (s, 1H) 6.82-6.87 (m,
3H) 7.07 (d, J=7.2Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.89 (s, 1H)
HPLC retention time: 24 min (Column name: SUMICHIRAL OA-2500,
30 mmtp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 25 ml/min)
[1029] Example 163: (EJ and
(S)-4-(3-{(4-carbamimidovlphenvlamino)-f2-fluoro-3-(3-hvdroxypropox
v)-5-methoxvphenyl1methvU-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vl)thiaz
ole-5-carboxylic acid
[1030] (163a)
2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxy
phenyl)thioacetamide
[1031] [Chemical Formula 414]

After adding 18 g of 4-aminobenzonitrile, 50 g of MS3A, 6.65 g of Yb(OTf>3 and 28.6 ml of trimethylsilyl cyanide to a solution of 50.04 g of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde (Example 3b) in 300 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. The reaction mixture was

filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was suspended in ethyl acetate-heptane (1:2) and the solid was filtered to give 4-{[cyano-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)methyl]a mino}benzonitrile (59.32 g).
To a solution of the 59.32 g of this compound in 690 ml of a methanol:THF = 2:1 mixed solvent there was added 230 ml of a 20% aqueous solution of ammonium sulfide, the mixture was stirred at room temperature for 6 hours. After adding ethyl acetate (1000 ml) and water (1000 ml) to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 200 ml of DMF, and then 6.3 g of imidazole and 15.1 g of chlorotriisopropylsilane were added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (57.97 g) as a light yellow solid.
'H-NMR (CDC13) 8 1.10-1.16 (m, 18H) 1.25-1.35 (m, 3H) 3.67 (s, 3H) 5.42 (d, J=4.8Hz, 1H) 6.03 (d, J=4.8Hz, 1H) 6.43-6.48 (m, 2H) 6.55 (d, J=8.8Hz, 2H) 7.34-7.38 (m, 1H) 7.38 (d, J=8.8Hz, 2H) 7.42-7.46 (m, 1H) [1032] (163b)
[2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-rnethoxyphenyl)-l-me thylsulfanylethylidenejcarbamic acid methyl ester [1033] [Chemical Formula 415]


To a suspension of 57.96 g of
2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxy
phenyl)thioacetamide in 200 ml of acetonitrile there was added 18.5 g of
Me30+BF4", and the mixture was stirred at room temperature for 3 hours.
After adding 2.1 g of Me30+BF4_ to the reaction mixture, it was further
stirred at room temperature for 1 hour. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture, and extraction was
performed with ethyl acetate. After washing the organic layer with
saturated brine, it was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off, and the filtrate was concentrated under
reduced pressure to give
2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxy phenyl)thioacetimidic acid methyl ester (crude product). The crude product was dissolved in 500 ml of ethyl acetate, 112 g of manganese dioxide was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
After dissolving the residue in 500 ml of toluene, 39 ml of
2,4,6-collidine and 23 ml of methyl chloroformate were added, and the
mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere.
After cooling the reaction mixture, IN hydrochloric acid was added and
extraction was performed with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(heptane-ethyl acetate) to give
[2-(4-cyanophenylimino)-2-(2-fluoro-5-methoxy-3-triisopropyIsilanyioxy phenyl)-l-methylsulfanylethylidene]carbamic acid methyl ester (45.78 g) as a yellow solid.

After dissolving the 45.78 g of this compound in 400 ml of THF, 90 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (27.83 g, isomeric mixture) as a light yellow solid. 'H-NMR (CDC13) Two main isomers:
8 2.34 (s, 3H) 3.62 (s, 3H) 3.67 (s, 3H) 5.37 (d, J=4.8Hz, 1H) 6.88-6.91 (m, 1H) 6.56 (dd, J=3.2, 7.2Hz, 1H) 7.10 (d, J=8.4Hz, 2H) 7.50 (d, J=8.4Hz, 2H)
8 2.48 (s, 3H) 3.61 (s, 3H) 3.80 (s, 3H) 5.26 (d, J=3.6Hz, 1H) 6.17-6.19 (m, 1H) 6.75 (dd, J=2.8, 6.8Hz, 1H) 6.81 (d, J=8.4Hz, 2H) 7.61 (d, J=8.4Hz, 2H) [1034] (163c)
(2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl }-2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid methyl ester

After adding 0.489 g of cesium carbonate and 0.348 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 0.401 g of [2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-l-me thylsulfanylethylidene]carbamic acid methyl ester in 10 ml of DMF, the mixture was stirred at room temperature for 24 hours. Next, 50 ml of water was added to the reaction mixture and extraction was performed with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over

anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate-heptane)
to give 0.517 g of the title compound.
'H-NMR (CDCI3) Two main isomers:
8 0.01 and 0.04 (s, 6H) 0.87 and 0.90 (s, 9H) 1.94 and 2.01 (quint,
J=6.0Hz, 2H) 2.34 and 2.46 (s, 3H) 3.60 and 3.63 (s, 3H) 3.66 and 3.81
(s, 3H) 3.74 and 3.79 (t, J=6.0Hz, 2H) 4.01 and 4.10 (t, J=6.0Hz, 2H)
6.11 and 6.89 (t, J=3.4Hz, 1H) 6.52 and 6.61 (dd, J=6.7,3.4Hz, 1H) 6.81
and 7.08 (d, J=8.5Hz, 2H) 7.47 and 7.60 (d, J=8.5Hz, 2H)
[1036] (163d) (R) and
(S)-4-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropox
y)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiaz
ole-5-carboxylic acid
[1037] [Chemical Formula 417]

After adding 172 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example 162c) and 138 u.1 of triethylamine to a solution of 517 mg of
(2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl }-2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid methyl ester in 15 ml of DMF, the mixture was stirred at 85°C for 24 hours under a nitrogen atmosphere.
The reaction mixture was concentrated, and the residue was dissolved in 30 ml of a methanol:THF = 2:1 mixed solvent. After adding 181 ul of acetic acid and 566 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 20 hours. Next, 100 ml of water was added to the reaction mixture and extraction was performed

with 200 ml of ethyl acetate. The organic layer was washed with 100 ml of water and 100 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml of methanol, and then 4 ml of 5N aqueous sodium hydroxide was added and the mixture was stirred at room temperature for 5 hours. Acetic acid was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was dissolved in 10 ml of methanol, and then 138 ul of triethylamine and 313 mg of hydroxylammonium chloride were added and the mixture was heated at 60°C for 20 hours under a nitrogen atmosphere. After cooling, 10 ml of acetic acid, 10 ml of water and 1.01 g of iron powder were added to the reaction mixture, and heating was continued at 60°C for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture, it was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 4-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropoxy)-5 -methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazoI-l-yI)thiazoIe-5-carboxylic acid trifluoroacetate.
This compound was optically resolved using a SUM1CHIRAL OA-2500 column, and the first eluting enantiomer (10.2 mg) of the title compound was obtained as a white solid.
^-NMR (CD3OD) 5 2.00 (quint, 6.3Hz, 2H) 3.74 (s, 3H) 3.75 (t, J=6.3Hz, 2H) 4.13 (t, J=6.3Hz, 2H) 5.94 (s, 1H) 6.52 (dd, J=6.7,3.0, 1H) 6.56 (dd, J=5.5, 3.0, 1H) 6.75 (d, J=8.9Hz, 2H) 7.64 (d, J=8.9Hz, 2H) 8.88 (s, 1H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mmcp * 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1038] Example 164: (R1 and
(S>-4-(3-[(4-carbamimidovlphenvlamino)-(5-fluoro-8-methoxy-4H-benzo

[1.31dioxin-6-vl)methvll-5-oxo-4.5-dihvdro-n.2.4]triazol-l-yl|thiazole-
5-carboxvlic acid amide
[1039] (164a)
4-{3-[(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(4-thiocarbamoylp
henylamino)methyI]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI}thiazole-5-car
boxylic acid amide
[1040] [Chemical Formula 418]

To a solution of 235 mg of
4-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid methyl ester (Example 165b) in 4 ml of pyridine there were added 0.2 ml of triethylamine and 4 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (109 mg) as a light yellow solid. Mass spectrum (ESI)m/z: 558 (M+H)+
[1041] (164b) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo [l,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid amide [1042] [Chemical Formula 419]


After adding 33 mg of Me30+BF4_ to a suspension of 109 mg of
4-{3-[(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-(4-thiocarbamoylp
henylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazoI-l-yl}thiazole-5-car
boxylic acid amide in 1 ml of acetonitrile, the mixture was stirred at
room temperature for 30 minutes. Next, 4 ml of isopropanol and 0.055
ml of 1,1,3,3-tetramethyldisilazane were added to the reaction mixture,
which was then stirred overnight at 60°C. The reaction mixture was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[l, 3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-c arboxylic acid amide (36 mg).
A SUM1CHIRAL OA-2500 column was used for optical resolution of 36
mg of this compound, and the first eluting enantiomer (12.26 mg) of the
, title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 3.75 (s, 3H) 4.81-4.92 (m, 2H) 5.23 (s, 2H) 5.79 (s, 1H) 6.79 (d, J=8.8Hz, 2H) 7.03 (d, J=6.8Hz, 1H) 7.58 (d, J=8.8Hz, 2H) 9.01 (s, 1H)
HPLC retention time: 12 min (Column name: SUMICHIRAL OA-2500, 30 mmp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1043] Example 165] (E) and
(S)-4-(3-[(4-carbamimidoylphenylammo)-(5-fluoro-8-methoxv-4H-benzo [1.31dioxin-6-ynmethyl]-5-oxo-4.5-dihvdro-ri.2.41triazol-l-vUthiazole-5-carboxvlic acid

[1044] (165a)
[2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester [1045] [Chemical Formula 420]

To a solution of 931 mg of
5-fluoro-8-methoxy-4H-benzo-[l,3]dioxine-6-carbaldehyde (Example 32b) in 20 ml of THF there were added 520 mg of 4-aminobenzonitrile, 1 g of MS3A, 270 mg of Yb(OTf)3 and 1 ml of trimethylsilyl cyanide, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure. To a solution of the residue in 15 ml of a methanol:THF = 2:1 mixed solvent there was added 5 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-(4-cyanophenylamino)-2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)thioacetamide (1.31 g).
To a solution of this compound in 10 ml of acetonitrile there was added 545 mg of Me30+BF4_, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.

To a solution of the residue in 15 ml of ethyl acetate there was added 2.8
g of manganese dioxide, and the mixture was stirred at room temperature
for 1 hour. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure.
After then adding 0.93 ml of 2,4,6-collidine and 0.54 ml of methyl
chloroformate to a solution of the residue in 10 ml of toluene, the
mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere.
After cooling the reaction mixture, 0.5 N hydrochloric acid was added
and extraction was performed with ethyl acetate. After washing the
organic layer with saturated brine, it was dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate-heptane) to
give the title compound (0.89 g, isomeric mixture) as a light yellow
solid.
'H-NMR (CDC13) Two main isomers:
5 2.34 (s, 3H) 3.64 (s, 3H) 3.92 (s, 3H) 4.91 (s, 2H) 5.34 (s, 2H) 6.82 (d,
J=8.0Hz, 1H) 7.06 (d, J=8.0Hz, 2H) 7.60 (d, J=8.0Hz, 2H)
8 2.49 (s, 3H) 3.62 (s, 3H) 3.70 (s, 3H) 4.75 (s, 2H) 5.27 (s, 2H) 6.45 (d,
J=5.6Hz, 1H) 7.35 (d, J=6.4Hz, 2H) 7.52 (d, J=6.4Hz, 2H)
[1046] (165b)
4-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid methyl ester
[ 1047] [Chemical Formula 421 ]

After adding 93 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example 162c) and 150 \i\ of triethylamine to a solution of 252 mg

of
[2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of DMF, the mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 8.8 ml of a THF:methanol:acetic acid = 5:5:1 mixed solvent. After adding 1 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (239 mg) as a light yellow solid. 'H-NMR (CD3OD) 8 3.79 (s, 3H) 3.82 (s, 3H) 4.93 (s, 2H) 5.26 (s, 2H) 5.90 (s, 1H) 6.80 (d, J=9.2Hz, 2H) 6.98 (d, J=6.8Hz, 1H) 7.46 (d, J=9.2Hz, 2H)9.16(s, 1H) [1048] (165c)
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[l, 3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-c arboxylic acid trifluoroacetate [1049] [Chemical Formula 422]

To a solution of 135 mg of
4-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid methyl ester in 2 ml of methanol there was added 0.5 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at room

temperature for 1 hour. After adding 0.45 ml of 5N hydrochloric acid
and 1 ml of IN hydrochloric acid to the reaction mixture, extraction was
performed with ethyl acetate. After washing the organic layer with
saturated brine, it was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure.
To a solution of the residue in 2 ml of pyridine there were added 0.1 ml
of triethylamine and 2 ml of a 20% aqueous solution of ammonium
sulfide, and the mixture was stirred overnight at 60°C under a nitrogen
atmosphere. The reaction mixture was concentrated, acetic acid was
added to the residue and the mixture was again concentrated. This was
purified by NAM silica gel column chromatography (methanol-ethyl
acetate) to give
4-{3-[(5-fluoro-8-methoxy-4H-benzo[l,3]dioxiri-6-yl)-(4-thiocarbamoylp
henylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-car
boxylic acid (106 mg) as a light yellow solid.
To a suspension of 106 mg of this compound in 1 ml of acetonitrile there
was added 31 mg of Me30+BF4_, and the mixture was stirred at room
temperature for 30 minutes. After adding 2 ml of isopropanol and 0.075
ml of 1,1,3,3-tetramethyldisilazane to the reaction mixture, it was stirred
at 60°C for 36 hours. The reaction mixture was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the
title compound (65 mg).
Mass spectrum (ESI)m/z: 542 (M+H)+
[1050] (165d) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo
[l,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-
5-carboxylic acid
[1051] [Chemical Formula 423]


A SUMICHIRAL OA-2500 column was used for optical resolution of 65
mg of
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-4H-benzo[l,
3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-c
arboxylic acid trifluoroacetate, and the first eluting enantiomer (19.86
mg) of the title compound was obtained as a white solid.
!H-NMR (CD3OD) 5 3.79 (s, 3H) 4.80-4.87 (m, 2H) 5.25 (s, 2H) 5.88 (s,
1H) 6.84 (d, J=8.8Hz, 2H) 7.01 (d, J=6.4Hz, 1H) 7.62 (d, J=8.8Hz, 2H)
8.87 (s, 1H)
HPLC retention time: 29 min (Column name: SUMICHIRAL OA-2500,
30 mmcp * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1052] Example 166j (R) and
(S)-4-{3-f(4-carbamimidovlphenvlamino)-(8-methoxv-4H-benzofl.31dio xin-6-vOmethvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vlUhiazole-5-carbox ylic acid [1053] (166a)
4-(3-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadia zol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thia zole-5-carboxylic acid methyl ester [1054] [Chemical Formula 424]


To a solution of 300 mg of
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl ester (Example 21h) in 7.5 ml of THF there were added 110.4 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example 162c) and 180 |xl of triethylamine, and the mixture was stirred overnight at 60°C under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was dissolved in 5 ml of DMF, 0.15 ml of triethylamine was added and the mixture was stirred at 80°C for 6 hours. The reaction mixture was then concentrated.
The residue was dissolved in 8.8 ml of a THFrmethanokacetic acid = 5:5:1 mixed solvent. After adding 1 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (290 mg) as a light yellow solid. Mass spectrum (ESI)m/z: 578 (M+H)+ [1055] (166b)
4-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid trifluoroacetate [1056] [Chemical Formula 425]


After dissolving 290 mg of
4-(3-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadia
zol-3-yl)phenylammo]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thia
zole-5-carboxylic acid methyl ester in 3 ml of methanol, 1 ml of a 5N
aqueous sodium hydroxide solution was added and the mixture was
stirred at room temperature for 0.5 hour.
After then adding 0.95 ml of 5N hydrochloric acid, 3 ml of acetic acid, 1
ml of water and 300 mg of iron powder to the reaction mixture, it was
stirred overnight at 60°C. Next, 1 ml of acetic acid was added to the
reaction mixture and stirring was continued at 60°C for 6 hours. After
cooling to room temperature, 0.4 ml of trifluoroacetic acid was added to
the reaction mixture. After filtering the reaction mixture, it was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give 175 mg of the title
compound as a white solid.
Mass spectrum (ESI)m/z: 524 (M+H)+
[1057] (166c) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dio
xin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carbox
ylic acid
[1058] [Chemical Formula 426]


A SUMICHIRAL OA-2500 column was used for optical resolution of 70
mg of
4-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid trifluoroacetate, and the first eluting enantiomer (21.51 mg) of the
title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 3.85 (s, 3H) 4.82-4.90 (m, 2H) 5.24 (s, 2H) 5.54 (s,
1H) 6.81 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.04 (s, 1H) 7.61 (d, J=8.8Hz,
2H) 8.87 (s, 1H)
HPLC retention time: 26 min (Column name: SUMICHIRAL OA-2500,
30 mm

Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1059] Example L£7j (R) and
(S)-4-(3-(f4-carbamimidovlphenvlamino)-[2-fluoro-3-(2-hvdroxvethoxv) -5-methoxyphenvl"|methvl}-5-0X0-4.5-dihvdron.2.4]triazol-l-vnthiazole -5-carboxvlic acid [1060] [Chemical Formula 427]

After adding 313 mg of potassium carbonate and 222 ul of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 520 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example 3d) in 10 ml of DMF, the mixture was stirred at room temperature for 29 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the

filtrate was concentrated under reduced pressure.
After dissolving 280 mg of the obtained residue in 10 ml of DMF, 83 mg
of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example 162c)
and 67 ul of triethylamine were added to the solution and the mixture
was stirred at 85°C for 24 hours under a nitrogen atmosphere. The
reaction mixture was then concentrated.
The residue was dissolved in 5 ml of THF, and then 479 y.1 of 5N aqueous
sodium hydroxide was added and the mixture was stirred at room
temperature for 16 hours. After adding 10 ml of water and 500 ul of 5N
hydrochloric acid to the reaction mixture, it was extracted with ethyl
acetate. After washing the organic layer with saturated brine, it was
dried over anhydrous magnesium sulfate. The desiccating agent was
filtered off and the filtrate was concentrated under reduced pressure.
To a solution of the residue in 9 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 300 mg of iron powder, and the
mixture was stirred at 60°C for 24 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 80 mg of
4-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-
methoxyphenyl]methyl}-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl)thiazole-5-
carboxylic acid trifluoroacetate.
Mass spectrum (ESI)m/z: 544 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (10 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.88 (dd, J=5.2, 4.4Hz, 2H) 4.10 (dd,
J=5.2, 4.4Hz, 2H) 5.95 (s, IH) 6.62-6.68 (m, 2H) 6.85 (d, J=9.2Hz, 2H)
7.63 (d, J=9.2Hz, 2H) 8.90 (s, IH)
HPLC retention time: 20 min (Column name: SUMICHIRAL OA-2500,
30 mm(p x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)

[1061] Example lj>8: (R) and
(S)-3-{3-f(4-carbamimidovlphenvlamino)-(5-fluoro-8-methoxv-2.3-dihyd robenzo[1.4]dioxin-6-vl)methvl]-5 [2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]d ioxin-6-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester [1063] [Chemical Formula 428]

After adding 17 ml of trimethylsilyl cyanide to a suspension of 17.4 g of 5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxine-6-carbaldehyde (Example 41c), 9.68 g of 4-aminobenzonitrile, 17 g of MS3A, 5 g of Yb(OTf)3 in 400 ml of THF, the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was washed with an ethyl acetate and heptane mixed solvent to give 4-{[cyano-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)methyl ]amino}benzonitrile (28.01 g).
To a solution of 28 g of this compound in 375 ml of a methanol:THF =
2:1 mixed solvent there was added 250 ml of a 20% aqueous solution of
ammonium sulfide, and the mixture was stirred overnight at room
temperature. Next, 500 ml of water was added to the reaction mixture
and the precipitated solid was filtered out. The solid was washed with
water and dried to give
2-(4-cyanophenylamino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]di oxin-6-yl)thioacetamide (28g).
'H-NMR (CDC13) 8 3.90 (s, 3H) 4.36 (d, J=8.8Hz, 4H) 4.46 (d, J=6.0Hz, 1H) 5.57 (d, J=4.4Hz, 1H) 6.64 (d, J=4.4Hz, 1H) 6.77 (d, J=7.2Hz, 2H)

7.55 (d, J=7.2Hz, 2H)
To a solution of 1.02 g of this compound in 10 ml of acetonitrile there
was added 0.426 g of Me30+BF4", and the mixture was stirred at room
temperature for 30 minutes. Saturated aqueous sodium
hydrogencarbonate was added to the reaction mixture, and extraction was
performed with ethyl acetate. The organic layer was washed with
saturated brine and then dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure.
To a solution of the residue in 10 ml of ethyl acetate there was added 2 g
of manganese dioxide, and the mixture was stirred at room temperature
for 1 hour. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure.
After then adding 0.73 ml of 2,4,6-collidine and 0.42 ml of methyl
chloroformate to a solution of the residue in 10 ml of toluene, the
mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere.
After cooling the reaction mixture, 0.5 N hydrochloric acid was added
and extraction was performed with ethyl acetate. The organic layer was
washed with saturated brine and then dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was designated as
"Residue 1".
Next, 5.03 g of
2-(4-cyanophenylamino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]di
oxin-6-yl)thioacetamide was used for follow-up synthesis. Here, the
reaction procedure was the same as described above, but the reagents
used were 2.1 g of Me30+BF4", 10 g of manganese dioxide, 3.6 ml of
2,4,6-collidine and 2.1 ml of methyl chloroformate.
The obtained residue was combined with "Residue 1" and purified by
silica gel column chromatography (ethyl acetate-heptane) to give the title
compound (3.08 g, isomeric mixture) as a light yellow solid.
'H-NMR (CDC13) Two main isomers:
8 2.34 (s, 3H) 3.65 (s, 3H) 3.91 (s, 3H) 4.27-4.29 (m, 2H) 4.32-4.37 (m,

2H) 6.81 (d, J=8.4Hz, 1H) 7.02-7.08 (m, 2H) 7.59 (d, J=8.0Hz, 2H)
5 2.48 (s, 3H) 3.65 (s, 3H) 3.72 (s, 3H) 4.32-4.37 (m, 2H) 4.40-4.44 (m,
2H) 6.17 (d, J=4.8Hz, 1H) 7.02-7.08 (m, 2H) 7.50 (d, J=8.0Hz, 2H)
[1064] (168b)
3 - {3 - [(4-cyanopheny lamino)-(5 -fluoro-8 -methoxy-2,3 -dihydrobenzo [1,4]
dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-c
arboxylic acid methyl ester
[1065] [Chemical Formula 429]

To a solution of 2 g of
[2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]d ioxin-6-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester in 24 ml of DMF there were added 720 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 1.2 ml of triethylamine, and the mixture was stirred overnight at 85°C under a nitrogen atmosphere.
The reaction mixture was concentrated, and the residue was dissolved in 21 ml of a methanol:THF:acetic acid = 10:10:1 mixed solvent. After adding 2 g of sodium cyanotrihydroborate to the solution, the mixture was stirred overnight at room temperature. Ethyl acetate was then added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (1.72 g) as a light yellow solid. [1066] (168c) 3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob
enzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiop hene-2-carboxylic acid trifluoroacetate [1067] [Chemical Formula 430]

To a solution of 472 mg of
3-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4] dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-c arboxylic acid methyl ester in 10 ml of ethanol there were added 488 mg of hydroxylammonium chloride and 1.22 ml of triethylamine, and the mixture was stirred overnight at 68°C under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 10 ml of acetic acid. After adding 1 ml of acetic anhydride and 500 mg of 10% palladium-carbon (hydrous) to the solution, the mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 4 ml of methanol and 7 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 hour. After adding 2.5 ml of trifluoroacetic acid, the solution was purified by reverse phase silica gel column chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (350 mg) as a light yellow solid. Mass spectrum (ESI)m/z: 541 (M+H)+
[1068] (168d) (R) and
(S)-3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihyd robenzo [ 1,4] dioxin-6-y l)methy 1] -5 -oxo-4,5 -dihydro-[ 1,2,4]tr iazol -1 -yl} t hiophene-2-carboxylic acid [1069] [Chemical Formula 431]


A SUMICHIRAL OA-2500 column was used for optical resolution of 120
mg of
3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob enzo [ 1,4] dioxin-6-yl)methy 1] -5 -oxo-4,5 -dihydro-[ 1,2,4]triazol-1 -y 1} thiop hene-2-carboxylic acid trifluoroacetate, and the first eluting enantiomer (38.5 mg) of the title compound was obtained as a white solid. 'H-NMR (CD3OD) 8 3.76 (s, 3H) 4.29 (s, 4H) 5.87 (s, 1H) 6.65 (d, J=6.0Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.09 (d, J=5.2Hz, 1H) 7.44 (d, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H)
HPLC retention time: 21 min (Column name: SUMICHIRAL OA-2500, 30 mm

[1070] Example 169j 3-{3-ICR) and
("S)-f4-carbamimidovlphenvlamino')-('5.6-dimethoxvpvridin-3-vl')methvl]-
5-oxo-4.5-dihvdro-p.2.4"|triazol-l-yl}thiophene-2-carboxvlic acid
acetate
[1071] (169a)
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester [1072] [Chemical Formula 432]

To a solution of 1.0 g of 5,6-dimethoxypyridine-3-carbaldehyde [CAS

No.52605-99-9] in 10 ml of THF there were added 1.15 g of 4-(5-methyl-[l,2,4]oxadiazol-3-yI)phenylamine, 5 g of MS3A and 371 mg of Yb(OTf)3 under a nitrogen atmosphere, and after stirring at room temperature for 2 hours, 4.5 ml of trimethylsilyl cyanide was added and the mixture was stirred at room temperature for 12 hours and 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A dichloromethane, heptane and ethyl acetate mixed solvent was added and the mixture was filtered to give (5,6-dimethoxypyridin-3-yl)-[4-(5-methyl[l,2,4]oxadiazol-3-yl)phenylam ino]acetonitrile (2.19 g) as a white solid.
'H-NMR (CDC13) 5 2.64 (s, 3H) 3.93 (s, 3H) 4.06 (s, 3H) 4.28 (d, J=8.0Hz, 1H) 5.45 (d, J=8.0Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.20 (d, J=2.0Hz, 1H) 7.95-8.05 (m, 3H)
To a solution of 2.19 g of the obtained white solid in 40 ml of a
methanol:THF = 3:1 mixed solvent there was added 40 ml of a 20%
aqueous solution of ammonium sulfide, and the mixture was stirred at
room temperature for 8 hours. After adding water to the reaction
mixture, it was filtered to give
2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl[l,2,4]oxadiazol-3-yl)phen ylamino]thioacetamide (2.18 g) as a white solid.
To a solution of 2.18 g of the obtained white solid in 20 ml of acetonitrile there was added 920 mg of Me30+BF4~, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure.
After adding 6 g of manganese dioxide to a solution of the residue in 80 ml of ethyl acetate, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. After then adding 1.86 ml of 2,4,6-collidine and 0.87 ml of methyl

chloroformate to a solution of the residue in 20 ml of toluene, the
mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere.
Water was added to the reaction mixture and extraction was performed
with ethyl acetate. The organic layer was washed with ice-cooled 0.5N
hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate,
water and saturated brine in that order, and then dried over anhydrous
magnesium sulfate. The desiccating agent was filtered off and the
Filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (heptane-ethyl acetate) to
give the title compound (1.36 g) as a yellow solid.
'H-NMR (CDC13) Main isomer:
5 2.34 (s, 3H) 2.66 (s, 3H) 3.67 (s, 3H) 3.97 (s, 3H) 4.09 (s, 3H) 7.16 (d,
J=8.8Hz, 2H) 7.74 (d, J=2.0Hz, 1H) 7.98-8.07 (m, 3H)
[1073] (169b) 3-{3-[(R) and
(S)-(4-carbamimidoylphenylamino)-(5,6-dimethoxypyridin-3-yl)methyl]-
5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
acetate
[1074] [Chemical Formula 433]

After adding 38 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.030 ml of triethylamine to a solution of 100 mg of {2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 90°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the

mixture was stirred at room temperature for 3 hours. Next, 1.0 ml of a
5N aqueous sodium hydroxide solution was added and the mixture was
stirred at room temperature for 2 hours. After then adding 0.3 ml of
acetic acid, the reaction mixture was crudely purified by reverse-phase
high performance liquid chromatography (acetonitrile-water, 0.1% acetic
acid) to give a crude product of
3-(3-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene-2-ca
rboxylic acid.
To a solution of this compound in 3 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 100 mg of iron powder, and the
mixture was stirred at 60°C for 12 hours under a nitrogen atmosphere.
After filtering the reaction mixture,, it was purified by reverse-phase
high performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give
3-{3-[(4-carbamimidoylphenylamino)-(5,6-dimethoxypyridin-3-yl)methy
l]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
trifluoroacetate.
Mass spectrum (ESI)m/z: 496 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (16.55 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.84 (s, 3H) 3.92 (s, 3H) 5.68 (s, 1H)
6.87 (d, J=8.8Hz, 2H) 7.07 (d, J=5.2Hz, 1H) 7.41 (d, J=2.0Hz, 1H) 7.43
(d, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 7.83 (d, J=2.0Hz, 1H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500,
30 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 25 ml/min)
[1075] Example 170j 3-13-fQO and
fS)-f4-carbamimidoylphenylamino)-(4.5-dimethoxvpyridin-2-yl)methyl1-5-0X0-4,5-dihvdro-fl.2.4]triazol-l-vUthiophene-2-carboxylic acid [1076] (170a)

{2-(4,5-dimethoxypyridin-2-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylitnino]-l-methylsulfanylethylidene}carbamic acid methyl ester [1077] [Chemical Formula 434]

The same procedure was carried out as in Example (19b), except that
4,5-dimethoxypyridine-2-carbaldehyde [CAS No.62885-51-2] was used
instead of the 2-methoxy-6-rnethylpyridine-4-carbaldehyde, to give the
title compound.
'H-NMR (CD3OD) Main isomer:
8 2.36 (s, 3H) 2.66 (s, 3H) 3.68 (s, 3H) 4.00 (s, 3H) 4.02 (s, 3H) 7.19 (d,
J=8.8Hz, 2H) 7.81 (s, 1H) 8.04 (d, J=8.8Hz, 2H) 8.18 (s, 1H)
[1078] (170b) 3-{3-[(R) and
(S)-(4-carbamimidoylphenylamino)-(4,5-dimethoxypyridin-2-yI)rnethyl]-
5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
[1079] [Chemical Formula 435]

The same procedure was carried out as in Example 155, except that
{2-(4,5-dimethoxypyridin-2-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester was
used instead of the
{2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli
mino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to give
3-{3-[(4-carbamimidoylphenylamino)-(4,5-dimethoxypyridin-2-yl)methy
l]-5-oxo-4,5-dihydro-[l,2,4]triazol-I-yl}thiophene-2-carboxylic acid

trifluoroacetate.
Mass spectrum (ESI)m/z: 496 (M+H)+
A 20 mg portion of this compound was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (3.68
mg) of the title compound was obtained.
'H-NMR (CD3OD) 8 3.90 (s, 3H) 3.91 (s, 3H) 5.66 (s, 1H) 6.92 (d,
J=8.8Hz, 2H) 7.09 (d, J=5.2Hz, 1H) 7.25 (s, 1H) 7.43 (d, J=5.2Hz, 1H)
7.64 (d, J=8.8Hz, 2H) 8.13 (s, 1H)
HPLC retention time: 20 min (Column name: SUMICHIRAL OA-2500,
30 mmq> * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1080] Example 171j (R) and
(S)-3-(3-r(4-carbamimidovlphenylamino)-(2-fluoro-4.5-dimethoxvphenvl
)methvl]-5-oxo-4.5-dihvdro[1.2.41triazol-l-vUthiophene-2-carboxylic
acid
[1081] [Chemical Formula 436]

After adding 566 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 457 fxl of triethylamine to a solution of 1.55 g of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example Id) in 50 ml of DMF, the mixture was stirred at 85°C for 23 hours under a nitrogen atmosphere. The reaction mixture was then concentrated.
A 400 mg portion of the residue was dissolved in 10 ml of methanol, 708 (il of a 5N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 24 hours. After then

adding 800 ul of 5N hydrochloric acid and water to the reaction mixture,
extraction was performed with ethyl acetate. The organic layer was
washed with saturated brine and then dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure.
To a solution of the residue in 12 ml of a methanol:watenacetic acid =
1:1:1 mixed solvent there was added 400 mg of iron powder, and the
mixture was stirred at 60°C for 16 hours under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 110 mg of
3-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid
trifluoroacetate.
Mass spectrum (ESI)m/z: 513 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (30.02 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 3.78 (s, 3H) 3.82 (s, 3H) 5.88 (s, 1H) 6.82-6.87 (m,
3H) 7.08 (d, J=7.2Hz, 2H) 7.42 (d, J=5.2Hz, 1H) 7.62 (d, J=8.8Hz, 2H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500,
30 mmq> x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 35 ml/min)
[1082] Example 172: £R) and
(S)-4-({[2-fluoro-3-(2-hvdroxvethoxv)-5-methoxvphenyl]-(5-oxo-l-pvri midin-2-vl-4.5-dihvdro-lH-fl.2.41triazol-3-vnmethvUamino)benzamidin e acetate [1083] (172a)
(2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2 -[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyli dene)carbamic acid methyl ester [1084] [Chemical Formula 4371


After adding 200 mg of potassium carbonate and 0.1 ml of
2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 80 mg of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl
ester (Example 3d) in 1 ml of DMF, the mixture was stirred at room
temperature for 14 hours. Water was added to the reaction mixture and
extraction was performed with ethyl acetate. The organic layer was
washed with water and dried through PRESEP™. The filtrate was
concentrated, and the residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound (69
mg) as a yellow oil.
'H-NMR (CDC13) 5 1.40-1.90 (m, 6H) 2.32 and 2.46 (s, 3H) 2.62 and
2.65 (s, 3H) 3.42-4.28 (m, 12H) 4.65 and 4.71 (br.t, J=3.2Hz, 1H)
6.10-6.17 and 6.95-7.01 (m, 1H) 6.54 and 6.75 (dd, J=2.8, 6.8Hz, 1H)
6.84 and 7.11 (d, J=8.4Hz, 2H) 7.89 and 8.03 (d, J=8.4Hz, 2H)
Mass spectrum (ESI)m/z: 587 (M+H)+
[1085] (172b)
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[1086] [Chemical Formula 438]

After adding 13 mg of 2-hydrazinopyrimidine and 0.016 ml of

triethylamine to a solution of 69 mg of
(2-{2-fluoro-5-methoxy-3-r2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2
-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyli
dene)carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred
at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture
was concentrated to give a crude product of
5-({2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[
4-(5-methyI-[l,2,4]oxadiazol-3-yl)phenyIimino]methyl)-2-pyrimidin-2-yl
-2,4-dihydro-[l,2,4]triazol-3-one.
Mass spectrum (ESI)m/z: 639 (M+Na)+
This compound was dissolved in 1 ml of methanol, 1 ml of THF and 0.1
ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate
to the solution, the mixture was stirred at room temperature for 3 hours.
The reaction mixture was crudely purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give a crude product of
5-({2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[
4-(5-methyl-[l,2,4]oxadiazol-3-yI)phenylamino]methyl)-2-pyrimidin-2-y
l-2,4-dihydro-[l,2,4]triazol-3-one.
'H-NMR (CD3OD) 5 1.40-1.90 (m, 6H) 2.59 (s, 3H) 3.43-4.30 (m, 9H)
4.70 (br.s, IH) 5.96 (s, IH) 6.62-6.75 (m, 2H) 6.82 (d, J=8.8Hz, 2H) 7.36
(t, J=4.8Hz, IH) 7.79 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 641 (M+Na)+
To a solution of this compound in 3 ml of a methanokwatenacetic acid -
1:1:1 mixed solvent there was added 100 mg of iron powder, and the
mixture was stirred at 60°C for 2 days under a nitrogen atmosphere.
After filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give the title compound (13.89 mg).
'H-NMR (CD3OD) 8 1.94 (s, 3H) 3.71 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.10
(t, J=4.8Hz, 2H) 5.99 (s, IH) 6.55-6.72 (m, 2H) 6.86 (d, J=8.8Hz, 2H)
7.34 (t, J=4.8Hz, IH) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 495 (M+H)+

[1087] (172c)
{[4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimi
din-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)phenyl]imino
methyl}carbamic acid ethyl ester, or
(1-amino-l-[4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-ox
o-1 -pyrimidin-2-yl-4,5-dihydro-1 H-[ 1,2,4]triazol-3 -yl)methyl} amino)phe
nyl]methylidene}carbamic acid ethyl ester
To a solution of 500 mg of
4-( {[2-fluoro-3-(2-hydroxyethoxy)-5 -methoxyphenyl]-(5 -oxo-1 -pyrim idi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate in 8 ml of DMF there were added 280 mg of ethyl
4-nitrophenylcarbonate [CAS No.6132-45-2] and 0.75 ml of
triethylamine, and the mixture was stirred at 50°C for 4 hours and 30
minutes. After adding 1 ml of acetic acid to the reaction mixture, it was
concentrated under reduced pressure. The obtained residue was purified
by NAM silica gel column chromatography (methanol-ethyl acetate) to
give the title compound (474 mg).
'H-NMR (CD3OD) 5 1.30 (t, J=7.2Hz, 3H) 3.78 (s, 3H) 3.88 (t, J=4.8Hz,
2H) 4.11 (t, J=4.8Hz, 2H) 4.18 (q, J=7.2Hz, 2H) 5.98 (s, 1H) 6.64 (dd,
J=3.2, 4.8Hz, 1H) 6.67 (dd, J=3.2, 6.8Hz, 1H) 6.80 (d, J=8.8Hz, 2H) 7.36
(t, J=4.8Hz, 1H) 7.70 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
[1088] (172d) (R) and
(S)-{[4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyr
imidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)phenyl]imi
nomethyl}carbamic acid ethyl ester, or
(R) and
(S)-{1-amino-l-[4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(
5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl} amino
)phenyl]methylidene}carbamic acid ethyl ester
A SUMICHIRAL OA-2500 column was used for optical resolution of 40
mg of this compound obtained in Example (172c), and the first eluting
enantiomer (17.6 mg) of the title compound was obtained.
HPLC retention time: 21 min (Column name: SUMICHIRAL OA-2500,

30 mmip x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1089] (172e) (R) or
(S)-4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyri
midin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidin
e acetate
N 090] rChemical Formula 439]
To a solution of 17.6 mg of the first eluting enantiomer compound obtained in Example (172d) in 0.5 ml of methanol there was added 0.5 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 hour. After adding 0.5 ml of 2N hydrochloric acid to the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (6.7 mg) as a white solid.
'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.71 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.09 (t, J=4.8Hz, 2H) 5.97 (s, 1H) 6.63-6.66 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.32 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 4.6 mm

[1091] Example 173: 2-(3-ffR) and
(S)-(4-carbamimidovl-3-fluorophenvlamino)-(2-methoxy-6-methvlpyridi n-4-vnmethvll-5-oxo-4.5-dihvdro-n.2.4]triazol-l-vUbenzoic acid [1092] [Chemical Formula 440]


The same procedure was carried out as in Examples (37a)-(37c), except
that 2-methoxy-6-methylpyridine-4-carbaldehyde (Example (19a)) was
used instead of the 3,4-dimethoxybenzaldehyde in Example (37a), to give
the title compound.
Mass spectrum (ESI)m/z: 492 (M+H)+
!H-NMR (CD3OD) 5 2.43 (s, 3H) 3.88 (s, 3H) 5.64 (s, 1H) 6.60 (dd,
J=14.4,2.4Hz, 1H) 6.69 (dd, J=8.8, 2.4Hz, IH) 6.76 (s, IH) 6.98 (s, 1H)
7.35-7.52 (m, 4H) 7.70 (dd, J=7.2, 1.6Hz, IH)
HPLC retention time: 13 min (Column name: SUM1CHIRAL OA-2500,
30 mmcp * 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 25 ml/min)
[1093] Example 174] (R) and
(SV4-((n-r6-aminopvridin-2-vlV5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-
vl]-f2-fluoro-3-('2-fluoroethoxv)-5-methoxvphenvnmethvl>amino')benza
midine acetate
[1094] (174a) 6-hydrazinopyridine-2-carboxylic acid methyl ester
hydrochloride
[1095] [Chemical Formula 441 ]

A solution of 2.12 g of 6-bromopyridine-2-carboxylic acid methyl ester, 0.65 g of 1,1'-bis (diphenylphosphino)ferrocene, 0.358 g of tris(dibenzylideneacetone) dipalladium(O), 3.19 g of cesium carbonate and 1.29 g of t-butyl carbazate in 15 ml of toluene was stirred at 100°C for 20 hours under a nitrogen atmosphere.

The solvent was concentrated under reduced pressure, 40 ml of a 10% solution of hydrogen chloride in methanol was added to the residue, and the mixture was heated to reflux for 20 hours. After cooling, the reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (0.48 g) as a yellow solid.
'H-NMR (CD3OD) 8 3.98 (s, 3H) 4.90 (br.s, 4H) 7.11 (d, J=7.5Hz, 1H) 7.72 (d, J=7.7Hz, 1H) 7.88 (dd, J=7.7, 7.5Hz, 1H) [1096] (174b)
6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2, 4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-1 -yl)pyridine-2-carboxylic acid methyl ester [1097] [Chemical Formula 442]

After adding 149 mg of 6-hydrazinopyridine-2-carboxylic acid methyl ester hydrochloride and 92 u.1 of triethylamine to a solution of 255 mg of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example (3e)) in 5 ml of DMF, the mixture was stirred at 85°C for 24 hours under a nitrogen atmosphere.
The reaction mixture was concentrated, and the residue was dissolved in 10 ml of methanol. After adding 87 u,l of acetic acid and 317 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. Purification was then

performed by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (167 mg) as a white solid.
'H-NMR (CD3OD) 8 2.57 (s, 3H) 3.72 (s, 3H) 3.94 (s, 3H) 4.22 (m, 1H) 4.28 (m, 1H) 4.65 (m, IH) 4.78 (m, 1H) 5.98 (s, 1H) 6.61 (m, 1H) 6.65 (m, IH) 6.80 (d, J=9.0Hz, 2H) 7.77 (d, J=9.0Hz, 2H) 7.98 (dd, J=7.8, 1.0Hz, IH) 8.05 (t, J=7.8Hz, IH) 8.23 (dd, J=7.8, 1.0Hz, IH) [1098] (174c)
6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2, 4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)pyridine-2-carboxylic acid [1099] [Chemical Formula 443]

After dissolving 167 mg of
6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2, 4]oxadiazol-3-yI)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI)pyridine-2-carboxylic acid methyl ester in 6 ml of a methanol:THF = 2:1 mixed solvent, there was added 562 u.1 of a 5N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 15 hours. The mixture was adjusted to acidic with acetic acid and then concentrated under reduced pressure. The residue was dissolved in methanol, and the solution was filtered through celite and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (81 mg) as a light yellow solid.
'H-NMR (CD3OD) 8 2.59 (s, 3H) 3.74 (s, 3H) 4.25 (m, IH) 4.32 (m, IH) 4.67 (m, IH) 4.79 (m, IH) 5.98 (s, IH) 6.68 (s, IH) 6.69 (s, IH) 6.83 (d, J=8.9Hz, 2H) 7.80 (d, J=8.9Hz, 2H) 8.05 (dd, J=7.4, 1.0Hz, IH) 8.07 (t,

J=7.4Hz, 1H) 8.32 (dd, J=7.4, 1.0Hz, 1H)
[1100] (174d)
2-(6-aminopyridin-2-yl)-5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphen
yl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro
-[l,2,4]triazol-3-one
[1101] [Chemical Formula 444]

After adding 41 u.1 of triethylamine and 63 u.1 of diphenylphosphorylazide to a solution of 81 mg of 6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2, 4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)pyridine-2-carboxylic acid in 4 ml of 1,4-dioxane under a nitrogen atmosphere, the mixture was heated for 20 hours at 80°C. After cooling, the reaction mixture was filtered and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (33 mg) as a white solid. 'H-NMR (CD3OD) 5 2.59 (s, 3H) 3.75 (s, 3H) 4.25 (m, 1H) 4.33 (m, 1H) 4.67 (m, 1H) 4.79 (m, 1H) 5.98 (s, 1H) 6.67 (d, J=8.3Hz, 1H) 6.68 (dd, J=5.1, 3.1Hz, 1H) 6.72 (dd, 6.5, 3.1Hz, 1H) 6.83 (d, J=8.9Hz, 2H) 7.30 (d, J=8.3Hz, 1H) 7.81 (d, J=8.9Hz, 2H) 7.87 (t, J=8.3Hz, 1H) [1102] (174e)
4-({[l-(6-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[ 2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]methyl}amino)benzamidin e trifluoroacetate [1103] [Chemical Formula 445]


To a solution of 33 mg of
2-(6-aminopyridin-2-yl)-5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphen
yl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro
-[l,2,4]triazol-3-one in 3 ml of a methanol:water:acetic acid = 1:1:1
mixed solvent there was added 34 mg of iron powder, and the mixture
was stirred at 60°C for 20 hours under a nitrogen atmosphere. After
filtering the reaction mixture, it was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give the title compound (11 mg) as a light brown
solid.
'H-NMR (CD3OD) 5 3.74 (s, 3H) 4.25 (m, 1H) 4.32 (m, 1H) 4.67 (m,
1H) 4.79 (m, 1H) 6.04 (s, 1H) 6.61 (d, J=8.2Hz, 1H) 6.63 (dd, J=5.1,
3.1Hz, 1H) 6.71 (dd, 6.6, 3.1Hz, 1H) 6.88 (d, J=8.9Hz, 2H) 7.24 (d,
J=8.2Hz, 1H) 7.65 (d, J=8.9Hz, 2H) 7.78 (t, J=8.2Hz, 1H)
[1104] (174f) (R) and
(S)-4-({[l-(6-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-
yI]-[2-fluoro-3-(2-fluoroethoxy)-5-methoxypheny]]methyl}amino)benza
midine acetate
[ 1105] [Chemical Formula 446]

11 mg of
4-({[l-(6-aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[ 2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]methyl}amino)benzamidin e trifluoroacetate was optically resolved using a SUMICHIRAL OA-2500

column, and the first eluting enantiomer (3 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 3.71 (s, 3H) 4.23 (m, 1H) 4.31 (m, 1H)
4.66 (m, 1H) 4.78 (m, 1H) 5.93 (s, 1H) 6.38 (d, J=8.0Hz, 1H) 6.63 (dd,
J=6.8, 3.1Hz, 1H) 6.68 (dd, 5.1, 3.1Hz, 1H) 6.85 (d, J=8.9Hz, 2H) 7.21
(d, J=8.0Hz, 1H) 7.48 (t, J=8.0Hz, 1H) 7.61 (d, J=8.9Hz, 2H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 20
mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 10 ml/min)
[1106] Example 175:
5-{3-[(4-carbamimidoylphenvlamino)-(5-fluoro-8-methoxy-2,3-dihydrob enzo[l,41dioxin-6-vnmethyl]-5-oxo-4-lH-pvrazole-4-carboxylic acid ethyl ester acetate [1107] (175a)
5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-0X0-4,5-dihydro-[ 1,2,4] triazol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester [1108] [Chemical Formula 447]

A solution of 62 mg of 3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 106 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carba mic acid methyl ester (Example 4Id) and 88 ul of triethylamine in 5 ml of DMF was heated at 85°C for 15 hours under a nitrogen atmosphere with stirring. After cooling the reaction mixture to room temperature,

the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of methanol, and then 133 mg of sodium cyanotrihydroborate, 49 ul of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (68 mg) as a light green solid. Mass spectrum (ESI)m/z: 615 (M+H)+ [1109] (175b)
5-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob enzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic acid ethyl ester acetate [1110] [Chemical Formula 448]

To a solution of 68 mg of
5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4] triazol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester in 6 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 68 mg of iron powder, and the mixture was stirred at 62.5°C for 40 hours under a nitrogen atmosphere. After cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid). The title

compound (16.0 mg) was obtained as a white solid.
'H-NMR (CD3OD) 5 1.20 (t, J=7.3Hz, 3H) 1.97 (s, 3H) 3.79 (s, 3H) 4.14-4.21 (m, 2H) 4.30 (s, 4H) 5.93 (s, 1H) 6.66 (d, J=6.6Hz, 1H) 6.87 (d, J=8.8Hz, 2H) 7.65 (d, J=8.8Hz, 2H) 8.26 (s, 1H)
[1111] Example 176: (R) and
(SV2-{3-[(4-carbamimidovlphenvlamino)-(6-fluoro-9-methoxv-3.4-dihvd
ro-2H-benzo[b][l,4]dioxepin-7-vnmethvl]-5-oxo-4.5-dihvdro-[1.2,41triaz
ol-1-vUnicotinic acid
[1112] (176a)
[2-(4-cyanophenylimino)-2-(5-fluoro-9-methoxy-3,4-dihydro-2H-benzo[
b][l,4]dioxepin-7-yI)-l-methylsuIfanylethyIidene]carbamic acid methyl
ester
[1113] [Chemical Formula 449]

To a solution of 1.294 g of
6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-carbaldehy de (Example 42b), 680 mg of 4-aminobenzonitrile, 1.3 g of MS3A and 355 mg of Yb(OTf)3 in 20 ml of THF there was added 1.2 ml of trimethylsilyl cyanide, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure.
To a solution of this compound in 15 ml of a methanol:THF = 2:1 mixed solvent there was added 5 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced

pressure to give
2-(4-cyanophenylamino)-2-(6-fluoro-9-methoxy-3,4-dihydrobenzo[b][l,4
]dioxepin-7-yl)thioacetamide.
To a solution of this compound in 20 ml of acetonitrile there was added 1
g of Me30+BF4_, and the mixture was stirred at room temperature for 30
minutes. Saturated aqueous sodium hydrogencarbonate was added to
the reaction mixture, and extraction was performed with ethyl acetate.
The organic layer was washed with saturated brine and then dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure.
After adding 6 g of manganese dioxide to a solution of the residue in 10
ml of ethyl acetate, the mixture was stirred at room temperature for 45
minutes. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure.
To a solution of the residue in 20 ml of toluene there were added 3 ml of
2,4,6-collidine and 1.5 ml of methyl chloroformate, and the mixture was
stirred at 80°C for 30 minutes under a nitrogen atmosphere. After
cooling the reaction mixture, 0.5 N hydrochloric acid was added and
extraction was performed with ethyl acetate. The organic layer was
washed with saturated brine and then dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate-heptane) to give the title
compound (1.263 g, isomeric mixture) as a light yellow solid.
'H-NMR (CDC13) Two main isomers:
5 2.31-2.34 (m, 2H) 2.34 (s, 3H) 3.63 (s, 3H) 3.88 (s, 3H) 4.36 (t,
J=5.6Hz, 2H) 4.45 (t,J=5.6Hz, 2H) 7.06 (d, J=8.4Hz, 2H) 7.10 (d,
J=5.6Hz, 1H) 7.60 (d, J=8.4Hz, 2H)
82.23-2.27 (m, 2H) 2.48 (s, 3H) 3.63 (s, 3H) 3.69 (s, 3H) 4.26 (t,
J=5.6Hz, 2H) 4.32-4.38 (m, 2H) 6.23 (d, J=5.6Hz, 1H) 6.81 (d, J=8.4Hz,
2H) 7.50 (d, J=8.4Hz, 2H)
[1114] (176b)
2-{3-[(4-cyanophenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo

[b][l,4]dioxepin-7-yl)methyI]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}nico
tinic acid
[1115] [Chemical Formula 450]

After adding 84 mg of 2-hydrazinonicotinic acid and 153 ul of
triethylamine to a solution of 229 mg of
[2-(4-cyanophenylimino)-2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[ b][l,4]dioxepin-7-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester in 15 ml of THF, the mixture was heated for 48 hours at 60°C under a nitrogen atmosphere. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in 8 ml of DMF, and then 153 \i\ of triethylamine was added and the mixture was heated for 24 hours at 85°C under a nitrogen atmosphere. After cooling, the mixture was concentrated under reduced pressure.
The residue was then dissolved in 10 ml of methanol. After adding 144 jil of acetic acid and 251 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 24 hours. Next, 50 ml of water was added to the reaction mixture and extraction was performed with 200 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (146 mg) as a light yellow solid.
'H-NMR (CD3OD) 5 2.18-2.25 (m, 2H) 3.77 (s, 3H) 4.13-4.28 (m, 4H) 5.93 (s, 1H) 6.78 (d, J=6.6Hz, 1H) 6.80 (d, J=8.9Hz, 2H) 7.45 (d, J=8.9Hz, 2H) 7.56 (dd, J=7.9, 4.7Hz,lH) 8.49 (dd, J=7.9, 1.8Hz, 1H)

8.66 (dd, J=4.7, 1.8Hz, 1H)
[1116] (176c)
2-(3-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[
4-(N-hydroxycarbamimidoy])phenylamino]methyl}-5-oxo-4,5-dihydro-[l
,2,4]triazol-l-yl)nicotinic acid
[1117] [Chemical Formula 451]

After adding 114 mg of hydroxylammonium chloride and 267 p.1 of
triethylamine to a solution of 146 mg of
2-{3-[(4-cyanophenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo
[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-y]}nico
tinic acid in 10 ml of methanol, the mixture was heated for 28 hours at
60°C. After cooling the reaction mixture, it was purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give the title compound (61 mg)
as a light yellow solid.
'H-NMR (CD3OD) 8 2.18-2.25 (m, 2H) 3.77 (s, 3H) 4.13-4.28 (m, 4H)
5.96 (s, 1H) 6.77 (d, J=6.1Hz, 1H) 6.87 (d, J=9.1Hz, 2H) 7.51 (d,
J=9.1Hz, 2H) 7.59 (dd, J=8.1, 4.3Hz, 1H) 8.41 (dd, J=8.1, 1.5Hz, 1H)
8.68 (dd, J=4.3, 1.5Hz, 1H)
[1118] (176d) (R) and
(S)-2-{3-[(4-carbamimidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihyd
ro-2H-benzo[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triaz
ol-l-yl}nicotinic acid
[1119] [Chemical Formula 452]


To a solution of 61 mg of
2-(3- {(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b] [ 1,4]dioxepin-7-yl)-[
4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l
,2,4]triazol-l-yl)nicotinic acid in 6 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent there was added 60 mg of iron powder, and the
mixture was stirred at 60°C for 30 hours under a nitrogen atmosphere.
Upon cooling, the reaction mixture was filtered through celite and
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give
2-{3-[(4-carbamirnidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-
2H-benzo[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-
1-yl}nicotinic acid.
Mass spectrum (ESI)m/z: 550 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (9.6 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 2.17-2.25 (m, 2H) 3.78 (s, 3H) 4.10-4.30 (m, 4H)
5.96 (s, 1H) 6.79 (d, J=6.2Hz, 1H) 6.86 (d, J=9.0Hz, 2H) 7.54 (dd, J=8.3,
4.3Hz, 1H) 7.65 (d, J=9.0Hz, 2H) 8.30 (dd, J=8.3, 1.3Hz, 1H) 8.66 (dd,
J=4.3, 1.3Hz, 1H)
HPLC retention time: 24 min (Column name: SUMICHIRAL OA-2500,
30 mmtp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1120] Example 177:
5-(3-{(4-carbamimidoylphenvlamino)-[2-fluoro-3-(3-hvdroxvpropoxy)-S -methoxvphenvl]methvU-5-oxo-4.5-dihydro-[1.2.41triazol-l-yl)-lH-pyra

zole-4-carboxvlic acid acetate
[1121] (177a)
(2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl
}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylet
hylidene)carbamic acid methyl ester
[1122] [Chemical Formula 453]

After adding 313 mg of cesium carbonate and 0.257 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 339 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)) in 8 ml of DMF, the mixture was stirred at room temperature for 15 hours. Next, 100 ml of water was added to the reaction mixture and extraction was performed with 300 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (413 mg). 'H-NlvIR (CDC13) Two main isomers:
8 0.01 (s, 6H) 0.87 (s, 9H) 1.95 (quint, J=6.6Hz, 2H) 2.57 (s, 3H) 2.64 (s, 3H) 3.65 (s, 3H) 3.66 (s, 3H) 3.75 (t, J=6.6Hz, 2H) 4.03 (t, J=6.6Hz, 2H) 6.12 (dd, J=4.5, 3.6Hz, 1H) 6.51 (dd, J=6.9, 3.6Hz, 1H) 6.86 (d, J=8.5Hz, 2H) 7.91 (d, J=8.5Hz, 2H)
5 0.06 (s, 6H) 0.92 (s, 9H) 2.04 (quint, J=6.6Hz, 2H) 2.35 (s, 3H) 2.67 (s, 3H) 3.52 (s, 3H) 3.83 (t, J=6.6Hz, 2H) 3.85 (s, 3H) 4.13 (t, J=6.6Hz, 2H) 6.72 (dd, J=7.1, 3.5Hz, 1H) 6.97 (dd, J=4.5, 3.5Hz, 1H) 7.13 (d, J=8.7Hz, 2H) 8.04 (d, J=8.7Hz, 2H) [1123] (177b)

5-[3-({3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphe nyI}-[4-(5-methyI-[l,2,4]oxadiazol-3-yl)phenylamino]methyl)-5-oxo-4,5 -dihydro-[l,2,4]triazol-l-yI]-lH-pyrazole-4-carboxylic acid ethyl ester and
5-(3-{[2-fluoro-3-(3-hydroxypropoxy)-5-methoxyphenyl]-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]tria zol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester [ 1124] [Chemical Formula 454]

A solution of 87 mg of 3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 206 mg of (2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl }-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylet hylidene)carbamic acid methyl ester and 0.160 ml of triethylamine in 10 ml of DMF was stirred at 85°C for 15 hours under a nitrogen atmosphere. The solvent was concentrated under reduced pressure. The residue was dissolved in 7 ml of methanol, and then 205 mg of sodium cyanotrihydroborate, 0.113 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (ethyl acetate-methanol) to give the title compounds (53 mg, 64 mg, respectively).
'H-NMR (CD3OD) 5 0.01 (s, 6H) 0.84 (s, 9H) 1.14 (t, J=7.5Hz, 3H) 1.95 (quint, J=6.5Hz, 2H) 2.55 (s, 3H) 3.60 (s, 3H) 3.71 (t, J=6.5Hz, 2H)

4.04-4.15 (m, 4H) 5.90 (s, 1H) 6.59 (dd, J=7.2, 2.9Hz, 1H) 6.62 (dd, J=5.4, 2.9Hz, 1H) 6.79 (d, J=9.0Hz, 2H) 7.77 (d, J=9.0Hz, 2H) 8.21 (s, 1H)
'H-NMR (CD3OD) 8 1.19 (t, J=7.5Hz, 3H) 1.97 (quint, J=6.5Hz, 2H) 2.55 (s, 3H) 3.70 (s, 3H) 3.71 (t, J=6.5Hz, 2H) 4.06-4.15 (m, 4H) 5.88 (s, 1H) 6.60 (s, 1H) 6.61 (s, 1H) 6.78 (d, J=9.0Hz, 2H) 7.75 (d, J=9.0Hz, 2H) 8.21 (s, 1H) [1125] (177c)
5-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropoxy)-5 -methoxyphenyl]methyl} -5-oxo-4,5-dihydro-[ 1,2,4]triazol-1 -yl)-1 H-pyra zoIe-4-carboxylic acid ethyl ester trifluoroacetate [1126] [Chemical Formula 455]

To a solution of 53 mg of
5-[3-({3-[3-(t-butyldimethylsiIanyloxy)propoxy]-2-fluoro-5-methoxyphe
nyl}-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl)-5-oxo-4,5
-dihydro-[l,2,4]triazol-l-yl]-lH-pyrazole-4-carboxylic acid ethyl ester
and 64 mg of
5-(3-{[2-fluoro-3-(3-hydroxypropoxy)-5-methoxyphenyl]-[4-(5-methyl-[ l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]tria zol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester in 6 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent there was added 150 mg of iron powder, and the mixture was stirred at 62.5°C for 20 hours under a nitrogen atmosphere. After cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid). The title compound (54.9 mg) was obtained as a white solid. 'H-NMR (CD3OD) 5 1.17 (t, J=7.1Hz, 3H) 1.99 (quint, J=6.2Hz, 2H)

3.74 (t, J=6.2Hz, 2H) 3.75 (s, 3H) 4.14 (t, J=6.2Hz, 2H) 4.15-4.20 (m,
2H) 5.88 (s, 1H) 6.61 (dd, J=4.9, 2.9Hz, 1H) 6.67 (dd, J=6.8, 2.9Hz, 1H)
6.87 (d, J=9.0Hz, 2H) 7.64 (d, J=9.0Hz, 2H) 8.25 (s, 1H)
[1127] (177d)
5-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropoxy)-5
-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-lH-pyra
zole-4-carboxylic acid
[1128] [Chemical Formula 456]

After adding 38 u.1 of triethylamine, 0.3 mg of 4-dimethylaminopyridine and 46 mg of di-t-butyl dicarbonate to a solution of 55 mg of 5-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropoxy)-5 -methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-lH-pyra zole-4-carboxylic acid ethyl ester trifluoroacetate in 6 ml of an acetonitrile:DMF = 2:1 mixed solvent, the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure, and then 1 ml of methanol and 1 ml of a IN aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature for 8 hours. After adding 5 ml of a methanolrwatenacetic acid = 1:1:1 mixed solvent to the reaction mixture, it was stirred and heated at 50°C for 15 hours. The mixture was cooled and then directly purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 16 mg of the title compound.
'H-NMR (CD3OD) 8 1.99 (quint, J=6.2Hz, 2H) 3.71 (s, 3H) 3.74 (t,
J=6.2Hz, 2H) 4.12 (t, J=6.2Hz, 2H) 5.93 (s, 1H) 6.61 (dd, J=4.9,2.9Hz,
1H) 6.63 (dd, J=6.7, 2.9Hz, 1H) 6.83 (d, J=9.0Hz, 2H) 7.61 (d, J=9.0Hz,
2H) 8.03 (s, 1H)
[1129] Example 178j (R) and

(S)-2-(3-((4-carbamimidovlphenvlamino)-[2-:fluoro-4-(2-hvdroxvethoxy)
-5-methoxvphenyllmethyl}-5-oxo-4.5-dihydro-[1.2.41triazol-l-vl)benzoi
c acid
[1130] (178a)
4-(t-butyldimethylsilanyloxy)-2-fluoro-5-methoxybenzaldehyde
[1131] [Chemical Formula 457]

The same procedure was carried out as in Example (4a), except that
2-fluoro-4-hydroxy-5-methoxybenzaldehyde [CAS No.79418-77-2] and
t-butylchlorodimethylsilane were used instead of respectively the
3-hydroxy-5-methoxybenzaldehyde and chlorotriisopropylsilane, to give
the title compound as a colorless oil.
'H-NMR (CDC13) 5 0.15 (s, 6H) 0.99 (s, 9H) 3.87 (s, 3H) 6.60 (d,
J=11.6Hz, 1H) 7.26 (d, J=8.4Hz, 1H) 10.17 (s, 1H)
[1132] (178b)
{2-(2-fluoro-4-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester
[1133] [Chemical Formula 458]

The same procedure was carried out as in Examples (4b)-(4c), except that 4-(t-butyldimethylsilanyloxy)-2-fluoro-5-methoxybenzaldehyde was used instead of the 3-methoxy-5-triisopropylsilanyloxybenzaldehyde in Example (4b), to give the title compound as a yellow solid. 1 H-NMR (CDCb) Two main isomers:
5 2.31 (s, 3H) 2.62 (s, 3H> 3.61 (s, 3H) 3.84 (s, 3H) 5.32 (s, 1H) 6.44 (d, J=10.0Hz, 1H) 6.67 (d, J=6.4Hz, 1H) 7.07-7.10 (m, 2H) 7.86-7.89 (m, 2H)

5 2.46 (s, 3H) 2.65 (s, 3H) 3.61 (s, 3H) 3.94 (s, 3H) 5.39 (s, 1H) 6.61 (d,
J=11.6Hz, 1H) 6.81-6.83 (m, 2H) 7.46 (d, J=7.2Hz, 1H) 7.98-8.01 (m,
2H)
[1134] (178c)
(2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-
2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy
lidene)carbamic acid methyl ester
[1135] [Chemical Formula 459]

The same procedure was carried out as in Example (3e), except that
{2-(2-fluoro-4-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester and (2-bromoethoxy)-t-butyldimethylsilane were used instead of
respectively the
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl
ester and l-fluoro-2-iodoethane, to give the title compound as a yellow
solid.
'H-NMR (CDC13) Two main isomers:
5 0.05 (s, 6H) 0.88 (s, 9H) 2.47 (s, 3H) 2.62 (s, 3H) 3.59 (s, 3H) 3.79 (s,
3H) 3.82-3.86 (m, 4H) 6.46 (d, J=10.8Hz, 1H) 6.58 (d, J=8.0Hz, 1H)
6.83 (d, J=8.4Hz, 2H) 7.90 (d, J=8.4Hz, 2H)
5 0.09 (s, 6H) 0.89 (s, 9H) 2.32 (s, 3H) 2.65 (s, 3H) 3.61 (s, 3H) 3.90 (s,
3H) 4.00 (t, J=5.2Hz, 2H) 4.13 (t, J=5.2Hz, 2H) 6.60 (d, J=12.4Hz, 1H)
7.10 (d,J=8.4Hz, 2H) 7.49 (d, J=7.2Hz, 1H) 8.01 (d, J=8.4Hz, 2H)
[1136] (178d) (R) and
(S)-2-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-4-(2-hydroxyethoxy)
-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoi
c acid

[1137] [Chemical Formula 460]

The same procedure was carried out as in Examples (3f)-(3h), except that (2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy lidene)carbamic acid methyl ester and 2-hydrazinobenzoic acid hydrochloride were used instead of respectively the {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (3f) and 2-hydrazinopyrimidine in Example (3f), to give the title compound as a white solid.
'H-NMR (CD3OD) 8 3.78-3.84 (m, 2H) 3.82 (s, 3H) 3.96-4.12 (m, 2H) 5.89 (s, 1H) 6.80-6.88 (m, 3H) 7.13 (d, J=7.2Hz, 1H) 7.34-7.46 (m, 3H) 7.54-7.62 (m, 2H) 7.70 (d, J=7.2Hz, 1H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mm

[1138] Example 179] (R) and
(SM-f3-[f4-carbamimidovlphenylamino)-(8-ethvl-4H-benzo[lJ1dioxin-
6-vl)methvll-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-yl>thiazole-5-carboxvlic
acid
[1139] (179a)
4-(3-{(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole
-5-carboxylic acid methyl ester
[1140] [Chemical Formula 461 ]


After adding 71 mg of 4-hydrazinothiazole-5-carboxylic acid methyl
ester (Example (162c)) and 300 ul of triethylamine to a solution of 198
mg of
[2-(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3
-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester
(Example (27b)) in 6 ml of THF, the mixture was stirred overnight at
60°C under a nitrogen atmosphere. The reaction mixture was then
concentrated. The residue was dissolved in 6 ml of DMF, and then 0.3
ml of triethylamine was added and the mixture was stirred at 80°C for 6
hours.
The reaction mixture was concentrated, and the residue was dissolved in
2.2 ml of a THF:methanol:acetic acid = 5:5:1 mixed solvent. After
adding 0.2 g of sodium cyanotrihydroborate to the solution, the mixture
was stirred at room temperature for 4 hours. Ethyl acetate was added to
the reaction mixture. After washing the organic layer with water and
saturated brine, it was dried over anhydrous magnesium sulfate. The
desiccating agent was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by NAM silica gel column
chromatography (methanol-ethyl acetate) to give the title compound (179
mg) as a light yellow solid.
Mass spectrum (ESI)m/z: 576 (M+H)+
[1141] (179b)
4-{3-[(4-carbamimidoylphenylamino)-(8-ethyl-4H-benzo[l,3]dioxin-6-yl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI}thiazoie-5-carboxyIic
acid trifluoroacetate
[1142] [Chemical Formula 462]


After dissolving 179 mg of
4-(3-{(8-ethyl-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-
3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole
-5-carboxyIic acid methyl ester in 2 ml of methanol, there was added 0.5
ml of a 5N aqueous sodium hydroxide solution and the mixture was
stirred at room temperature for 1 hour. After adding 0.5 ml of 5N
hydrochloric acid to the reaction mixture, extraction was performed with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate. The desiccating agent was filtered off and the filtrate was
concentrated under reduced pressure.
The residue was dissolved in 1 ml of methanol, 1.3 ml of acetic acid and
1 ml of water, and then 200 mg of iron powder was added and the
mixture was stirred at 60°C for 20 hours. After adding 0.4 ml of
trifluoroacetic acid to the reaction mixture, it was filtered and then
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give 143 mg of the title
compound as a white solid.
Mass spectrum (ESI)m/z: 522 (M+H)+
[1143] (179c) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(8-ethyl-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid
[1144] [Chemical Formula 463]


A SUMICHIRAL OA-2500 column was used for optical resolution of 143
mg of
4-{3-[(4-carbamimidoylphenylamino)-(8-ethyl-4H-benzo[l,3]dioxin-6-yl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid trifluoroacetate, and the first eluting enantiomer (30.36 mg) of the
title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.18 (t, J=7.2Hz, 3H) 2.61 (q, J=7.2Hz, 2H)
4.85-4.89 (m, 2H) 5.25 (s, 2H) 5.53 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.03
(s, 1H) 7.21 (s, 1H) 7.61 (d, J=8.8Hz, 2H) 8.88 (s, 1H)
HPLC retention time: 17 min (Column name: SUMICHIRAL OA-2500,
30 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1145] Example \S0l ffi) and
(SV4-l3-[f4-carbamimidovlphenylamino)-(9-methoxv-3.4-dihvdro-2H-be nzorb][1.4]dioxepin-7-vnmethvl1-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vl}t hiazole-5-carboxvlic acid [1146] (180a)
4-(3-{(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2, 4]triazol-l-yl)thiazole-5-carboxylic acid methyl ester [1147] [Chemical Formula 464]


After adding 55 mg of 4-hydrazinothiazole-5-carboxylic acid methyl
ester (Example (162c)) and 300 jil of triethylamine to a solution of 160
mg of
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb amic acid methyl ester (Example 30c) in 5 ml of THF, the mixture was stirred overnight at 60°C under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 5 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80°C for 6 hours.
The reaction mixture was concentrated, and the residue was dissolved in 2.2 ml of a THF:methanol:acetic acid = 5:5:1 mixed solvent. After adding 0.2 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (135 mg) as a light yellow solid. Mass spectrum (ESI)m/z: 592 (M+H)+ [1148] (180b)
4-{3-[(4-carbamimidoylphenylamino)-(9-methoxy-3,4-dihydro-2H-benzo [b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thia zole-5-carboxylic acid trifluoroacetate [1149] [Chemical Formula 465]


After dissolving 135 mg of
4-(3-{(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,
4]triazol-l-yl)thiazole-5-carboxylic acid methyl ester in 2 ml of
methanol, 0.5 ml of a 5N aqueous sodium hydroxide solution was added
and the mixture was stirred at room temperature for 1 hour. After
adding 0.5 ml of 5N hydrochloric acid to the reaction mixture, extraction
was performed with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure.
The residue was dissolved in 1 ml of methanol, 1.3 ml of acetic acid and
1 ml of water, and then 150 mg of iron powder was added and the
mixture was stirred at 60°C for 20 hours. After adding 0.4 ml of
trifluoroacetic acid to the reaction mixture, it was filtered and then
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give 109 mg of the title
compound as a white solid.
Mass spectrum (ESI)m/z: 538 (M+H)+
[1150] (180c) (R) and
(S)-4-{3-[(4-carbamimidoylphenylamino)-(9-methoxy-3,4-dihydro-2H-be
nzo[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}t
hiazole-5-carboxylic acid
[1151] [Chemical Formula 466]


A SUMICHIRAL OA-2500 column was used for optical resolution of 109
mg of
4-{3-[(4-carbamimidoylphenylamino)-(9-methoxy-3,4-dihydro-2H-benzo [b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thia zole-5-carboxylic acid trifluoroacetate, and the first eluting enantiomer (30.53 mg) of the title compound was obtained as a white solid. 'H-NMR (CD3OD) 8 2.11-2.20 (m, 2H) 3.83 (s, 3H) 4.10-4.19 (m, 4H) 5.52 (s, 1H) 6.80 (d, J=2.0Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 6.89 (d, J=2.0Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.88 (s, 1H)
HPLC retention time: 22 min (Column name: SUMICHIRAL OA-2500, 30 mmcp * 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1152] Example 181:
4-({f2-fluoro-3-(2-hydroxvethoxv)-5-methoxyphenvl]-(5-oxo-1-pyrimidi
n-2-yl-4,5-dihydro-lH-[1.2.4]triazoI-3-yl)methyl}amino)benzamidine
acetate
[1153] (181a)
(2- {3 - [2-(t-butyldimethy lsilanyloxy )ethoxy] -2-fluoro-5 -methoxypheny 1} -
2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid
methyl ester
[1154] [Chemical Formula 467]


After adding 1.8 g of potassium carbonate and 3 g of
(2-bromoethoxy)-t-butyldimethyIsilane to a solution of 3.45 g of
[2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-l-me
thylsulfanylethylidene]carbamic acid methyl ester (Example (163b)) in
10 ml of DMF, the mixture was stirred at 50°C for 5 hours. Water was
added to the reaction mixture and extraction was performed with ethyl
acetate. The organic layer was washed with water and dried over
anhydrous magnesium sulfate. The desiccating agent was filtered off
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (heptane-ethyl acetate)
to give the title compound (3.73 g, isomeric mixture) as a light yellow
solid.
'H-NMR (CDC13) Two main isomers:
5 0.05 (s, 6H) 0.88 (s, 9H) 2.47 (s, 3H) 3.64 (s, 3H) 3.67 (s, 3H) 3.92 (t,
J=4.8Hz, 2H) 3.98 (t, J=4.8Hz, 2H) 6.13-6.17 (m, 1H) 6.53 (dd, J=2.8,
6.8Hz, 1H) 6.81 (d, J=8.4Hz, 2H) 7.48 (d, J=8.4Hz, 2H)
8 0.10 (s, 6H) 0.90 (s, 9H) 2.33 (s, 3H) 3.60 (s, 3H) 3.81 (s, 3H) 3.98 (t,
J=4.8Hz, 2H) 4.08 (t, J=4.8Hz, 2H) 6.74 (dd, J=2.8, 6.8Hz, 1H)
6.90-6.94 (m, 1H) 7.08 (d, J=8.4Hz, 2H) 7.60 (d, J=8.4Hz, 2H)
Mass spectrum (ESI)m/z: 560 (M+H)+
[1155] (181b)
4-[({3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}
-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)ami
no]benzonitrile
[1156] [Chemical Formula 468]

After adding 600 mg of 2-hydrazinopyrimidine and 1.5 ml of
triethylamine to a solution of 3.2 g of

(2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-
2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid
methyl ester in 30 ml of THF, the mixture was stirred overnight at 60°C under a nitrogen atmosphere. Next, 30 ml of methanol and 4.5 ml of acetic acid were added to the reaction mixture. After then adding 3 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (3.4 g, crude product) as a light yellow solid.
'H-NMR (CD3OD) 8 0.08 (s, 6H) 0.87 (s, 9H) 3.65 (s, 3H) 3.94-4.01 (m, 2H) 4.07-4.12 (m, 2H) 5.95 (s, 1H) 6.61 (dd, J=2.8, 4.8Hz, 1H) 6.67 (dd, J=2.8, 6.8Hz, 1H) 6.80 (d, J=9.2Hz, 2H) 7.36 (t, J=4.8Hz, 1H) 7.45 (d, J=9.2Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 592 (M+H)+ [1157] (181c)
4-( {[2-fluoro-3 -(2-hydroxyethoxy)-5 -methoxyphenyl] -(5 -oxo-1 -pyrimidi n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzonitrile [1158] [Chemical Formula 469]

After dissolving 3.4 g of
4-[({3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl} -(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl)ami no]benzonitrile in 100 ml of acetic acid, 5 ml of water was added and the mixture was stirred overnight at 50°C. The reaction mixture was concentrated, and the residue was purified by NAM silica gel column

chromatography (methanol-ethyl acetate) to give the title compound
(2.25 g) as a light yellow solid.
'H-NMR (CD3OD) 8 3.73 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.11 (t, J=4.8Hz,
2H) 5.95 (s, 1H) 6.61 (dd, J=2.8, 4.8Hz, 1H) 6.68 (dd, J=2.8, 6.8Hz, 1H)
6.80 (d, J=8.8Hz, 2H) 7.36 (t, J=4.8Hz, 1H) 7.45 (d, J=8.8Hz, 2H) 8.78
(d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 478 (M+H)+
[1159] (181d)
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzamidine
acetate
[1160] [Chemical Formula 470]

To a solution of 2.25 g of
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)benzonitrile in
30 ml of pyridine there were added 1.5 ml of triethylamine and 30 ml of
a 20% aqueous solution of ammonium sulfide, and the mixture was
stirred overnight at 60°C under a nitrogen atmosphere. The reaction
mixture was concentrated, acetic acid was added to the residue, and the
mixture was again concentrated.
The residue was washed with an ethyl acetate-methanol mixed solvent to
give
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi
n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl}amino)thiobenzamide
(2.00 g) as a light yellow solid.
After suspending 2 g of this compound in 25 ml of acetonitrile, 652 mg
of Me30+BF4" was added and the mixture was stirred at room temperature

for 30 minutes. Next, 315 mg of Me30+BF4_ was further added and stirring was continued for 30 minutes. Next, 20 ml of isopropanol and 0.83 ml of 1,1,3,3-tetramethyldisilazane were added to the reaction mixture, which was then stirred overnight at 60°C. The reaction mixture was concentrated, and the residue was purified by reverse-phase silica gel chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (1.128 g).
'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.71 (s, 3H) 3.82-3.94 (m, 2H) 4.02-4.16 (m, 2H) 5.95 (s, 1H) 6.57-6.70 (m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.30 (t, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=5.2Hz, 2H) Mass spectrum (ESI)m/z: 495 (M+H)+
[1161] Example 182:
4-(3-{(4-carbamimidovlphenvlamino)-[2-fluoro-3-(2-hvdroxvethoxv)-5-methoxvphenyllmethyn -5-oxo-4.5-dihydro|"1.2.41triazol-l-vl)thiazole-5-carboxvlic acid trifluoroacetate [1162] (182a)
{2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyph enyl]-l-methylsulfanylethylidene}carbamic acid methyl ester [1163] [Chemical Formula 471]
After adding 0.09 ml of acetic acid and 1.3 ml of TBAF (1.0 M, THF
solution) to a solution of 616 mg of
(2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-
2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid
methyl ester (Example (181a)) in 5 ml of THF, the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica

gel column chromatography (heptane-ethyl acetate) to give the title
compound (394 mg, isomeric mixture) as a light yellow solid.
'H-NMR (CDCb) Two main isomers:
8 2.47 (s, 3H) 3.64 (s, 3H) 3.67 (s, 3H) 3.90-3.96 (m, 2H) 4.13 (t,
J=4.4Hz, 2H) 6.16 (t, J=3.2Hz, 1H) 6.54 (dd, J=3.2, 6.4Hz, 1H) 6.82 (d,
J=8.4Hz, 2H) 7.51 (d, J=8.4Hz, 2H)
8 2.34 (s, 3H) 3.61 (s, 3H) 3.82 (s, 3H) 3.96-4.01 (m, 2H) 4.04 (t,
J=4.4Hz, 2H) 6.73 (dd, J=3.2, 6.4Hz, 1H) 6.97 (t, J=3.2Hz, IH) 7.09 (d,
J=8.4Hz, 2H) 7.62 (d, J=8.4Hz, 2H)
[1164] (182b)
4-(3-{(4-cyanophenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyp
henyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-5-carboxyli
c acid methyl ester
[1165] [Chemical Formula 472]

After adding 153 mg of 4-hydrazinothiazole-5-carboxyIic acid methyl
ester (Example (162c)) and 600 u.1 of triethylamine to a solution of 394
mg of
{2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyph enyl]-l-methylsulfanylethylidene}carbamic acid methyl ester in 6 ml of THF, the mixture was stirred at 60°C for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was dissolved in 5 ml of DMF, 600 u,l of triethylamine was added and the mixture was stirred overnight at 85°C.
The reaction mixture was concentrated, and the residue was dissolved in 10 ml of a methanohTHF = 1:1 mixed solvent. After adding 500 u,l of acetic acid and 700 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 19 hours. Water was

added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (375 mg). 'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.82 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.10 (t, J=4.8Hz, 2H) 5.95 (s, 1H) 6.60-6.62 (m, 1H) 6.66-6.70 (m, 1H) 6.80 (d, J=8.8Hz, 2H) 7.45 (d, J=8.8Hz, 2H) 9.15 (s, 1H) [1166] (182c)
4-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl)thiazole-5-carboxylic acid trifluoroacetate [1167] [Chemical Formula 473]

After dissolving 375 mg of
4-(3-{(4-cyanophenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyp henyl]methyl}-5-oxo~4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-5-carboxyli c acid methyl ester in 10 ml of THF, 694 u.1 of a 5N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 5 hours. After further adding 800 ul of 5N hydrochloric acid and water to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the residue in 8 ml of ethanol there were added 241 mg of hydroxylammonium chloride and 677 ul °f triethylamine, arid the mixture was stirred at 70°C for 18 hours under a nitrogen atmosphere.

The reaction mixture was concentrated, and the residue was dissolved in 10 ml of acetic acid. After adding 0.5 ml of acetic anhydride and 100 mg of 10% palladium-carbon (hydrous) to the solution, the mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (260 mg). Mass spectrum (ESI)m/z: 544 (M+H)+
'H-NMR (CD3OD) 8 3.74 (s, 3H) 3.88 (br.s, 2H) 4.10 (br.s, 2H) 6.00 (s, 1H) 6.59-6.61 (br.s, 1H) 6.68 (br.d, J=6.8Hz, 1H) 6.86 (d, J=8.4Hz, 2H) 7.63 (d, J=8.4Hz, 2H) 8.28 (br.s, 1H) 8.80 (br.s, 1H) 9.13 (s, 1H)
[1168] Example 183: 2-(3-f(R) and
(S)-(4-carbamimidovl-3-hvdroxvphenvlaminoW3.4-dimethoxvphenvDme thvl"|-5-oxo-4.5-dihvdro-n.2.41triazol-l-yl}benzoic acid [1169] (183a)
2-{3-[(3-benzyloxy-4-cyanophenylamino)-(3,4-dimethoxyphenyl)methyl] -5-0X0-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid [1170] [Chemical Formula 474]

The same procedure was carried out as in Examples (37a)-(37b), except that 2-benzyloxy-4-aminobenzonitrile [CAS No.284044-40-2] was used instead of the 2-fluoro-4-aminobenzonitrile in Example (37a), to give the title compound.
'H-NMR (d6-DMSO) 8 3.76 (s, 3H) 3.77 (s, 3H) 5.11 (d, J=3.6Hz, 2H) 5.63 (d, J=6.4Hz, 1H) 6.43 (dd, J=8.4, 1.6Hz, 1H) 6.59 (d, J=1.6Hz, 1H) 6.97 (d, J=8.4Hz, 1H) 7.05 (dd, J=8.4, 2.0Hz, 1H) 7.16 (d, J=2.0Hz, 1H) 7.30-7.47 (m, 9H) 7.62 (td, J=7.6, 1.6Hz, 1H) 7.78 (dd, J=8.4, 2.0Hz,

1H)
[1171] (183b) 2-{3-[(R) and
(S)-(4-carbamimidoyl-3-hydroxyphenylamino)-(3,4-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid
[1172] [Chemical Formula 475]

After adding 72 mg of hydroxylammonium chloride and 203 p.1 of
triethylamine to a solution of 120 mg of
2-{3-[(3-benzyloxy-4-cyanophenylamino)-(3,4-dimethoxyphenyl)rnethyl]
-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}benzoic acid in 3 ml of ethanol,
the mixture was stirred at 70°C for 36 hours under a nitrogen
atmosphere. The reaction mixture was then concentrated.
The residue was dissolved in 4 ml of acetic acid. After adding 0.4 ml of
acetic anhydride and 25 mg of 10% palladium-carbon (hydrous) to this
solution, the mixture was stirred at room temperature for 9 hours under a
hydrogen atmosphere. Next, 25 mg of 10% palladium-carbon (hydrous)
was added to the reaction mixture, and the mixture was stirred at room
temperature for 19 hours under a hydrogen atmosphere. The reaction
mixture was filtered through celite, and the filtrate was concentrated
under reduced pressure. The residue was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1%
trifluoroacetic acid) to give 30 mg of
2-{3-[(4-carbamimidoyl-3-hydroxyphenylamino)-(3,4-dimethoxyphenyl)
methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl} benzoic acid
trifluoroacetate as a light yellow solid. Mass spectrum (ESI)m/z: 505 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (1.59 mg) of the title compound

was obtained as a white solid.
'H-NMR (CD3OD) 8 3.84 (s, 3H) 3.88 (s, 3H) 5.39 (s, 1H) 6.44 (dd, J=9.2, 2.0Hz, 1H) 6.75 (br.s, 1H) 6.99 (d, J=8.4Hz, 1H) 7.05 (dd, J=8.4, 2.4Hz, 1H) 7.22 (d, J=2.4Hz, 1H) 7.39-7.47 (m, 4H) 7.68 (m, 1H) HPLC retention time: 23 min (Column name: SUMICHIRAL OA-2500, 30 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1173] Example L84j CE) and
(S')-4-('((2-fluoro-4.5-dimethoxvphenvn-n-(3-fluoropvridin-2-vn-5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-3-yl]methyUamino')benzamidine acetate [ 1174] [Chemical Formula 476]

76 mg of
4-({(2-fluoro-4,5-dimethoxyphenyl)-[l-(3-fluoropyridin-2-yl)-5-oxo-4,5-
dmydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine acetate
(Example 125) was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (33.78 mg) of the title
compound was obtained as a white solid.
*H-NMR (CD3OD) 5 1.91 (s, 3H) 3.69 (s, 3H) 3.80 (s, 3H) 5.94 (s, 1H)
6.81 (d, J=11.2Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.08 (d, J=7.2Hz, 1H) 7.51
(Sept, J=4.0Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 7.80 (t, J=8.4Hz, 1H) 8.35 (d,
J=4.8Hz, 1H)
HPLC retention time: 12 min
[1175] Example l_85j 4-(3-f(R) and
fS)-(4-Carbamimidovlphenvlamino)-C5-ethoxv-6-methoxvpvridin-3-vl)m ethvn-5-oxo-4.5-dihvdro-ri.2.4]triazol-l-vUthiazole-5-carboxvlic acid (185a) 4-Amino-2-methanesulfonylthiazole-5-carboxylic acid ethyl ester


After adding 41.8 g of 4-amino-2-methylsulfanylthiazole-5-carboxylic acid ethyl ester [CAS No. 39736-29-3] to 3 liters of a water:methanol = 1:1 mixed solvent at room temperature, 352 g of Oxone™ was added thereto in small portions over a period of 15 minutes with stirring. The mixture was stirred at room temperature for 16 hours and then poured into a mixture of 8 liters of ethyl acetate and 5 liters of water. The organic layer was washed with 5 liters of water and 3 liters of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (34.5 g) as a light yellow solid.
'H-NMR (CDC13) 5 1.36 (t, J=7.5Hz,3H) 3.29 (s, 3H) 4.34 (q,J=7.5Hz, 2H) 6.00 (br.s, 2H) [1177] (185b) 4-Aminothiazole-5-carboxylic acid ethyl ester

To 1 liter of a methanol:THF =1:1 mixed solvent solution containing 34.5 g of 4-amino-2-methanesulfonylthiazole-5-carboxyIic acid ethyl ester, 10.4 g of sodium borohydride was added in small portions over a period of 20 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then was poured into 8 liters of ethyl acetate and 4 liters of water. The organic layer was washed with 3 liters of water and 3 liters of saturated brine, and the aqueous layer was extracted with ethyl acetate again. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (19.3 g)

as a light yellow solid.
'H-NMR (CDCI3) 8 1.37 (t, J=7.5Hz, 3H) 4.30 (t, J=7.5Hz, 2H) 5.87
(br.s, 2H) 8.54 (s, 1H)
[1179] (185c) 4-Hydrazinothiazole-5-carboxylic acid ethyl ester
[1180] [Chemical Formula 479]

To 100 ml of a concentrated hydrochloric acid solution containing 19.3 g of 4-aminothiazole-5-carboxyIic acid ethyl ester, 12 ml of an aqueous solution of 8.5 g of sodium nitrite was added dropwise at 0 to 5°C. This mixture was stirred at 0°C for 30 minutes, and then 120 ml of a concentrated hydrochloric acid solution containing 84.9 g of stannous chloride was added dropwise thereto at 0 to 10°C. The mixture was further stirred at the same temperature for 2 hours and then stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was carefully added to 2 liters of an ethyl acetate suspension containing 500 g of potassium carbonate and 100 g of celite with stirring. Further, the filtered substance was added to this ethyl acetate suspension, and then the suspension was made basic with 150 ml of a 5 N sodium hydroxide aqueous solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A: 1.5 liters) was collected. The remaining suspension was filtered through celite, and the celite was washed with 1 liter of ethyl acetate and 500 ml of water. The filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (1 liter) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layers, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl
acetate-methanol) to give the title compound (11.9 g) as a light yellow
solid.
'H-NMR (CDCI3) 5 1.35 (t, J=7.5Hz, 3H) 4.14 (br.s, 2H) 4.30 (q,
J=7.5Hz, 2H) 7.55 (br.s, 1H) 8.60 (s, 1H)
[1181] (185d)
4-(3-{(5-ethoxy-6-methoxypyridin-3-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3
-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-
5-carboxylic acid ethyl ester
[1182] [Chemical Formula 480]

To 4 ml of a DMF solution containing 117 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example 160a), 52 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester and 0.038 ml of triethylamine were added. The mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 10 ml of methanol and 0.05 ml of acetic acid, and then 125 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (65 mg).

'H-NMR (CDCb) 8 1.22 (t, J=7.3Hz, 3H) 1.40 (t, J=6.8Hz, 3H) 2.59 (s, 3H) 3.94 (s, 3H) 4.08 (q, J=7.3Hz, 2H) 4.25 (q, J=6.8Hz, 2H) 5.69 (s, 1H) 6.85 (d, J=9.2Hz, 2H) 7.38 (s, 1H) 7.80 (d, J=9.2Hz, 2H) 7.84 (s, lH)9.16(s, 1H)
[1183] (185e) 4-{3-[(R) and
(S)-(4-Carbamimidoylphenylamino)-(5-ethoxy-6-methoxypyridin-3-yl)m ethyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid [ 1184] [Chemical Formula 481]

To 2 ml of a methanol solution containing 64 mg of
4-(3-{(5-ethoxy-6-methoxypyridin-3-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3
-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-
5-carboxylic acid ethyl ester, 500 u.1 of a 5 N sodium hydroxide aqueous
solution was added. The mixture was stirred at room temperature for 4
hours, and 6 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent
and 62 mg of iron powder were added thereto. The mixture was stirred
at 60°C for 15 hours under a nitrogen atmosphere. The reaction mixture
was filtered and then was purified by reverse-phase high performance
liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to
give
4-{3-[(4-carbamimidoylphenylamino)-(5-ethoxy-6-methoxypyridin-3-yl)
methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
trifluoroacetate.
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (10.3 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 1.39 (t, J=7.2Hz, 3H) 3.94 (s, 3H) 4.09 (q, J=7.2Hz,
2H) 5.78 (s, 1H) 6.88 (d, J=8.9Hz, 2H) 7.36 (d, J=1.2Hz, 1H) 7.64 (d,
J=8.9Hz, 2H) 7.83 (d, J=1.2Hz, 1H) 8.90 (s, 1H)
HPLC retention time: 27 min (Column name: SUMICHIRAL OA-2500, 30 mm(() x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1185] Example JL86: 4-flYR) and
fS)-ri-r3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41tria2ol-3-vn-(5.6-dimethoxvpvridin-3-vl)methvl]amino)benzamidine acetate (186a)
5-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen ylamino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one [1186] [Chemical Formula 482]

The same procedure was carried out as in Example (34a), except that
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (169a)) was used instead of the
[2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth
yl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carba
mic acid methyl ester, to give the title compound.
!H-NMR (CD3OD) 8 2.58 (s, 3H) 3.97 (s, 3H) 4.05 (s, 3H) 5.73 (s, 1H)
6.85 (d, J=8.9Hz, 2H) 7.39 (d, J=1.5Hz, 1H) 7.65 (dd, J=7.5, 3.4Hz, 1H)
7.80 (d, J=8.9Hz, 2H) 7.85 (d, J=1.5Hz, 1H) 8.48 (dd, J=7.5, 0.8Hz, 1H)
8.77 (dd, J=3.4, 0.8Hz, 1H)
[1187] (186b) 4-{[(R) and
(S)-[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-
(5,6-dimethoxypyridin-3-yl)methyl]amino}benzamidine acetate
[1188] [Chemical Formula 483]


The same procedure was carried out as in Example (34a), except that
5-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyI-[l,2,4]triazol-3-yl)phenyla
mino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one
was used instead of the
5-{(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[4-(5-methyl
-[l,2,4]oxadiazol-3-yl)phenylamino]methyI]-2-(3-nitropyridin-2-yl)-2,4-
dihydro-[l,2,4]triazol-3-one, to give
4-{[[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-(5,6-dimethoxypyridin-3-yl)methyl]amino}benzamidine trifluoroacetate. This compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (16.0 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.84 (s, 3H) 3.93 (s, 3H) 5.67 (s, 1H) 6.88 (d, J=8.9Hz, 2H) 7.21 (dd, J=7.9,4.5Hz, 1H) 7.33 (dd, J=7.9, 1.3Hz, 1H) 7.40 (d, J=1.5Hz, 1H) 7.62 (d, J=8.9Hz, 2H) 7.83 (dd, J=4.5, 1.3Hz, 1H) 7.84 (d, J= 1.5Hz, 1H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30 mm(j) x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1189] Example 187: 5-(3-mi^ or
(S)-(4-Carbamimidovlphenvlamino)-(2-fluoro-4.5-dimethoxvphenvl)met
hvll-5-oxo-4.5-dihydro-[1.2.4]triazol-l-vU-3H-imidazole-4-carboxylic
acid
(187a)
3-Benzyl-5-(N'-t-butoxycarbonylhydrazino)-3H-imidazole-4-carboxylic
acid ethyl ester


An aqueous solution (2 ml) of sodium nitrite (869 mg) was added dropwise to 10 ml of a 35% hydrochloric acid solution containing 2.94 g of 5-amino-3-benzyl-3H-imidazole-4-carboxylic acid ethyl ester [CAS No. 169616-29-9] at 0 to 5°C. This mixture solution was stirred at 0°C for 30 minutes, and then 10 ml of a concentrated hydrochloric acid solution containing 9.1 g of stannous chloride was added dropwise thereto at 0 to 10°C. The mixture was further stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with a small amount of water. To this solid, 100 ml of water and 100 ml of dichloromethane were added. The resulting mixture was made basic with potassium carbonate, and then 3.9 g of di-t-butyl dicarbonate was added thereto. The mixture was stirred at room temperature for 48 hours, and 400 ml of ethyl acetate and 200 ml of water were added. The layers were separated and the aqueous layer was extracted with 200 ml of ethyl acetate twice. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (3.71 g) as a white solid.
'H-NMR (CDC13) 5 1.33 (t, J=7.6Hz, 3H) 1.49 (s, 9H) 4.28 (q, J=7.6Hz, 2H) 5.37 (s, 2H) 6.59 (br.s, 1H) 7.15 (m, 2H) 7.27-7.35 (m, 3H) [1191] (187b) 3-Benzyl-5-hydrazino-3H-imidazole-4-carboxylic acid ethyl ester [1192] [Chemical Formula 485]


To 50 ml of a dichloromethane solution containing 3.7 g of
3-benzyl-5-(N'-t-butoxycarbonylhydrazino)-3H-imidazole-4-carboxylic
acid ethyl ester, 20 ml of trifluoroacetic acid was added. The resulting
mixture was stirred at room temperature for 4 hours, and 100 ml of
toluene was added thereto. The mixture was concentrated under
reduced pressure. The residue was dissolved in 400 ml of ethyl acetate,
and the solution was washed with 200 ml of a 2 N sodium hydroxide
solution. The aqueous layer was extracted with 200 ml of ethyl acetate,
and the organic layers were combined and dried over anhydrous
magnesium sulfate. The desiccating agent was removed by filtration,
and the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (methanol-ethyl
acetate) to give the title compound (1.65 g) as a light yellow solid.
'H-NMR (CDC13) 8 1.34 (t, J=7.2Hz, 3H) 4.22 (q, J=7.2Hz, 2H) 5.39 (s,
2H) 6.50 (br.s, 1H) 7.15 (d, J=7.7Hz, 2H) 7.28-7.36 (m, 3H)
[1193] (187c) 3-Benzyl-5-{3-[(R) and
(S)-(4-cyanophenylamino)-(2-fluoro-4,5-dimethoxyphenyl)methyI]-5-oxo -4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic acid ethyl ester

The same procedure was carried out as in Example (2a) to (2e), except

that 2-fluoro-4,5-dimethoxybenzaldehyde was used instead of the
2-fluoro-3,5-dimethoxybenzaldehyde in Example (2a), to give
[2-(4-Cyanophenylimino)-2-(2-fluoro-4,5-dimethoxyphenyl)-l-methylsul
fanylethylidene]carbamic acid methyl ester.
To 8 ml of a DMF solution containing 415 mg of this compound, 286 mg
of 3-benzyl-5-hydrazino-3H-imidazole-4-carboxylic acid ethyl ester and
0.153 ml of triethylamine were added. The resulting mixture was
stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction
mixture was concentrated. The residue was dissolved in 15 ml of
methanol and 0.23 ml of acetic acid, and then 628 mg of sodium
cyanotrihydroborate was added thereto. The mixture was stirred at
room temperature for 15 hours, and then 100 ml of ethyl acetate and 50
ml of water were added thereto. The organic layer was washed with 20
ml of water and then with 20 ml of saturated brine and was dried over
anhydrous magnesium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
3-benzyl-5-{3-[(4-cyanophenylamino)-(2-fluoro-4,5-dimethoxyphenyl)m
ethyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic
acid ethyl ester (153 mg).
This compound was optically resolved using a CHIRALPAK AD-H
column, and the first eluting enantiomer (46 mg) of the title compound
was obtained as a light yellow solid.
'H-NMR (CD3OD) 8 1.01 (t, J=7.6Hz, 3H) 3.76 (s, 3H) 3.83 (s, 3H) 4.10
(m, 2H) 5.59 (s, 2H) 5.87 (s, 1H) 6.79 (d, J=8.8Hz, 2H) 6.85 (d,
J= 10.2Hz, 1H) 7.06 (d, J=7.4Hz, 1H) 7.22 (br.d, J=8.8Hz, 2H) 7.26-7.34
(m, 3H) 7.44 (d, J=8.8Hz, 2H) 8.01 (s, 1H)
HPLC retention time: 23 min (Column name: CHIRALPAK AD-H, 20
mm x 25 cm, Manufacturer: Daicel Chemical Industries, Ltd., Mobile
phase: ethyl acetate/heptane = 1/1, Elution rate: 10 ml/min)
[1195] (187d) 3-Benzyl-5-(3-{(R) or
(S)-(2-fluoro-4,5-dimethoxyphenyl)-[(4-(N-hydroxycarbamimidoyl)phen

ylamino]-methyI}-5-oxo-4,5-dihydro-[l,2,4]triazoI-l-yl)-3H-imidazole-4 -carboxylic acid

To 3 ml of a methanol solution containing 45 mg of 3-benzyl-5-{(R) or
(S)-3-[(4-cyanophenylamino)-(2-fluoro-4,5-dimethoxyphenyl)methyl]-5-
oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic acid
ethyl ester (Example (187c)), 0.4 ml of a 5 N sodium hydroxide solution
was added. The resulting mixture was stirred at room temperature for 5
hours, and then 0.4 ml of 5 N hydrochloric acid was added thereto. The
mixture was concentrated under reduced pressure.
The residue was dissolved in 3 ml of methanol, and 52 mg of
hydroxylammonium chloride and 0.126 ml of triethylamine were added
thereto. The mixture was stirred at 65°C for 16 hours under a nitrogen
atmosphere. After the addition of the same amounts of the reagents, the
mixture was further stirred at 65°C for 24 hours. After cooling, the
reaction mixture was purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the
title compound (34 mg) as a white solid.
'H-NMR (CD3OD) 8 3.76 (s, 3H) 3.81 (s, 3H) 5.65 (d, J=14.9Hz, 1H)
5.70 (d, J=14.9Hz, 1H) 5.84 (s, 1H) 6.79 (d, J=9.1Hz, 2H) 6.82 (d,
J=11.2Hz, 1H) 7.05 (d, J=7.1Hz, 1H) 7.23-7.31 (m, 5H) 7.45 (d,
J=9.1Hz, 2H)7.74(s, 1H)
[1197] (187e) 5-{3-[(R) or
(S)-(4-Carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)met
hyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic

acid
[1 198] [Chemical Formula 488]
To 6 ml of an ethanol solution containing 30 mg of 3-benzyl-5-(3-{(R) or (S)-(2-fluoro-4,5-dimethoxyphenyl)-[(4-(N-hydroxycarbamimidoyl)phen ylamino]-methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-3H-imidazole-4 -carboxylic acid (Example (187d)), 10 mg of 5% palladium carbon powder and 94 mg of ammonium formate were added. The resulting mixture was stirred at 80°C for 60 hours under a nitrogen atmosphere. After cooling, the reaction mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (0.36 mg) as a brown solid. 'H-NMR (CD3OD) 8 3.77 (s, 3H) 3.85 (s, 3H) 5.88 (s, 1H) 6.85 (m, 3H) 7.07 (d, J=7.0Hz, 1H) 7.62 (m, 3H)
[1199] Example L88j 4-(3400 and
(S)-(4-Carbamimidovlphenvlamino)-(5-fluoro-8-methoxv-2.3-dihvdroben
zo[1.4]dioxin-6-vnmethvl]-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vl}thiazol
e-5-carboxylic acid
(188a) 4-(5-Trifluoromethyl-[l,2,4]oxadiazoI-3-yl)phenylamine
[1200] [Chemical Formula 489]
FjC~f Y
To 500 ml of a dichloromethane solution containing 10.2 g of [4-(N-hydroxycarbamimidoyl)phenyl]carbamic acid t-butyl ester (Tetrahedron Lett. 2003, 44, 8697), 8.8 ml of diisopropylethylamine and 8.6 ml of trifluoroacetic anhydride were added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 20 hours, and then

500 ml of ethyl acetate and 500 ml of water were added thereto. The organic layer was washed with 200 ml of water and then with 200 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give [4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenyl]carbamic acid t-butyl ester (9.6 g).
'H-NMR (CDC13) 8 1.55 (s, 9H) 6.66 (s, 1H) 7.54 (d, J=8.5Hz, 2H) 8.03 (d, J=8.5Hz, 2H)
To 30 ml of a dichloromethane solution containing 9.6 g of this compound, 30 ml of trifluoroacetic acid was added. The resulting mixture was stirred at room temperature for 3 hours, and then 500 ml of ethyl acetate and 300 ml of a saturated sodium hydrogen carbonate aqueous solution were added thereto. The organic layer was washed with 300 ml of water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (6.8 g) as a pink solid.
'H-NMR (CDC13) 8 6.75 (d, J=8.5Hz, 2H) 7.90 (d, J=8.5Hz, 2H) [1201] (188b)
[2-(5-Fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-triflu oromethyl-[ 1,2,4]oxadiazol-3-yI)phenylimino]-l -methylsulfanylethyliden ejcarbamic acid methyl ester [1202] [Chemical Formula 490]

The same procedure was carried out as in Example (4Id), except that 4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenylamine was used instead of the 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, to give the title

compound as a light yellow compound.
'H-NMR (CDCI3) Main isomer:
8 2.34 (s, 3H) 3.65 (s, 3H) 3.93 (s, 3H) 4.36 (m,2H) 4.44 (m, 2H) 6.89
(d,J=9.2Hz,lH) 7.10 (d, J=8.9Hz, 2H) 8.09 (d, J=8.9Hz, 2H)
[1203] (188c)
4-(3-{(5-Fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(5-trifI
uoromethyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihyd
ro-[l,2,4]triazol-l-yl)thiazole-5-carboxylic acid ethyl ester
[1204] [Chemical Formula 491]

To 5 ml of a DMF solution containing 113 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-2-[4-(5-triflu oromethyl-[l,2,4]oxadiazol-3-yI)phenyIimino]-l-methylsulfanylethyliden e]carbamic acid methyl ester, 40 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.030 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and 0.035 ml of acetic acid, and 103 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (57 mg).

'H-NMR (CD3OD) 5 1.25 (t, J=7.3Hz, 3H) 3.78 (s, 3H) 4.27 (q, J=7.3Hz,
2H) 4.29 (s, 4H) 5.93 (s, 1H) 6.68 (d, J=5.5Hz, 1H) 6.86 (d, J=8.9Hz,
2H) 7.89 (d, J=8.9Hz, 2H) 9.15 (s, 1H)
[1205] (188d) 4-{3-[(R) and
(S)-(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydroben
zo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazol
e-5-carboxylic acid
[1206] [Chemical Formula 492]

To 2 ml of a methanol solution containing 57 mg of
4-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yI)-[4-(5-trifl
uoromethyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihyd
ro-[l,2,4]triazol-l-yl)thiazole-5-carboxylic acid ethyl ester, 0.2 ml of a 5
N sodium hydroxide aqueous solution was added. The resulting mixture
was stirred at room temperature for 18 hours, and then 2 ml of methanol,
2 ml of acetic acid, and 38 mg of iron powder were added thereto. The
mixture was stirred at 60°C for 18 hours and then at 65°C for 6 hours,
under a nitrogen atmosphere. After cooling, the reaction mixture was
purified by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob
enzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiaz
ole-5-carboxylic acid.
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (2.9 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 3.77 (s, 3H) 4.29 (s, 4H) 5.85 (s, 1H) 6.66 (d,
J=6.4Hz, 1H) 6.84 (d, J=8.4Hz, 2H) 7.63 (d, J=8.4Hz, 2H) 8.86 (s, 1H)

HPLC retention time: 29 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1207] Example 189:
5-{3-[(4-CarbamimidovlphenvlaminoH5-fluoro-8-methoxvchroman-6-vl
^methvl]-5-oxo-4.5-dihvdro-ri.2.41triazol-l-vU-lH-pvrazole-4-carboxvli
c acid
(189a)
[2-(5-Fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid
methyl ester
[1208] [Chemical Formula 493]

The same procedure was carried out as in Example (33d), except that
4-(5-trifluoromethyl-[l ,2,4]oxadiazol-3-yl)phenylamine (Example
(188a)) was used instead of the
4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, to give the title compound as a light yellow solid. 'H-NMR (CDC13) Main isomer:
5 2.05 (m, 2H) 2.34 (s, 3H) 2.77 (t, J=6.8Hz, 2H) 3.64 (s, 3H) 3.92 (s, 3H) 4.34 (t, J=5.5Hz, 2H) 7.14 (d, J=8.6Hz, 2H) 8.08 (d, J=8.6Hz, 2H) [1209] (189b)
5.(3-{(5-Fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[l,2,4]ox adiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl) -lH-pyrazole-4-carboxylic acid ethyl ester [1210] [Chemical Formula 494]


To 5 ml of a DMF solution containing 160 mg of
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid
methyl ester, 87 mg of 3-hydrazino-lH-pyrazole-4-carboxyIic acid ethyl ester bishydrochloride (Example (157b)) and 0.124 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 8 ml of methanol and 0.068 ml of acetic acid, and then 187 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (39 mg).
'H-NMR (CD3OD) 8 1.25 (t, J=7.3Hz, 3H) 1.97 (quint, J=6.7Hz, 2H) 2.75 (t, J=6.7Hz, 2H) 3.66 (s, 3H) 4.12-4.19 (m, 4H) 5.88 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.94 (d, J=6.3Hz, 1H) 7.87 (d, J=8.8Hz, 2H) 8.24 (s, 1H) [1211] (189c)
5-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl )methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxyli c acid [1212] [Chemical Formula 495]


Iron powder (64 mg) was added to 6 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent solution containing 74 mg of
5-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[l,2,4]ox
adiazol-3-yI)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)
-lH-pyrazole-4-carboxylic acid ethyl ester. The resulting mixture was
stirred at 60°C for 20 hours under a nitrogen atmosphere. After
filtration, the reaction mixture was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give 22 mg of
5-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl) methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic acid ethyl ester.
To a solution of 22 mg of this compound in 1 ml of acetonitrile and 0.5 ml of DMF, 0.016 ml of triethylamine, 0.3 mg of 4-dimethylaminopyridine, and 0.091 ml of an acetonitrile solution of 1M di-t-butyl dicarbonate were added. The resulting mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure. To the residue, 1 ml of methanol and 1 ml of a 5 N sodium hydroxide aqueous solution were added. The mixture was stirred at room temperature for 8 hours, and then 2 ml of acetic acid, 1 ml of water, and 1 ml of methanol were added to this reaction mixture. The mixture was stirred at 50°C for 15 hours. The reaction mixture was cooled and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (7 mg).
'H-NMR (CD3OD) 8 2.00 (m, 2H) 2.76 (t, J=6.6Hz, 2H) 3.75 (s, 3H) 4.18 (t, J=5.6Hz, 2FH 5.86 (s. 1FH 6.84 (d. J=8.6Hz. 2rtt 6.91 (d.

J=6.5Hz, 1H) 7.62 (d, J=8.6Hz, 2H) 7.99 (s,lH)
[1213] Example 190j 4-i3-\(R) and
(S)-(4-Carbamimidovlphenvlamino)-(5-fluoro-8-methoxvchroman-6-vl)m
ethvll-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vl}thiazole-5-carboxylic acid
(190a)
4-(3-{(5-Fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[l,2,4]ox
adiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)
thiazole-5-carboxylic acid ethyl ester
[1214] [Chemical Formula 496]

To 4 ml of a DMF solution containing 111 mg of
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[l,2,4]oxa
diazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid
methyl ester (Example (189a)), 37 mg of
4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.031 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 4 ml of methanol and 0.032 ml of acetic acid, and then 83 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (74 mg).

'H-NMR (CD3OD) 1.24 (t, J=7.3Hz, 3H) 2.00 (tt, J=7.0,5.6Hz, 2H) 2.78
(t, J=7.0Hz, 2H) 3.77 (s, 3H) 4.20 (t, J=5.6Hz, 2H) 4.25 (q, J=7.3Hz, 2H)
5.91 (s, 1H) 6.85 (d, J=9.0Hz, 2H) 6.94 (d, J=7.3Hz, 1H) 7.87 (d,
J=9.0Hz, 2H)9.15(s, 1H)
[1215] (190b)
4-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl
)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic
acid trifluoroacetate
[1216] [Chemical Formula 497]

To 2 ml of a methanol solution containing 74 mg of 4-(3-{(5-fluoro-8-methoxychroman-6-yI)-[4-(5-trifluoromethyl-[l,2,4]ox adiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl) thiazoIe-5-carboxylic acid ethyl ester, 0.5 ml of a 5 N sodium hydroxide aqueous solution was added. The resulting mixture was stirred at room temperature for 18 hours, and then 2 ml of acetic acid, 1.5 ml of water, and 74 mg of iron powder were added thereto. The mixture was stirred at 60°C for 15 hours under a nitrogen atmosphere. The reaction mixture was filtered and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (34 mg).
'H-NMR (CD3OD) 6 2.00 (tt, J=7.0,5.6Hz, 2H) 2.76 (t, J=7.0Hz, 2H) 3.76 (s, 3H) 4.20 (t, J=5.6Hz, 2H) 5.94 (s, 1H) 6.86 (d, J=8.9Hz, 2H) 6.88 (d, J=7.5Hz, 1H) 7.64 (d, J=9.0Hz, 2H) 8.29 (br.s, 1H) 8.78 (br.s, lH)9.14(s, 1H)
[1217] (190c) 4-{3-[(R) and
(S)-(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl)m ethyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid

[1218] [Chemical Formula 498]

4-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl )methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid trifluoroacetate (33 mg) was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (5.0 mg) of the title compound was obtained as a white solid. ^-NMR (CD3OD) 8 2.00 (tt, J=7.0,5.3Hz, 2H) 2.76 (t, J=7.0Hz, 2H) 3.76 (s, 3H) 4.20 (t, J=5.3Hz, 2H) 5.87 (s, 1H) 6.84 (d, J=8.9Hz, 2H) 6.91 (d, J=7.0Hz, 1H) 7.64 (d, J=8.9Hz, 2H) 8.87 (s, 1H) HPLC retention time: 26 min (Column name: SUMICHIRAL OA-2500, 30 mm [1219] Example \9U 5-f3-MO or
(SH4-Carbamimidovlphenylamino)-C5-fluoro-8-methoxv-2.3-dihvdroben
zo[1.4'|dioxin-6-vI')methvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vl>-3H-im
idazole-4-carboxvlic acid trifluoroacetate
(191a)
3-Benzyl-5-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydro
benzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H
-imidazole-4-carboxylic acid ethyl ester
[1220] [Chemical Formula 499]


The same procedure was carried out as in Example (168b), except that
3-benzyl-5-hydrazino-3H-imidazole-4-carboxylic acid ethyl ester
(Example (187b)) was used instead of the
3-hydrazinothiophene-2-carboxylic acid methyl ester, to give the title
compound as a light yellow solid.
'H-NMR (CDCb) 8 1.05 (t, J=7.2Hz, 3H) 3.72 (s, 3H) 4.14 (m, 2H) 4.35
(s, 4H) 5.50 (s, 2H) 5.63 (d, J=5.3Hz, 1H) 5.75 (d, J=5.3Hz, 1H) 6.45 (d,
J=6.9Hz, 1H) 6.59 (d, J=8.8Hz, 2H) 7.23-7.25 (m, 3H) 7.37 (d, J=7.8Hz,
2H) 7.39 (d, J=8.8Hz, 2H) 7.54 (s, 1H)
[1221] (191b) 3-Benzyl-5-{3-[(R) and
(S)-(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]di
oxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4
-carboxylic acid ethyl ester
[1222] [Chemical Formula 500]

3-Benzyl-5-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydro benzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H -imidazole-4-carboxylic acid ethyl ester (306 mg) was optically resolved

using a CHIRALPAK AD-H column, and the second eluting enantiomer
(97 mg) of the title compound was obtained as a light yellow solid.
:H-NMR (CDCI3) 8 0.98 (t, J=7.2Hz, 3H) 3.74 (s, 3H) 4.12 (m, 2H) 4.30
(m, 4H) 5.48 (d, J=15.3Hz, 1H) 5.53 (d, J=15.3Hz, 1H) 5.73 (s, 1H) 6.47
(d, J=6.9Hz, 1H) 6.55 (d, J=8.8Hz, 2H) 7.23 (m, 2H) 7.31-7.39 (m, 3H)
7.39 (d, J=8.8Hz, 2H) 7.54 (s, 1H)
HPLC retention time: 35 min (Column name: CHIRALPAK AD-H, 20
mm x 25 cm, Manufacturer: Daicel Chemical Industries, Ltd., Mobile
phase: ethyl acetate/heptane = 6/4, Elution rate: 10 ml/min)
[1223] (191c) 3-Benzyl-5-(3-{(R) or
(S)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(N-hydro
xycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol
-l-yl}-3H-imidazole-4-carboxylic acid
[1224] [Chemical Formula 501]

The same procedure was carried out as in Example (187d), except that
3-benzyl-5-{3-[(R) or
(S)-(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]di
oxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4
-carboxylic acid ethyl ester (Example (191b)) was used instead of the
3-benzyl-5-{(R) or
(S)-3-[(4-cyanophenylamino)-(2-fluoro-4,5-dimethoxyphenyl)methyl]-5-
oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-imidazole-4-carboxylic acid
ethyl ester in Example (187d), to give the title compound.
'H-NMR (CD3OD) 8 3.75 (s, 3H) 4.28 (s, 4H) 5.65 (d, J=14.5Hz, 1H)
5.69 (d, J=14.5Hz, 1H) 5.84 (s, 1H) 6.63 (d, J=5.7Hz, 1H) 6.79 (d,

J=8.8Hz, 2H) 7.22-7.30 (m, 5H) 7.45 (d, J=8.8Hz, 2H) 7.75 (s, 1H)
[1225] (191d) 5-{3-[(R) or
(S)-(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydroben zo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-3H-im idazole-4-carboxylic acid trifluoroacetate [1226] [Chemical Formula 502]

The same procedure was carried out as in Example (187e), except that
3-benzyl-5-(3-{(R) or
(S)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-[4-(N-hydro
xycarbamimidoyl)phenylamino]methyI}-5-oxo-4,5-dihydro-[l,2,4]triazol
-l-yl}-3H-imidazole-4-carboxylic acid (Example (191c)) and 0.1%
trifluoroacetic acid were used instead of respectively 3-benzyl-5-(3-{(R)
or
(S)-(2-fluoro-4,5-dimethoxyphenyl)-[(4-(N-hydroxycarbamimidoyl)phen
ylamino]-methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-3H-imidazole-4
-carboxylic acid and 0.1% acetic acid, to give the title compound as a
brown solid.
'H-NMR (CD3OD) 5 3.76 (s, 3H) 4.30 (s, 4H) 5.88 (s, 1H) 6.65 (d,
J=6.0Hz, 1H) 6.84 (d, J=9.1Hz, 2H) 7.60 (s, 1H) 7.62 (d, J=9.1Hz, 2H)
[1227] Example 192:
5-{3-[(4-Carbamimidovlphenvlamino)-(6-fluoro-9-methoxv-3.4-dihvdro-
2H-benzofbin,41dioxepin-7-vl)methvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-
l-vl}-lH-pyrazole-4-carboxylic acid ethyl ester acetate
(192a)
5-(3-{(6-Fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-
[4-(5-methyl[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihyd
ro-[l,2,4]triazol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester

[1228] [Chemical Formula 503]

The same procedure was carried out as in Examples (le) to (If), except
that
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester (Example (30c)) and
3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester bishydrochloride
(Example (157b)) were used instead of respectively the
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)
phenylimino]-l-rnethylsulfanyletbylidene]carbamic acid methyl ester and
2-hydrazinobenzoic acid hydrochloride in Example (le), to give the title
compound.
Mass spectrum (ESI) m/z: 629 (M+Na)+
[1229] (192b)
5-{3-[(4-Carbamimidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-
2H-benzo[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-
l-yl}-lH-pyrazole-4-carboxylic acid ethyl ester acetate
[1230] [Chemical Formula 504]

The same procedure was carried out as in Example (lg), except that

5-(3-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-[
4-(5-methyl[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydr
o-[l,2,4]triazol-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester and 0.1%
acetic acid were used instead of respectively
2-(3-{(2-fluoro-4,5-dimethoxyphenyI)-[4-(5-methyl-[l,2,4]oxadiazoI-3-y
l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic
acid and 0.1% trifluoroacetic acid, to give the title compound as a light
yellow solid.
'H-NMR (CD3OD) 8 1.20 (t, J=7.1Hz, 3H) 1.97 (s, 3H) 2.22 (m, 2H)
3.78 (s, 3H) 4.12-4.30 (m, 6H) 5.95 (s, 1H) 6.80 (d, J=6.2Hz, 1H) 6.87
(d, J=9.0Hz, 2H) 7.65 (d, J=9.0Hz, 2H) 8.26 (s, 1H)
[1231] Example 193j (R) and
(S)-4-(3-r(4-Carbamimidovlphenvlamino)-r3.4-dimethoxvphenvnmethvl ]-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vU-thiazole-5-carboxvlic acid (193a)
{2-(3,4-dimethoxyphenyl)-l-methylsulfanyl-2-[4-(5-trifluoromethyl-[l,2, 4]oxadiazol-3-yl)phenylimino]ethylidene}carbamic acid methyl ester [1232] [Chemical Formula 505]

The same procedure was carried out as in Example (la) to (Id), except that 4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenylamine (Example (188a)) and 3,4-dimethoxybenzaldehyde were used instead of respectively 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine and 2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to give the title compound as a light yellow solid.
'H-NMR (CDCI3) 5 2.34 (s, 3H) 3.65 (s, 3H) 3.96 (s, 3H) 3.97 (s, 3H) 6.90 (d, J=8.6Hz, 1H) 7.23 (d, J=8.3Hz, 2H) 7.30 (dd, J=8.6,2.3Hz, 1H) 7.61 (d, J=2.3Hz, 1H) 8.09 (d, J=8.3Hz, 2H) [1233] (193b)

4-(3-{(3,4-Dimethoxyphenyl)-[4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-5-carboxylic acid ethyl ester [1234] [Chemical Formula 506]

The same procedure was carried out as in Example (185d), except that
{2-(3,4-dimethoxyphenyl)-l-methylsulfanyl-2-[4-(5-trifluoromethyl-[l,2,
4]oxadiazol-3-yl)phenylimino]ethylidene}carbamic acid methyl ester was
used instead of the
{2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester,
to give the title compound.
'H-NMR (CD3OD) 8 1.19 (t, J=7.3Hz, 3H) 3.84 (s, 3H) 3.86 (s, 3H) 4.44
(q, J=7.3Hz, 2H) 5.62 (s, 1H) 6.87 (d, J=8.7Hz, 2H) 6.98 (d, J=8.2Hz,
1H) 7.11 (dd, J=8.2,1.8Hz, 1H) 7.15 (d, J=1.8Hz, 1H) 7.87 (d, J=8.7Hz,
2H)9.16(s, 1H)
[1235] (193c)
4-{3-[(4-Carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl]-5-
oxo-4,5-dihydro-[l,2,4]triazol-l -yl}thiazole-5-carboxylic acid
trifluoroacetate
[1236] [Chemical Formula 507]


The same procedure was carried out as in Example (190b), except that
4-(3-{(3,4-dimethoxyphenyl)-[4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl
)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiazole-5-c
arboxylic acid ethyl ester was used instead of the
4-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[l,2,4]ox
adiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)
thiazole-5-carboxylic acid ethyl ester, to give the title compound.
'H-NMR (CD3OD) 8 3.82 (s, 3H) 3.85 (s, 3H) 5*60 (s, 1H) 6.86 (d,
J=8.9Hz, 2H) 6.97 (d, J=8.3Hz, 1H) 7.09 (dd, J=8.3,1.8Hz,lH) 7.15 (d,
J=1.8Hz, 1H) 7.61 (d, J=8.9Hz, 2H) 8.90 (s, 1H)
[1237] (193d) (R) and
(S)-4-{3-[(4-Carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl
]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid
[1238] [Chemical Formula 508]

4-{3-[(4-Carbamimidoylphenylamino)-(3,4-dimethoxyphenyl)methyl]-5-
oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiazole-5-carboxylic acid (15 mg)
was optically resolved using a SUM1CHIRAL OA-2500 column, and the
first eluting enantiomer (3.1 mg) of the title compound was obtained as a
white solid.
'H-NMR (CD3OD) 8 3.82 (s, 3H) 3.85 (s, 3H) 5.57 (s, 1H) 6.86 (d,
J=8.9Hz, 2H) 6.97 (d, J=8.3Hz, 1H) 7.09 (dd, J=8.3,1.8Hz,lH) 7.15 (d,
J=1.8Hz, 1H) 7.62 (d, J=8.9Hz, 2H) 8.88 (s, 1H)
HPLC retention time: 23 min (Column name: SUMICHIRAL OA-2500,
30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1239] Example 194: (E) and

(S)-5-(3-[f4-Carbamimidovlphenylamino)-(2-fluoro-4.5-dimethoxvphenv l)methvl]-5-oxo-4.5-dihvdro-[ 1,2,4]triazol-1 -vll-1 H-pvrazole-4-carboxvl ic acid acetate [1240] [Chemical Formula 509]

5-{3-[(4-Carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)m ethyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic acid acetate (Example (157e), 0.8 mg) was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (0.3 mg) of the title compound was obtained.
'H-NMR (CD3OD) 8 1.98 (s, 3H) 3.78 (s, 3H) 3.82 (s, 3H) 5.92 (s, 1H) 6.84 (d, J=10.6Hz, 1H) 6.86 (d, J=9.1Hz, 2H) 7.07 (d, J=6.8Hz, 1H) 7.63 (d, J=9.1Hz, 2H)7.98(s, 1H)
HPLC retention time: 20 min (Column name: SUMICHIRAL OA-2500, 30 mm [1241] Example 195: 3-(3-fflO and
(S)-(4-Carbamimidovlphenvlamino)-r3-methoxv-4-f2-methoxvethoxv)ph
envl]methvU-5-oxo-4.5-dihvdro-n.2.41triazol-l-vnthiophene-2-carboxvl
ic acid
(195a)
{2-[3-Methoxy-4-(2-methoxyethoxy)phenyl]-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester
[ 1242] [Chemical Formula 510]


The same procedure was carried out as in Example (18e), except that
l-bromo-2-methoxyethane was used instead of the iodoethane, to give
the title compound.
[1243] (195b) 3-(3-{(R) and
(S)-(4-Carbamimidoylphenylamino)-[3-methoxy-4-(2-methoxyethoxy)ph
enyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene-2-carboxyl
ic acid
[1244] [Chemical Formula 511]

The same procedure was carried out as in Example (169b), except that
{2-[3-methoxy-4-(2-methoxyethoxy)phenyl]-2-[4-(5-methyl-[l,2,4]oxadi
azol-3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid
methyl ester was used instead of
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to
give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 3.41 (s, 3H) 3.72-3.74 (m, 2H) 3.84 (s, 3H)
4.11-4.13 (m, 2H) 5.56 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.98 (d, J=8.4Hz,
1H) 7.06 (dd, J=2.0, 8.4Hz, 1H) 7.07 (d, J=5.6Hz, 1H) 7.16 (d, J=2.0Hz,
1H) 7.43 (d, J=5.6Hz, 1H) 7.60 (d, J=8.8Hz, 2H)
HPLC retention time: 12 min (Column name: SUMICHIRAL OA-2500,
30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,

Elution rate: 30 ml/min)
[1245] Example 196:
543-[(4-Carbamimidoylphenylamino)-(6-fluoro-9-methoxv-3.4-dihvdro-2H-benzo[b][1.4]dioxepin-7-vl)methvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vU-lH-pvrazole-4-carboxvlic acid acetate [1246] [Chemical Formula 512]

The same procedure was carried out as in Example (157e), except that
5-{3-[(4-carbamimidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-
2H-benzo[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-
l-yl}-lH-pyrazole-4-carboxylic acid ethyl ester acetate (Example
(192b)) was used instead of
5-{3-[(4-carbamimidoylphenylamino)-(2-fluoro-4,5-dimethoxyphenyl)me
thyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-4-carboxylic
acid ethyl ester acetate, to give the title compound.
'H-NMR (CD3OD) 5 1.95 (s, 3H) 2.21 (m, 2H) 3.75 (s, 3H) 4.08-4.30
(m, 4H) 5.90 (s, 1H) 6.79 (d, J=6.2Hz, 1H) 6.84 (d, J=8.6Hz, 2H) 7.62
(d, J=8.6Hz, 2H) 8.01 (s, 1H)
[1247] Example 197:
5-{3-r(4-Carbamimidovlphenvlamino)-(5-fluoro-8-methoxv-2.3-dihvdrob enzo[L4]dioxin-6-vl)methvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vl}-lH-pvrazole-4-carboxvlic acid ethyl ester trifluoroacetate (197a)
5-{3-[(4-Cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4 ]dioxin-6-yI)methyl]-5-oxo-4,5-dihydro-[ 1,2,4]triazol-1 -y 1} -1 H-pyrazole -4-carboxylic acid ethyl ester [1248] [Chemical Formula 513]


The same procedure was carried out as in Example (168b), except that
3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester bishydrochloride
(Example (157b)) was used instead of
3-hydrazinothiophene-2-carboxylic acid methyl ester, to give the title compound as a light yellow solid.
'H-NMR (CDCI3) 8 1.20 (t, J=7.2Hz, 3H) 3.82 (s, 3H) 4.15 (m, 2H) 4.21 (s, 4H) 5.80 (s, 1H) 6.50 (br.s, 1H) 6.62 (d, J=8.5Hz, 2H) 7.35 (d, J=8.5Hz, 2H) 8.04 (s, 1H) [1249] (197b)
5-(3-{(5-Fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-4-(N-hydr oxycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazo l-l-yl)-lH-pyrazole-4-carboxylic acid ethyl ester [1250] [Chemical Formula 514]

The same procedure was carried out as in Example (176c), except that
5-{3-[(4-cyanophenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]
dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-pyrazole-
4-carboxylic acid ethyl ester was used instead of
2-{3-[(4-cyanophenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo
[b][l,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}nico

tinic acid, to give the title compound as a brown solid.
'H-NMR (CD3OD) 8 1.17 (t, J=7.3Hz, 3H) 3.77 (s, 3H) 4.15 (m, 2H)
4.19 (m, 4H) 5.83 (s, 1H) 6.68 (d, J=6.2Hz, 1H) 6.75 (d, J=8.8Hz, 2H)
7.43 (d, J=8.8Hz, 2H) 8.25 (s, 1H)
[1251] (197c)
5-{3-[(4-Carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrob
enzo[l,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}-lH-
pyrazole-4-carboxylic acid ethyl ester trifluoroacetate
[1252] [Chemical Formula 515]

The same procedure was carried out as in Example (Ig), except that 15
mg of
5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]dioxin-6-yl)-4-(N-hydr
oxycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazo
l-l-yI)-lH-pyrazole-4-carboxylic acid ethyl ester and 0.1% acetic acid
were used instead of respectively
2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-y l)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)benzoic acid and 0.1% trifluoroacetic acid, to give the title compound as a light yellow solid.
'H-NMR (d6-DMSO) 8 1.05 (t, J=7.1Hz, 3H) 3.64 (s, 3H) 4.00 (q, J=7.1Hz, 2H) 4.21-4.80 (m, 4H) 5.62 (s, 1H) 6.77 (d, J=6.2Hz,lH) 6.79 (d, J=8.7Hz, 2H) 7.44 (br.s, 1H) 7.56 (d, J=8.7Hz, 2H)
[1253] Example 198; (R) or
(S~)-5-f3-(f4-Carbamimidovlphenvlamino)-[2-fluoro-3-(3-hvdroxvpropox v)-5-methoxvphenvl]methvl}-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vl)-lH-pyrazole-4-carboxvlic acid acetate

(198a) 3-(N'-t-Butoxycarbonylhydrazino)pyrazole-l,4-dicarboxyIic acid 4-benzyl ester 1 -t-butyl ester [1254] [Chemical Formula 516]

The same procedure was carried out as in Example (157a), except that
3-amino-lH-pyrazole-4-carboxylic acid benzyl ester was used instead of
3-amino-lH-pyrazole-4-carboxylic acid ethyl ester, to give the title
compound as a white solid.
'H-NMR (CDC13) 8 1.60 (s, 18H) 5.29 (s, 2H) 6.56 (br.s, 1H) 7.21 (br.s,
1H) 7.43-7.42 (m, 5H) 8.32 (s, 1H)
[1255] (198b) 5-Hydrazino-lH-pyrazole-4-carboxylic acid benzyl ester
bishydrochloride
[1256] [Chemical Formula 517]

The same procedure was carried out as in Example (157b), except that
3-(N'-t-butoxycarbonylhydrazino)pyrazole-l,4-dicarboxylic acid
4-benzyl ester 1-t-butyl ester was used instead of the
3-(N'-t-butoxycarbonylhydrazino)-lH-pyrazole-4-carboxylic acid ethyl
ester, to give the title compound as a white solid.
'H-NMR (CD3OD) 5 5.29 (s, 2H) 7.30-7.44 (m, 5H) 8.08 (s, 1H)
[1257] (198c)
5-{3-[{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphe
nyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl
}-lH-pyrazole-4-carboxylic acid benzyl ester
[1258] [Chemical Formula 518]


The same procedure was carried out as in Example (177b), except that
(2- {3 - [3 -(t-butyldimethylsilanyloxy)propoxy] -2-fluoro-5 -methoxyphenyl
}-2-(4-cyanophenylimino)-l-methylsulfanylethylidene)carbamic acid
methyl ester (Example (163c)) and
5-hydrazino-lH-pyrazole-4-carboxylic acid benzyl ester bishydrochloride
were used instead of respectively
(2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl
}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylet
hylidene)carbamic acid methyl ester and
3-hydrazino-lH-pyrazole-4-carboxylic acid ethyl ester bishydrochloride, to give the title compound as a light yellow solid.
'H-NMR (CD3OD) 5 0.06 (s, 6H) 0.84 (s, 9H) 1.94 (quint, J=6.5Hz, 2H) 3.68 (s, 3H) 3.80 (t, J=6.5Hz, 2H) 4.08 (t, J=6.5Hz, 2H) 5.12 (d, J=12.8Hz, 1H) 5.15 (d, J=12.8Hz, 1H) 5.76 (s, 1H) 6.54 (t, J=2.9Hz, 1H) 6.58 (dd, J=7.5,2.9Hz, 1H) 6.72 (d, J=8.9Hz, 2H) 7.27 (s, 5H) 7.49 (d, J=8.9Hz, 2H) 8.25 (s, 1H) [1259] (198d)
3-{3-[{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphe nyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl }-l-trityl-lH-pyrazole-4-carboxylic acid benzyl ester [1260] [Chemical Formula 519]


To 10 ml of dichloromethane solution containing 259 mg of 5-{3-[{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphe nyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl }-lH-pyrazole-4-carboxylic acid benzyl ester, 0.060 ml of triethylamine and 109 mg of a-chlorotriphenylmethane were added at 0°C. The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 3 hours. Then, 150 ml of ethyl acetate and 50 ml of water were added to the reaction mixture. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (177 mg).
'H-NMR (CDC13) 5 0.06 (s, 6H) 0.90 (s, 9H) 2.04 (m, 2H) 3.64 (s, 3H) 3.83 (t, J=6.1Hz, 2H) 4.08 (t, J=6.1Hz, 2H) 5.05 (d, J=12.7Hz, 1H) 5.14 (d, J=12.7Hz, 1H) 5.42 (d, J=4.8Hz, 1H) 5.45 (d, J=4.8Hz, 1H) 6.30 (m, 1H) 6.50 (m, 1H) 6.52 (d, J=9.0Hz, 2H) 7.11-7.25 (s, 20H) 7.38 (d, J=9.0Hz, 2H) 7.98 (s, 1H)
[1261] (198e) (R) and
(S)-3-{3-[{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methox yphenyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazoI -l-yl}-l-trityl-lH-pyrazole-4-carboxylic acid benzyl ester [1262] [Chemical Formula 520]


3-{3-[{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphe
nyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl
}-l-trityl-lH-pyrazole-4-carboxylic acid benzyl ester (177 mg) was
optically resolved using a CHIRALPAK IA column, and the second
eluting enantiomer (44 mg) of the title compound was obtained as a light
yellow solid.
'H-NMR (CD3OD) 8 0.00 (s, 6H) 0.84 (s, 9H) 1.93 (quint, J=6.1Hz, 2H)
3.64 (s, 3H) 3.79 (t, J=6.1Hz, 2H) 4.07 (t, J=6.1Hz, 2H) 5.07 (d,
J=12.4Hz, 1H) 5.11 (d, J=12.4Hz, 1H) 5.73 (s, 1H) 6.50 (dd,J=4.5,2.9Hz,
1H) 6.50 (dd,J=7.4,2.9Hz, 1H) 6.69 (d, J=8.8Hz, 2H) 7.11-7.34 (s, 20H)
7.37 (d, J=8.8Hz, 2H) 7.92 (s, 1H)
HPLC retention time: 35 min (Column name: CHIRALPAK IA, 20 mm
x 25 cm, Manufacturer: Daicel Chemical Industries, Ltd., Mobile phase:
ethyl acetate/heptane = 2/8, Elution rate: 10 ml/min)
[1263] (198f) (R) or
(S)-5-(3-{(4-Carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropox
y)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)-lH-
pyrazole-4-carboxylic acid acetate
[1264] [Chemical Formula 521]

To 4 ml of a methanol solution containing 44 mg of (R) or (S)-3-{3-[{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxy

phenyl}-(4-cyanophenylamino)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazoI-l-yl}-l-trityl-lH-pyrazole-4-carboxylic acid benzyl ester (Example (198e)), 32 mg of hydroxylammonium chloride and 0.063 ml of triethylamine were added. The resulting mixture was stirred at 60°C for 15 hours under a nitrogen atmosphere.
The solvent was removed under reduced pressure. The residue was dissolved in 6 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent. The resulting solution was stirred at 60°C for 24 hours under a nitrogen atmosphere.
The solvent was removed under reduced pressure. The residue was dissolved in 5 ml of methanol, and then 0.04 g of 10% palladium carbon was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere of 4.5 kg/cm2 for 12 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (4 mg) as a brown solid.
'H-NMR (CD3OD) 5 1.95 (s, 3H) 2.00 (quint, J=6.1Hz, 2H) 3.74 (s, 3H) 3.76 (t, J=6.1Hz, 2H) 4.13 (t, J=6.1Hz, 2H) 5.93 (s, 1H) 6.60 (dd, J=4.8,2.9Hz, 1H) 6.65 (dd, J=7.2,2.9Hz, 1H) 6.85 (d, J=8.9Hz, 2H) 7.62 (d, J=8.9Hz, 2H) 8.04 (s, 1H)
[1265] Example 199: (R) and
(S)-4-({[2-Fluoro-3-f2-hvdroxvethoxy)-5-methoxvphenvl]-[5-oxo-l-(3-o xo-3.4-dihvdropvrazin-2-vl)-4.5-dihvdro-lH-[1.2.41triazol-3-vnmethvUa mino)benzamidine acetate (199a)
3-(3-{{3-[2-(t-Butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphen yl}-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H- [ 1,2,4]triazol-1 -yl)-1 H-pyrazin-2-one [1266] [Chemical Formula 522]


To 2 ml of a dichloromethane solution containing 139 mg of (3-t-butoxypyrazin-2-yl)hydrazine (Example (154a)), 2 ml of trifluoroacetic acid was added. The resulting mixture was stirred at room temperature for 2 hours, and then 50 ml of toluene was added thereto. The mixture was concentrated under reduced pressure, and 50 ml of methanol was added thereto. Then, the mixture was concentrated under reduced pressure. The residue was treated with 10 ml of diethylether and a 4 N hydrogen chloride-ethyl acetate solution, and 3-hydrazino-lH-pyrazin-2-one hydrochloride was collected by filtration. 3-Hydrazino-lH-pyrazin-2-one hydrochloride (24 mg) and triethylamine (0.033 ml) were added to 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy lidene)carbamic acid methyl ester (Example (200a)). The resulting mixture was stirred at 85°C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were further added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (34 mg).
'H-NMR (CD3OD) 5 0.01 (s, 6H) 0.80 (s, 9H) 2.50 (s, 3H) 3.64 (s, 3H) 3.89 (t, J=4.6Hz, 2H) 4.01 (t, J=4.6Hz, 2H) 5.86 (s, 1H) 6.52-6.57 (m,

2H) 6.81 (d, J=9.1Hz, 2H) 7.30 (d, J=4.1Hz, 1H) 7.42 (d, J=4.1Hz, 1H)
7.70 (d, J=9.1Hz, 2H)
[1267] (199b) (R) and
(S)-4-({[2-Fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-[5-oxo-l-(3-o
xo-3,4-dihydropyrazin-2-yl)-4,5-dihydro-lH-[l,2,4]triazol-3-yl]methyl}a
mino)benzamidine acetate
[1268] [Chemical Formula 523]

Iron powder (55 mg) was added to 4.5 ml of a methanokwatenacetic acid = 1:1:1 mixed solvent solution containing 34 mg of 3-(3-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphen yl}-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-l-yl)-lH-pyrazin-2-one. The mixture was stirred at 65°C for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-[5-oxo-l-(3-0X0-3, 4-dihydropyrazin-2-yl)-4,5-dihydro-lH-[l,2,4]triazol-3-yl]methyI} amino )benzamidine acetate (5.9 mg).
This compound (5.9 mg) was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (1.8 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.71 (s, 3H) 3.87 (t, J=4.7Hz, 2H) 4.08 (t, J=4.7Hz, 2H) 5.94 (s, 1H) 6.63-6.65 (m, 2H) 6.83 (d, J=8.8Hz, 2H) 7.47 (br.s, 1H) 7.61 (d, J=8.8Hz, 2H) 7.65 (br.s, 1H) HPLC retention time: 21 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 15 ml/min)

[1269] Example 200:
4-f{n-f3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-[1.2.41triazol-3-vn-
[2-fluoro-3-(2-hvdroxvethoxv)-5-methoxvphenvllmethvllamino)benzami
dine acetate
(200a)
(2-{3-[2-(t-Butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}
-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanyleth
ylidene)carbamic acid methyl ester
[ 1270] [Chemical Formula 524]

To 15 ml of a DMF solution containing 522 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)), 173 mg of potassium carbonate and 0.269 ml of (2-bromoethoxy)-t-butyldimethylsilane were added. The resulting mixture was stirred at room temperature for 15 hours, and then 25 ml of water and 25 ml of saturated ammonium chloride aqueous solution were added thereto. The mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (210 mg). 'H-NMR (CDC13) Two main isomers:
8 0.03 (s, 6H) 0.85 (s, 9H) 2.46 (s, 3H) 2.52 (s, 3H) 3.63 (s, 3H) 3.64 (s, 3H) 3.91 (t, J=4.9Hz, 2H) 3.98 (t, J=4.9Hz, 2H) 6.13 (dd, J=3.8,2.8Hz, 1H) 6.51 (dd, J=7.2,2.8Hz, 1H) 6.84 (d, J=8.5Hz, 2H) 7.89 (d, J=8.5Hz, 2H) 8 0.09 (s, 6H) 0.90 (s, 9H) 2.33 (s, 3H) 2.65 (s, 3H) 3.60 (s, 3H) 3.82 (s,

3H) 3.99 (t, J=4.9Hz, 2H) 4.08 (t, J=4.9Hz, 2H) 6.73 (dd, J=7.2,2.8Hz,
1H) 6.97 (dd, J=3.8,2.8Hz, 1H) 7.11 (d, J=8.5Hz, 2H) 8.03 (d, J=8.5Hz,
2H)
[1271] (200b)
5-{{3-[2-(t-Butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}
-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyri
din-2-yl)-2,4-dihydro-[ 1,2,4]triazol-3-one
[1272] [Chemical Formula 525]

To 3 ml of a DMF solution containing 70 mg of
(2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-
2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy
lidene)carbamic acid methyl ester, 19 mg of
(3-Nitropyridin-2-yl)hydrazine and 0.017 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 16 hours and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (55 mg). 'H-NMR (CD3OD) 8 0.01 (s, 6H) 0.82 (s, 9H) 2.51 (s, 3H) 3.67 (s, 3H) 3.91 (m, 2H) 4.13 (m, 2H) 5.92 (s, 1H) 6.55-6.59 (m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.53 (dd, J=7.8,4.7Hz, 1H) 7.73 (d, J=8.8Hz, 2H) 8.48 (dd,

J=7.8,1.5Hz, 1H) 8.66 (dd, J=4.7,1.5Hz, 1H)
[1273] (200c)
4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-
[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)benzami
dine acetate
[1274] [Chemical Formula 526]

Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent solution containing 55 mg of 5- {{3 - [2-(t-butyldimethylsilanyloxy)ethoxy] -2-fluoro-5 -methoxyphenyl} -[4-(5-methyl-[ 1,2,4]oxadiazol-3 -yl)phenylamino]methyl} -2-(3 -nitropyri din-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one. The mixture was stirred at 65°C for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (21 mg).
'H-NMR (CD3OD) 8 1.96 (s, 3H) 3.72 (s, 3H) 3.89 (t, J=4.9Hz, 2H) 4.11 (t, J=4.9Hz, 2H) 6.02 (s, 1H) 6.62 (dd, J=4.8,3.1Hz, 1H) 6.68 (dd, J=7.5,3.1Hz, 1H) 6.87 (d, J=9.2Hz, 2H) 7.23 (dd, J=8.0,4.6Hz, 1H) 7.33 (dd, J=8.0,1.5Hz, 1H) 7.63 (d, J=9.2Hz, 2H) 7.81 (dd, J=4.6,1.5Hz, 1H)
[1275] Example 20jj 4-(((R) and
(SVn-(3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-ri.2.41triazol-3-viy
[2-fluoro-3-(2-hvdroxvethoxv)-5-methoxvphenvl]methvUamino)benzami
dine acetate
[1276] [Chemical Formula 527]


4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)benzami dine acetate (Example (200c), 21 mg) was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (9.1 mg) of the title compound was obtained as a white solid. 'H-NMR (CD3OD) 8 1.96 (s, 3H) 3.72 (s, 3H) 3.88 (t, J=4.9Hz, 2H) 4.09 (t, J=4.9Hz, 2H) 5.99 (s, 1H) 6.62-6.67 (m, 2H) 6.85 (d, J=9.2Hz, 2H) 7.21 (dd, J=8.0,4.6Hz, 1H) 7.32 (dd, J=8.0,1.5Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 7.81 (dd, J=4.6,1.5Hz, 1H)
HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500, 30 mm(j) x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1277] Example 202:
4-r(ri-r3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vll-
r2-fluoro-5-methoxv-3-f2-methoxvethoxv)phenvl]methyl)amino)benzami
dine acetate
(202a) 2-Fluoro-5-methoxy-3-(2-methoxyethoxy)benzaldehyde
[1278] [Chemical Formula 528]
rirF
^0'^/^0'"^/0^
The same procedure was carried out as in Example (3e), except that 2-fluoro-3-hydroxy-5-methoxybenzaldehyde [CAS No. 883576-31-6] and 2-bromoethylmethyl ether were used instead of respectively [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl ester and l-fluoro-2-iodoethane, to give the title compound was obtained

as a white solid.
'H-NMR (CDCI3) 8 3.47 (s, 3H) 3.79 (m, 2H) 4.20 (m, 2H) 3.80 (s, 3H)
6.80-6.84 (m, 2H) 10.35 (s, 1H)
[1279] (202b)
{2-[2-Fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-l-methylsulfanyl-
2-[4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenylimino]ethylidene}ca
rbamic acid methyl ester
[1280] [Chemical Formula 529]

The same procedure was carried out as in Examples (la) to (Id), except
that 4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenylamine (Example
(188a)) and 2-fluoro-5-methoxy-3-(2-methoxyethoxy)benzaldehyde were
used instead of respectively the
4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine and
2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to give the title compound as a light yellow solid. 'H-NMR (CDCI3) Main isomer: 8 2.47 (s, 3H) 3.46 (s, 3H) 3.64 (s, 3H) 3.69 (t, J=4.8Hz, 2H) 3.84 (s, 3H) 4.06 (t, J=4.8Hz, 2H) 6.16 (t, J=3.3Hz, 1H) 6.52 (dd, J=7.1,3.3Hz, 1H) 6.88 (d, J=9.2Hz, 2H) 7.95 (d, J=9.2Hz, 2H) [1281] (202c)
5-{[2-Fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-[4-(5-trifluoromet hyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2 ,4-dihydro-[ 1,2,4]triazol-3-one [1282] [Chemical Formula 530]


To 3 ml of a DMF solution containing 86 mg of {2-[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-l-methylsulfanyl-2 -[4-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)phenylimino]ethylidene}car bamic acid methyl ester, 25 mg of (3-nitropyridin-2-yl)hydrazine and 0.023 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 16 hours and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 66 mg of sodium cyanotrihydroborate and 0.085 ml of acetic acid were added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 50 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (55 mg).
'H-NMR (CD3OD) 5 3.41 (s, 3H) 3.73 (s, 3H) 3.74 (m, 2H) 4.15 (m, 2H) 6.00 (s, 1H) 6.61-6.64 (m, 2H) 6.85 (d, J=8.9Hz, 2H) 7.60 (dd, J=8.0,4.5Hz, 1H) 7.85 (d, J=8.9Hz, 2H) 8.46 (dd, J=8.0,1.6Hz, 1H) 8.72 (dd, J=4.5,1.6Hz, 1H) [1283] (202d)
4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yI]-[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]methyl}amino)benzami dine acetate [1284] [Chemical Formula 531]
Iron powder (55 mg) was added to 4.5 ml of a methanolrwater.acetic acid = 1:1:1 mixed solvent solution containing 38 mg of 5-{[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-[4-(5-trifluorometh

yl-[l,2,4]oxadiazol-3-yI)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2, 4-dihydro-[l,2,4]triazol-3-one. The mixture was stirred at 65°C for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (25 mg).
'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.41 (s, 3H) 3.72 (s, 3H) 3.75 (m, 2H) 4.17 (m, 2H) 6.02 (s, 1H) 6.62 (dd, J=4.0,2.9Hz, 1H) 6.67 (dd, J=6.6,2.9Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.22 (dd, 8.0,4.7Hz, 1H) 7.33 (dd, J=8.0,1.3Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 7.81 (dd, J=4.7,1.3Hz, 1H)
[1285] Example 203j 4-(i(R) and
(SVri-(3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-[1.2.41triazol-3-vl]-[2-fluoro-5-methoxv-3-(2-methoxvethoxv)phenvl]methyl)amino)benzami dine acetate

4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[2-fluoro-3-(2-methoxyethoxy)-5-methoxyphenyl]methyl}amino)benzami dine acetate (24 mg) was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (9.5 mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.41 (s, 3H) 3.70 (s, 3H) 3.74 (m, 2H) 4.15 (m, 2H) 5.97 (s, 1H) 6.61-6.65 (m, 2H) 6.84 (d, J=9.2Hz, 2H) 7.20 (dd, 8.1,4.5Hz, 1H) 7.31 (dd, J=8.1,1.3Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 7.81 (dd, J=4.5,1.3Hz, 1H)
HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mmij) x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 15 ml/min)

[1287] Example 204:
4-f(n-f3-Aminopvndin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vll-
r5-ethvl-2-fluoro-3-("3-hvdroxvpropoxv)phenvnmethvllamino)benzamidi
ne acetate
(204a)
5-{{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-5-ethyl-2-fluorophenyl}-[
4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridi
n-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one

The same procedure was carried out as in Example (135f), except that
(3-bromopropoxy)-t-butyldimethylsilane was used instead of
2-chloro-N,N-dimethylacetamide, to give
{2-{3-[3-(t-Butyldimethylsilanyloxy)propoxy]-5-ethyl-2-fluorophenyl}-2 -[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethyli dene}carbamic acid methyl ester.
The same procedure was carried out as in Example (34a), except that this
compound was used instead of
[2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-meth yl-[ 1,2,4]oxadiazol-3-yl)phenylimino]-1 -methylsulfanylethylidene]carba mic acid methyl ester, to give the title compound as a light yellow solid. 'H-NMR (CD3OD) 8 0.01 (s, 6H) 0.84 (s, 9H) 1.15 (t, J=7.3Hz, 3H) 1.95 (quint, J=6.3Hz, 2H) 2.54 (s, 3H) 2.55 (q, J=7.3Hz, 2H) 3.80 (t, J=6.3Hz, 2H) 4.11 (t, J=6.3Hz, 2H) 5.94 (s, 1H) 6.80 (d, J=8.8Hz, 2H) 6.87-6.92 (m, 2H) 7.56 (dd, J=8.0,4.2Hz, 1H) 7.77 (d, J=8.8Hz, 2H) 8.41 (dd, J=8.0,2.0Hz, 1H) 8.69 (dd, J=4.2,2.0Hz, 1H) [1289] (204b) 4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-

[5-ethyl-2-fluoro-3-(3-hydroxypropoxy)phenyl]methyl}amino)benzamidi ne acetate

The same procedure was carried out as in Example (3g), except that 5-{{3-[3-(t-butyldimethylsilanyloxy)propoxy]-5-ethyl-2-fluorophenyl}-[ 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridi n-2-yl)-2,4-dihydro-[l,2,4]triazol-3-one was used instead of 5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[l,2,4]o xadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4] triazol-3-one, to give the title compound.
'H-NMR (CD3OD) 51.16 (t, J=7.1Hz, 3H) 1.95 (s, 3H) 2.01 (quint, J=6.3Hz, 2H) 2.57 (q, J=7.1Hz, 2H) 3.75 (t, J=6.3Hz, 2H) 4.16 (t, J=6.3Hz, 2H) 5.98 (s, 1H) 6.85 (d, J=9.0Hz, 2H) 6.89-6.96 (m, 2H) 7.22 (dd, J=8.3,4.6Hz, 1H) 7.32 (dd, J=8.3,1.7Hz, 1H) 7.62 (d, J=9.0Hz, 2H) 7.82 (dd,J=4.6,1.7Hz, 1H)
[1291] Example 205: (R) and
fS)-4-({[l-f3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-["5-ethvl-2-fluoro-3-(3-hvdroxypropoxv)phenvl]methvl)amino)benza midine acetate

4-({[l-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]-[5-ethyl-2-fluoro-3-(3-hydroxypropoxy)phenyl]methyl}amino)benzamidi ne acetate (Example (204b), 34 mg) was optically resolved using a

SUMICHIRAL OA-2500 column, and the first eluting enantiomer (15.6
mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 81.16 (t, J=7.1Hz, 3H) 1.95 (s, 3H) 2.01 (quint,
J=6.3Hz, 2H) 2.57 (q, J=7.1Hz, 2H) 3.75 (t, J=6.3Hz, 2H) 4.16 (t,
J=6.3Hz, 2H) 5.98 (s, 1H) 6.85 (d, J=9.0Hz, 2H) 6.89-6.96 (m, 2H) 7.22
(dd, J=8.3,4.6Hz, 1H) 7.32 (dd, J=8.3,1.7Hz, 1H) 7.62 (d, J=9.0Hz, 2H)
7.82 (br.s, 1H)
HPLC retention time: 6 min (Column name: SUMICHIRAL OA-2500, 30
mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution
rate: 15 ml/min)
[1293] Example 206j 3-f3-fQ» and
(S)-(4-Carbamimidovlphenvlamino)-[4-(3-hvdroxypropoxv)-3-methoxvp
henvl]methyl}-5-oxo-4J-dihvdro-[l,2,41triazol-l-vl)thiophene-2-carbox
vlic acid
(206a)
{2-{4-[3-(t-Butyldimethylsilanyloxy)propoxy]-3-methoxyphenyl}-2-[4-(
5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene
}carbamic acid methyl ester
[1294] [Chemical Formula 536]

The same procedure was carried out as in Example (18e), except that
3-bromopropoxy-t-butyldimethylsilane was used instead of iodoethane,
to give the title compound.
[1295] (206b) 3-(3-{(R) and
(S)-(4-Carbamimidoylphenylamino)-[4-(3-hydroxypropoxy)-3-methoxyp
henyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene-2-carbox
ylic acid
[1296] [Chemical Formula 537]


The same procedure was carried out as in Example (169b), except that
{2-{4-[3-(t-butyIdimethylsilanyloxy)propoxy]-3-methoxyphenyl}-2-[4-(5
-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}
carbamic acid methyl ester was used instead of
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsuIfanylethyIidene}carbamic acid methyl ester, to
give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 6 1.95-2.02 (m, 2H) 3.74 (t, J=6.4Hz, 2H) 3.84 (s,
3H) 4.10 (t, J=6.4Hz, 2H) 5.54 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.98 (d,
J=8.4Hz, 1H) 7.05-7.08 (m, 2H) 7.15 (d, J=1.6Hz, 1H) 7.42 (d, J=5.2Hz,
1H) 7.61 (d, J=8.8Hz, 2H)
HPLC retention time: 12 min (Column name: SUM1CHIRAL OA-2500,
30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 40 ml/min)
[1297] Example ; 207:
4-r(ri-(3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-
f3-(2-hvdroxvethoxv)-5-methoxvphenvl]methvl}amino)benzamidine
acetate

The same procedure was carried out as in Examples (200a) to (200c),
except that

{2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)p
henylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (4c)) was used instead of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenyIimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in Example (200a), to give the title compound. 'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.77 (s, 3H) 3.83 (t, J=4.9Hz, 2H) 4.12 (t, J=4.9Hz, 2H) 5.66 (s, 1H) 6.51 (s, 1H) 6.67 (m, 2H) 6.85 (d, J=9.1Hz, 2H) 7.23 (m, 1H) 7.34 (br.d, J=7.7Hz, 1H) 7.62 (d, J=9.1Hz, 2H) 7.83 (br.s, 1H)
[1299] Example 208j 4-UfR) and
('S)-[2-Fluoro-4-(2-hvdroxvethoxv)-5-methoxyphenyl]-(5-oxo-l-pvrimidi
n-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvl]amino}benzamidine
acetate
[1300] [Chemical Formula 539]

The same procedure was carried out as in Examples (3f) to (3h), except that
(2-{4-[2-(t-butyldimethyIsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy lidene)carbamic acid methyl ester (Example (178c)) was used instead of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4 ]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester in Example (3f), to give the first eluting enantiomer of the title compound as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.76-3.79 (m, 2H) 3.82 (s, 3H) 3.93-3.96 (m, 2H) 5.91 (s, 1H) 6.83 (d, J=11.6Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.12 (d, J=7.2Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H)

8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1301] Example 209:
4-(fn-(3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vn-
(5-fluoro-8-methoxychroman-6-yl)methvl]amino}benzamidine
trifluoroacetate

The same procedure was carried out as in Examples (200b) to (200c),
except that
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester
(Example (33d)) and 0.1% trifluoroacetic acid were used
instead of respectively the
(2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-
2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy
lidene)carbamic acid methyl ester in Example (200b) and 0.1% acetic
acid in Example (200c), to give the title compound.
'H-NMR (CD3OD) 5 1.98 (quint, J=6.8Hz, 2H) 2.76 (t, J=6.8Hz, 2H)
3.75 (s, 3H) 4.19 (t, J=6.8Hz, 2H) 5.94 (s, 1H) 6.85 (d, J=9.0Hz, 2H)
6.90 (d, J=5.9Hz, 1H) 7.23 (dd, J=7.6,4.9Hz, 1H) 7.33 (d, J=7.6Hz,lH)
7.63 (d, J=9.0Hz, 2H) 7.81 (d, J=4.9Hz, 1H)
[1303] Example 210:
6-(3-[(4-Carbamimidovlphenvlamino)-(2-fluoro-3.5-dimethoxvphenvl)m ethvl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vUpvridine-2-carboxvlic acid

trifluoroacetate
[1304] [Chemical Formula 541]

The same procedure was carried out as in Example (3e), except that
methyl iodide was used instead of l-fluoro-2-iodoethane, to give
[2-(2-Fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl
)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester.
The same procedure was carried out as in Examples (180a) to (180b),
except that
[2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl) phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester and 6-hydrazinopyridine-2-carboxyIic acid methyl ester hydrochloride (Example (174a)) were used instead of respectively {2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb amic acid methyl ester and 4-hydrazinothiazole-5-carboxylic acid methyl ester in Example (180a), to give the title compound as a yellow solid. 'H-NMR (CD3OD) 5 3.70 (s, 3H) 3.84 (s, 3H) 5.83 (s, 1H) 6.63 (br.s, 2H) 6.85 (d, J=8.5Hz, 2H) 7.63 (d, J=8.5Hz, 2H) 8.05-8.30 (m, 3H) Mass spectrum (ESI) m/z: 508 (M+H)+
[1305] Example 21Jj (R) and
(S)-2-{3-[(4-Carbamimidoylphenvlamino)-(8-methoxv-4H-benzo[1.3]dio
xin-6-vl)methvl]-5-oxo-4.5-dihvdro[1.2.41triazol-l-vl>benzoic acid
amide acetate
[1306] [Chemical Formula 542]


To 2 ml of a DMF solution containing 130 mg of
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl
ester (Example (2lb.)), 46 mg of 2-hydrazinobenzoic acid hydrochloride
and 0.200 ml of triethylamine were added. The resulting mixture was
stirred at 80°C for 8 hours under a nitrogen atmosphere, and then the
reaction mixture was concentrated. The residue was dissolved in 3 ml
of methanol and 0.3 ml of acetic acid, and 250 mg of sodium
cyanotrihydroborate was added thereto. The mixture was stirred at
room temperature overnight. To this reaction mixture, water was added
and extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
2-(3-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadia zol-3-yI)phenyIamino]methyl}-5-oxo-4,5-dihydro[l,2,4]triazol-l-yI)benz oic acid.
To 2 ml of a DMF solution of this compound, 500 mg of benzotriazol-1 -yloxytris(pyrrolidino)phosphinium hexafluorophosphate, 130 mg of 1 -hydroxybenzotriazole, 0.33 ml of N,N-diisopropylethylamine, and 50 mg of ammonium chloride were added. The mixture was stirred at room temperature for 3 hours, and water was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (methanol-ethyl acetate) to give
2-(3-{(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-[4-(5-methyl-[l,2,4]oxadia
zoI-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl)benz
oic acid amide.
Iron powder (200 mg) was added to 3 ml of a methanol:water:acetic acid
= 1:1:1 mixed solvent solution of this compound. The resulting mixture
was stirred at 60°C overnight under a nitrogen atmosphere. The
reaction mixture was filtered and purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
2-{3-[(4-carbamimidoylphenylamino)-(8-methoxy-4H-benzo[l,3]dioxin-
6-yl)methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl}benzoic acid amide
acetate (16 mg).
This compound (16 mg) was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (5.93 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.84 (s, 3H) 4.84-4.93 (m, 2H) 5.24 (s,
2H) 5.58 (s, 1H) 6.80 (d, J=2.0Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.03 (d,
J=2.0Hz, 1H) 7.46 (dt, J=2.0,7.8Hz, 1H) 7.51-7.59 (m, 2H) 7.63 (d,
J=8.8Hz, 2H) 7.65-7.68 (m, 1H)
HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500,
30 mm Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1307] Example 2J2j (R) and
(S)-4- (I" [3 -Ethvn vl -5 -f 2-h vdroxvethoxv)phenvl1 -(5 -oxo-1 -pvrimidin-2-y 1 -4.5-dihvdro-lH-ri.2.41triazol-3-vl)methyl]amino}benzamidine acetate


To 6 ml of a DMF solution containing 512 mg of
{2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (45b)), 1.3 g of potassium carbonate and 0.64 ml of
2-(2-bromoethoxy)tetrahydropyran were added. The resulting mixture
was stirred at room temperature overnight, and then water was added
thereto and extracted with ethyl acetate. The organic layer was washed
with water and dried over anhydrous magnesium sulfate. The
desiccating agent was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (heptane-ethyl acetate) to give
[2-{3-ethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene]carb
amic acid methyl ester (491 mg, isomer mixture) as a light yellow solid.
To 7 ml of a DMF solution containing 451 mg of this compound, 75 mg
of 2-hydrazinopyrimidine and 0.5 ml of triethylamine were added. The
resulting mixture was stirred at 85°C overnight under a nitrogen
atmosphere. The reaction mixture was concentrated, and the residue
was dissolved in 6 ml of methanol and 0.6 ml of acetic acid. After
adding 600 mg of sodium cyanotrihydroborate to this reaction mixture,
the resulting mixture was stirred at room temperature for 2 hours.
Water was added to the reaction mixture, and then the mixture was
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by NAM silica gel column chromatography
(methanol-ethyl acetate) to give
5-{{3-ethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-meth yl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihy dro-[l,2,4]triazol-3-one (236 mg) as a light yellow solid. Iron powder (136 mg) was added to 4 ml of a methanol:water:acetic acid = 1.5:1.5:1 mixed solvent solution containing this compound. The mixture was stirred at 60°C for 2 days under a nitrogen atmosphere.

The reaction mixture was filtered and then purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{[[3-ethynyl-5-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-
dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (26
mg).
This compound (26 mg) was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (10.15 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.48 (s, 1H) 3.82 (t, J=4.4Hz, 2H)
3.98-4.03 (m, 2H) 5.64 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.96-6.98 (m, 1H)
7.17 (t, J=2.0Hz, 1H) 7.25 (s, 1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d,
J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 20 min (Column name: SUMICHIRAL OA-2500,
30 mm(j) x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1309] Example 213: (R) and
(-S)-4-(rr8-Methoxv-4H-benzo["1.31dioxin-6-vl)-(5-oxo-l-pyridin-2-vl-4.5 -dihvdro-lH-n.2.4]triazol-3-yl)methvllamino}benzamidine acetate [1310] [Chemical Formula 544]

The same procedure was carried out as in Examples (21i) to (21k), except that 2-hydrazinopyridine dihydrochloride was used instead of 2-hydrazinopyrimidine in Example (21 i), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.81 (s, 3H) 4.84-4.93 (m, 2H) 5.22 (s, 2H) 5.61 (s, 1H) 6.81 (s, 1H) 6.86 (dd, J=2.0,8.8Hz, 2H) 7.04 (br.s, 1H)

7.27 (br.t, J=5.2Hz, 1H) 7.60 (dd, J=2.0,8.8Hz, 2H) 7.89 (t, J=8.0Hz, 1H) 8.08 (d, J=7.6Hz, 1H) 8.44 (br.d, J=4.8Hz, 1H)
HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mm [1311] Example 2J4: (R) and
(S)-2-{3-[(4-Carbamimidovlphenvlamino)-(9-methoxv-3.4-dihvdro-2H-b enzofblfl^ldioxepin^-vnmethvn-S-oxo^.S-dihvdron^^ltriazol-l-vl} benzoic acid amide acetate [1312] [Chemical Formula 545]

The same procedure was carried out as in Example (211), except that
{2-(9-methoxy-3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-[4-(5-met
hyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carb
amic acid methyl ester (Example (30c)) was used instead of
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl
ester (Example (21h)), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.91 (s, 3H) 2.11-2.19 (m, 2H) 3.83 (s, 3H) 4.14
(dd, J=6.0,11.2Hz, 4H) 5.56 (s, 1H) 6.79 (d, J=2.0Hz, 1H) 6.83-6.86 (m,
1H) 6.85-6.88 (m, 2H) 7.43-7.49 (m, 1H) 7.51-7.59 (m, 2H) 7.62 (d,
J=8.8Hz, 2H) 7.61-7.67 (m, 1H)
HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500,
30 mm Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)

[1313] Example 215: (R) and
(S)-3-{3-[(4-Carbamimidoylphenylamino)-(4-fluoro-7-methoxy-2.3-dihv
drobenzofuran-5-vnmethvll-5-oxo-4.5-dihvdro[1.2.41triazol-l-vl}thioph
ene-2-carboxylic acid
[1314] [Chemical Formula 546]

The same procedure was carried out as in Examples (168b) to (168d),
except that
[2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-
5-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester (Example
(161b)) was used instead of
[2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[l,4]d ioxin-6-yl)-l-methylsulfanylethylidene]carbamic acid methyl ester in Example (168b), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 3.25-3.35 (m, 2H) 3.78 (s, 3H) 4.66 (t, J=8.8Hz, 2H) 5.83 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.94 (d, J=6.4Hz, 1H) 7.07 (d, J=5.2Hz, 1H) 7.42 (d, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H) HPLC retention time: 13 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1315] Example 2J6] (R) and
fS)-4-{[[2-Fluoro-3-('2-hvdroxvethoxvmethvn-5-methoxvphenvl]-(5-oxo-
l-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvl]amino}benza
midine acetate
(216a) (3-Dimethoxymethyl-2-fluoro-5-methoxyphenyl)methanol
[1316] [Chemical Formula 547]


To 15 ml of a THF solution containing 3.665 g of 2-dimethoxymethyl-l-fluoro-4-methoxybenzene [CAS No. 883576-30-5] and 3.48 g of N,N,N',N',N"-pentamethyldiethylenetriamine, 7.1 ml of n-butyllithium (2.66 M, hexane solution) was added dropwise at -74°C. The resulting mixture was stirred at -60°C for 3 hours, and then 3 ml of N-formylmorpholine was added thereto. The temperature of the reaction mixture was slowly allowed to rise to room temperature. Then, water was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of 3-dimethoxymethyl-2-fluoro-5-methoxybenzaldehyde. Then, this compound was dissolved in 30 ml of THF and 30 ml of water, and 3 g of sodium tetrahydroborate was further added thereto. The resulting mixture was stirred at room temperature for 1 hour, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (3.889 g).
'H-NMR (CD3OD) 8 3.45 (s, 6H) 3.78 (s, 3H) 4.63 (s, 2H) 5.56 (s, 1H) 6.96 (dd, J=3.2,4.8Hz, 1H) 7.01 (dd, J=3.2,6.0Hz, 1H) [1317] (216b)
2-[2-(3-Dimethoxymethyl-2-fluoro-5-methoxybenzyloxy]ethoxy]tetrahyd ropyran [1318] [Chemical Formula 548]


(3-Dimethoxymethyl-2-fluoro-5-methoxyphenyl)methanol (1.861 g) was
dissolved in 10 ml of DMF, and 390 mg of sodium hydride, 300 mg of
tetrabutylammonium iodide, and 1.8 ml of
2-(2-bromoethoxy)tetrahydropyran were added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (1.035 g).
'H-NMR (CD3OD) 5 1.45-1.62 (m, 4H) 1.66-1.74 (m, 1H) 1.78-1.88 (m, 1H) 3.35 (s, 6H) 3.46-3.54 (m, 1H) 3.58-3.64 (m, 1H) 3.69 (t, J=4.8Hz, 2H) 3.78 (s, 3H) 3.83-3.90 (m, 2H) 4.59-4.62 (m, 2H) 4.64 (t, J=4.8Hz, 1H) 5.55 (s, 1H) 6.97-7.03 (m, 2H) [1319] (216c)
2-Fluoro-3-(2-hydroxyetboxymethyl)-5-methoxybenzaldehyde [1320] [Chemical Formula 549]

2-[2-(3-Dimethoxymethyl-2-fluoro-5-methoxybenzyloxy]ethoxy]tetrahyd ropyran (1.035 g) was dissolved in 10 ml of THF and 3 ml of water, and 1 g of p-toluenesulfonic acid was added thereto. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (305

nig).
'H-NMR (CDCb) 5 3.67 (t, J=4.4Hz, 2H) 3.80 (t, J=4.4Hz, 2H) 3.83 (s,
3H) 4.65 (s, 2H) 7.23-7.25 (m, 2H) 10.33. (s, 1H)
[1321] (216d)
2-Fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxymethyl)benzaldeh
yde

2-Fluoro-3-(2-hydroxyethoxymethyl)-5-methoxybenzaldehyde (305 mg) was dissolved in 3 ml of DMF, and 300 mg of imidazole and 283 mg of chlorotriisopropylsilane were added thereto. The resulting mixture was stirred at 50°C for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of the title compound (533 mg). [1323] (216e)
{2-(4-Cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxymethyl)-5-met hoxyphenyl]-l-methylsulfanylethylidene}carbamic acid methyl ester [1324] [Chemical Formula 551]

The same procedure was carried out as in Examples (163a) to (163b),
except that
2-fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxymethyl)benzaldehy
de was used instead of
2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde in Example (163a), to give the title compound. [1325] (216f)

4-{[[2-Fluoro-3-(2-hydroxyethoxymethyl)-5-methoxyphenyl]-(5-oxo-l-p
yrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yI)methyl]amino}benzonit
rile
[1326] [Chemical Formula 552]

The same procedure was carried out as in Example (3f), except that
{2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxymethyl)-5-met
hoxyphenyl]-l-methylsulfanylethylidene}carbamic acid methyl ester was
used instead of
{2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester, to give the title compound.
[1327] (216g)
4-{[[2-FIuoro-3-(2-hydroxyethoxymethyI)-5-methoxyphenyI]-(5-oxo-l-p
yrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzami
dine acetate
[1328] [Chemical Formula 553]

The same procedure was carried out as in Example (181d), except that
4-{[[2-fluoro-3-(2-hydroxyethoxymethyl)-5-methoxyphenyl]-(5-oxo-l-py
rimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzonitri
le was used instead of
4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi

n-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyI}amino)benzonitrile, to
give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) S 1.92 (s,3H) 3.60 (t, J=4.8Hz, 2H) 3.70 (t, J=4.8Hz,
2H) 3.74 (s, 3H) 4.62-4.64 (m, 2H) 5.94 (s, 1H) 6.85 (d, J=8.8Hz, 2H)
7.03 (d, J=5.6Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76
(d, J=4.8Hz, 2H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30
mmiji x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 20 ml/min)
[1329] Example 2VL (R) and
(SV4-(r[2-Fluoro-3-(rSV2-hvdroxv-l-methvlethoxvV5-methoxvphenvl1-r5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH-[1.2.41triazol-3-vnmethvl]amin olbenzamidine acetate [1330] (217a)
{2-{3-[(S)-2-(t-Butyldimethylsilanyloxy)-l-methylethoxy]-2-fluoro-5-me thoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-meth ylsulfanylethylidene}carbamic acid methyl ester [1331] [Chemical Formula 554]

[2-(2-Fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl
ester (Example (3d), 275 mg),
(R)-l-(t-butyldimethylsilanyloxy)propan-2-ol [CAS No. 136918-07-5]
(171 mg), and triphenylphosphine (236 mg) were dissolved in 3 ml of
THF under a nitrogen atmosphere, and the resulting mixture was cooled
to -78°C. After the addition of 0.177 ml of
N,N'-diisopropylazodicarboxylate, the mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column

chromatography (heptane-ethyl acetate) to give the title compound (343
mg)-
[1332] (217b)
4-{[[2-Fluoro-3-((S)-2-hydroxy-l-methylethoxy)-5-methoxyphenyl]-(5-o
xo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}be
nzamidine acetate
[1333] [Chemical Formula 555]

The same procedure was carried out as in Examples (3e) to (3h), except
that
{2-{3-[(S)-2-(t-butyldimethylsilanyloxy)-l-methylethoxy]-2-fluoro-5-me
thoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-meth
ylsulfanylethylidene}carbamic acid methyl ester was used instead of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l -methylsulfanylethylidene]carbamic acid methyl
ester in Example (3e), to give the first eluting enantiomer of the title
compound.
'H-NMR (CD3OD) 5 1.26 (d, J=6.0Hz, 3H) 1.91 (s, 3H) 3.60-3.69 (m,
2H) 3.66 (s, 3H) 4.41-4.48 (m, 1H) 5.96 (s, 1H) 6.61-6.66 (m, 2H) 6.83
(d, J=8.8Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.73 (d,
J=4.8Hz, 2H)
HPLC retention time: 14 min (Column name: SUM1CHIRAL OA-2500,
30 mmij) x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1334] Example 218; (R) and
(S)-2-Fluoro-4-([[2-fluoro-3-(2-hvdroxvethoxv)-5-methoxvphenvl]-(5-ox o-l-pvrimidin-2-vl-4.5-dihydro-lH-[l,2.4]triazol-3-vnmethvl]amino>ben

zamidine acetate
(218a)
[2-(4-Cyano-3-fluorophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphe
nyl)- 1-methylsulfanylethylidene] carbarn ic acid methyl ester
[1335] [Chemical Formula 556]

2-Fluoro-4-aminobenzonitrile [CAS No. 53312-80-4] (1.02 g), MS3A (7
g), and Yb(OTf>3 (465 mg) were added to 30 ml of a THF solution
containing 2.45 g of
2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde (Example
(3b)) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours, and then 1.1 ml of trimethylsilyl cyanide was added thereto. The mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 4-{[cyano-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)methyl]a mino}-2-fluorobenzonitrile (2.05 g) as a yellow oil. To 30 ml of a methanohTHF = 2:1 mixed solvent solution containing this compound, 30 ml of a 20% ammonium sulfide aqueous solution was added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 2-(4-cyano-3-fluorophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsi lanyloxyphenyl)thioacetamide (1.55 g) as a white solid. Me30+BF4" (498 mg) was added to 15 ml of an acetonitrile solution of

this compound. The resulting mixture was stirred at room temperature for 40 minutes under a nitrogen atmosphere, and then a saturated sodium hydrogen carbonate aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure.
To 15 ml of an ethyl acetate solution containing the residue, 3 g of
manganese dioxide was added, and the resulting mixture was stirred at
room temperature for 30 minutes. The reaction mixture was filtered,
and the filtrate was concentrated under reduced pressure.
To 10 ml of a toluene solution of the residue, 1.4 ml of 2,4,6-collidine
and 0.7 ml of methyl chloroformate were added. The resulting mixture
was stirred at 80°C for 4 hours under a nitrogen atmosphere. The
reaction mixture was filtered, and IN hydrochloric acid was added to the
filtrate. The mixture was extracted with ethyl acetate. The organic
layer was washed with water and saturated brine and dried over
anhydrous magnesium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
[2-[4-cyano-3-fluorophenylimino]-2-(2-fluoro-5-methoxy-3-triisopropyls ilanyloxyphenyl)-l-methylsulfanylethylidene]carbamic acid methyl ester (824 mg) as a yellow oil.
To 15 ml of a THF solution of this compound, 1.5 ml of TBAF (1.0 M, THF solution) was added. The resulting mixture was stirred at room temperature for 1 hour, and a saturated ammonium chloride aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (466

mg) as a yellow solid.
Mass spectrum (ESI) m/z: 420 (M+H)+
[1336] (218b) (R) and
(S)-2-Fluoro-4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-ox
o-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}ben
zamidine acetate
[1337] [Chemical Formula 557]

To 2 ml of a DMF solution containing 200 mg of
[2-(4-cyano-3-fluorophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphen
yl)-l-methylsulfanylethylidene]carbamic acid methyl ester, 300 mg of
potassium carbonate and 0.2 ml of
2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting
mixture was stirred at room temperature for 18 hours, and then water was
added thereto. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and then with saturated brine and
dried over anhydrous sodium sulfate. The desiccating agent was
removed by filtration, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
(2-(4-cyano-3-fluorophenylimino)-2-{2-fluoro-5-methoxy-3-[2-(tetrahydr opyran-2-yloxy)ethoxy]phenyl}-l-methylsulfanylethylidene)carbamic acid methyl ester (150 mg) as a yellow oil.
To 1.5 ml of a DMF solution of this compound, 30 mg of 2-hydrazinopyrimidine and 0.038 ml of triethylamine were added. The resulting mixture was stirred at 70°C for 23 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 1.5 ml of THF, 1.5 ml of methanol, and 0.1 ml of acetic acid,

and 200 mg of sodium cyanotrihydroborate was added to this mixture.
The mixture was stirred at room temperature for 4 hours. The reaction
mixture was concentrated, and the residue was crudely purified by NAM
silica gel column chromatography (methanol-ethyl acetate) to give a
crude product of
2-fluoro-4-{[{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]
phenyl} -(5-oxo-1 -pyrim idin-2-y 1-4,5 -dihydro-1 H-[ 1,2,4]triazol-3 -yl)met
hyl]amino}benzonitrile.
To 1.9 ml of pyridine solution of this crude product, 0.306 ml of
triethylamine and 1.9 ml of a 20% ammonium sulfide aqueous solution
were added. The resulting mixture was stirred at 50°C for 2 hours
under a nitrogen atmosphere and then purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
2-fluoro-4-{[{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]
phenyl}-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)met
hyl]amino}thiobenzamide (44 mg) as a light yellow solid.
To 1.5 ml of an acetonitrile solution of this compound, 12 mg of
Me30+BF4~ was added. The resulting mixture was stirred at room
temperature for 3 hours under a nitrogen atmosphere, and then 1 ml of
acetonitrile, 1 ml of isopropanol, and 0.04 ml of
1,1,3,3-tetramethyldisilazane were added thereto. The mixture was
stirred at 70°C for 2 hours under a nitrogen atmosphere and then
concentrated. To the residue, 1.5 ml of a methanol:water:acetic acid =
1:1:1 mixed solvent was added. The mixture was stirred at 60°C for 3
hours and purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give
2-fluoro-4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-
pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzam
idine acetate.
Mass spectrum (ESI) m/z: 513 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (6.79 mg) of the title compound

was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.71 (s, 3H) 3.88 (t, J=4.8Hz, 2H) 4.09
(t, J=4.8Hz, 2H) 5.91 (s, 1H) 6.50-6.74 (m, 4H) 7.29 (t, J=4.8Hz, 1H)
7.46 (t, J=8.4Hz, 1H) 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500,
30 mm(|> x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1338] Example 219: (R) and
(S)-44rf5-Ethoxy-2-fluoro-3-(2-hvdroxvethoxv)phenvl]-(5-oxo-l-pyrimi
din-2-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvl]amino}benzamidine
acetate
(219a)
{2-(5-Ethoxy-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazo
l-3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid methyl
ester
[1339] [Chemical Formula 558]

To 150 ml of a THF solution containing 10.5 g of l-ethoxy-4-fluorobenzene, 50 ml of n-butyllithium (1.58 M, hexane solution) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred for 4 and a half hours, then 8.9 ml of trimethoxy boron was added thereto. Then, the temperature of the mixture was slowly allowed to rise to room temperature. The reaction mixture was stirred for 3 and a half hours, then 12.9 ml of acetic acid and 12.7 ml of a 30% hydrogen peroxide aqueous solution were added thereto at 0°C. The mixture was stirred at room temperature overnight, and then a saturated sodium sulfite aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium

sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a crude product of 5-ethoxy-2-fluorophenol. To 100 ml of a DMF solution of this crude product, 3.06 g of imidazole and 6.4 ml of chlorotriisopropylsilane were added. The resulting mixture was stirred at room temperature overnight, and water was added thereto. The mixture was extracted with diethyl ether. The organic layer was washed with 1 N hydrochloric acid cooled with ice, water, a saturated sodium hydrogen carbonate aqueous solution, water, and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give (5-ethoxy-2-fluorophenoxy)triisopropylsilane (4.06 g) as a colorless oil.
To 50 ml of a THF solution containing this compound and 2.85 ml of
N,N,N',N',N"-pentamethyldiethylene triamine, 8.6 ml of n-butyllithium
(1.58 M, hexane solution) was added dropwise at -78°C under a nitrogen
atmosphere. The resulting mixture was stirred for 7 hours at a
temperature range of -60 to -65°C, and then 1.7 ml of
N-formylmorpholine was added thereto. The temperature of the mixture
was allowed to rise to room temperature. The reaction mixture was
stirred overnight, and saturated ammonium chloride aqueous solution
was added thereto. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine and dried over
anhydrous magnesium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
5-ethoxy-2-fluoro-3-triisopropylsilanyloxybenzaldehyde (4.04 g) as a light yellow oil. To 100 ml of a dichlorom ethane solution of this compound, 2.01 g of

4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamine, 10 g of MS3A, 738 mg
of Yb(OTf)3, and 3.0 ml of trimethylsilyl cyanide were added under a
nitrogen atmosphere. The resulting mixture was stirred at room
temperature for 3 days and then filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
(5-ethoxy-2-fluoro-3-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[l,2,4]o xadiazol-3-yl)phenylamino]acetonitrile (1.68 g) was a yellow oil. To 60 ml of a methanohTHF = 2:1 mixed solvent solution containing this compound, 20 ml of a 20% ammonium sulfide aqueous solution was added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted from ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure.
To 5 ml of a DMF solution of the residue, 327 mg of imidazole and 0.51
ml of chlorotriisopropylsilane were added. The resulting mixture was
stirred at room temperature for 7 and a half hours, and then water was
added thereto. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine and then dried
over anhydrous sodium sulfate. The desiccating agent was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate-heptane) to give
2-(5-ethoxy-2-fluoro-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l, 2,4]oxadiazol-3-yl)phenylamino]thioacetamide (1.49 g) as a light yellow oil.
To 20 ml of a dichloromethane solution of this compound, 454 mg of MeaCTBFV was added. The resulting mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate

aqueous solution, water, and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. To 20 ml of a dichloromethane solution of the residue, 5 g of manganese dioxide was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
To 10 ml of a toluene solution of the residue, 1.28 ml of 2,4,6-collidine
and 0.64 ml of methyl chloroformate were added. The resulting mixture
was stirred at 80°C overnight under a nitrogen atmosphere. The
reaction mixture was filtered, and water was added to the filtrate. The
mixture was extracted with ethyl acetate. The organic layer was washed
with 1 N hydrochloric acid cooled with ice, water, a saturated sodium
hydrogen carbonate aqueous solution, water, and saturated brine in this
order, and then dried over anhydrous sodium sulfate. The desiccating
agent was removed by filtration, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
2-(5-ethoxy-2-fluoro-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[l, 2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester (1.45 g) as a yellow oil.
To 20 ml of a THF solution of this compound, 2.42 ml of TBAF (1.0 M, THF solution) was added. The resulting mixture was stirred at 0°C for 3 hours, and then a saturated ammonium chloride aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (866 mg) as a yellow solid. 'H-NMR (CDC13) Two main isomers:
5 1.31 (t, J=7.2Hz, 3H) 2.47 (s, 3H) 2.62 (s, 3H) 3.62 (s, 3H) 3.84 (q, J=7.2Hz, 2H) 5.17 (br.d, J=3.6Hz, 1H) 6.19 (dd, J=2.8, 4.8Hz, 1H) 6.53

(dd, J=2.8, 6.8Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.90 (d, J=8.8Hz, 2H)
5 1.40 (t, J=6.8Hz, 3H) 2.33 (s, 3H) 2.66 (s, 3H) 3.60 (s, 3H) 4.02 (q,
J=6.8Hz, 2H) 5.30 (br.d, J=4.8Hz, 1H) 6.73 (dd, J=3.2, 6.8Hz, 1H) 6.92
(dd, J=3.2, 5.2Hz, 1H) 7.12 (d, J=8.8Hz, 2H) 8.03 (d, J=8.8Hz, 2H)
[1340] (219b) (R) and
(S)-4-{[[5-Ethoxy-2-fluoro-3-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimi
din-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine
acetate
[1341] [Chemical Formula 559]

To 2 ml of a DMF solution containing 75 mg of {2-(5-ethoxy-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, 100 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature for 10 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{5-ethoxy-2-fluoro-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[ 4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylid ene}carbamic acid methyl ester (51 mg) as a yellow oil. To 1 ml of a DMF solution of this compound, 9.3 mg of 2-hydrazinopyrimidine and 0.012 ml of triethylamine were added. The resulting mixture was stirred at 85°C for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of methanol and 0.05 ml of acetic acid. To this

mixture, 100 mg of sodium cyanotrihydroborate was added. The
mixture was stirred at room temperature overnight and crudely purified
by reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give a crude product of
5-{{5-ethoxy-2-fluoro-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-
(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-
2,4-dihydro-[l,2,4]triazol-3-one.
Iron powder (100 mg) was added to 3 ml of a methanol :water:acetic acid
= 1:1:1 mixed solvent solution containing this crude product. The
mixture was stirred at 60°C overnight under a nitrogen atmosphere.
The reaction mixture was filtered and then purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
4-{[[5-ethoxy-2-fluoro-3-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimidin-
2-yl-4,5-dihydro-1 H-[ 1,2,4]triazol-3 -yl)methyl]amino} benzamidine
acetate.
Mass spectrum (ESI) m/z: 509 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (1.73 mg) of the title compound
was obtained as a white solid.
'H-NMR (CD3OD) 8 1.30 (t, J=6.8Hz, 3H) 1.91 (s, 3H) 3.87 (t, J=4.8Hz,
2H) 3.93 (q, J=6.8Hz, 2H) 4.08 (t, J=4.8Hz, 2H) 5.92 (s, 1H) 6.56-6.68
(m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz,
2H) 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30
mm(|) x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd.,
Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution
rate: 40 ml/min)
[1342] Example 220; (R) and
(S)-4-{[[3-Ethoxv-5-(2-hydroxyethoxy)phenvl1-(5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH-[l,2.4]triazol-3-vl)methvl]amino}benzamidine acetate [1343] [Chemical Formula 560]


To 1 ml of a DMF solution containing 80 mg of
{2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (78a)), 200 mg of potassium carbonate and 0.1 ml of
2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting
mixture was stirred at room temperature overnight, and then water was
added thereto. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine and then
concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give
{2-{3-ethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-met hyl-[l,2,4]oxadiazoI-3-yl)phenyIimino]-l-methylsulfanyIethyIidene}carb amic acid methyl ester (76 mg) as a yellow oil.
To 1 ml of a DMF solution of this compound, 14 mg of
2-hydrazinopyrimidine and 0.018 ml of triethylamine were added. The
resulting mixture was stirred at 85°C for 28 hours under a nitrogen
atmosphere, and the mixture was then concentrated. The residue was
dissolved in 1 ml of methanol, 1 ml of THF, and 0.1 ml of acetic acid.
Then, 100 mg of sodium cyanotrihydroborate was further added to the
mixture. The resulting mixture was stirred at room temperature for 3
hours and then crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude
product of
5-{{3-ethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-methy l-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihyd ro-[ 1,2,4]triazol-3-one. Iron powder (100 mg) was added to 3 ml of a methanol:water:acetic acid

= 1:1:1 mixed solvent solution containing this crude product. The
resulting mixture was stirred at 60°C for 2 days under a nitrogen
atmosphere. The reaction mixture was filtered and purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[[3-ethoxy-5-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate. 'H-NMR (CD3OD) 8 1.34 (t, J=6.8Hz, 3H) 1.94 (s, 3H) 3.82 (t, J=4.4Hz, 2H) 3.92-4.07 (m, 4H) 5.62 (s, 1H) 6.46 (t, J=2.0Hz, 1H) 6.71 (br.s, 1H) 6.73 (br.s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.35 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H) Mass spectrum (ESI) m/z: 491 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (3.17 mg) of the title compound was obtained as a white solid.
:H-NMR (CD3OD) 8 1.33 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 3.82 (t, J=4.8Hz, 2H) 3.92-4.06 (m, 4H) 5.55 (s, 1H) 6.43 (t, J=1.6Hz, 1H) 6.72 (t, J=1.6Hz, 1H) 6.74 (t, J=1.6Hz, 1H) 6.85 (d, J=9.2Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30 mmij) x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1344] Example 22JJ (R) and
(S)-4-{[(3-Ethoxv-5-hvdroxvphenvlV(5-oxo-l-pvrimidin-2-vl-4.5-dihvdr o-lH-fl.2.4]triazol-3-yDmethyl1amino}benzamidine acetate [1345] [Chemical Formula 561]


To 1 ml of a DMF solution containing 45 mg of
{2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (78a)), 11 mg of 2-hydrazinopyrimidine and 0.014 ml of
triethylamine were added. The resulting mixture was stirred at 85°C for
one day under a nitrogen atmosphere and then concentrated. The
residue was dissolved in 1 ml of methanol, 1 ml of THF, and 0.1 ml of
acetic acid, and 100 mg of sodium cyanotrihydroborate was further added
thereto. The mixture was stirred at room temperature for 3 hours. The
reaction mixture was crudely purified by reverse-phase high performance
liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a
crude product of
5-{(3-ethoxy-5-hydroxyphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phen
ylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[l,2,4]triazol-3-one.
Iron powder (100 mg) was added to 3 ml of a methanol:water:acetic acid
= 1:1:1 mixed solvent solution containing this crude compound. The
resulting mixture was stirred at 60°C for 2 days under a nitrogen
atmosphere. The reaction mixture was filtered and purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% acetic acid) to give
4-{[(3-ethoxy-5-hydroxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-l H-[l ,2,4]triazol-3-yl)methyl]amino}benzamidine acetate. Mass spectrum (ESI) m/z: 447 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500 column, and the first eluting enantiomer (5.06 mg) of the title compound was obtained as a white solid.
!H-NMR (CD3OD) 8 1.33 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 3.96 (q, J=7.2Hz, 2H) 5.52 (s, 1H) 6.29 (t, J=1.6Hz, 1H) 6.56 (t, J=1.6Hz, 1H) 6.60 (t, J=1.6Hz, 1H) 6.85 (d, J=9.2Hz, 2H) 7.29 (br.t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30 mmiji x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution

rate: 40 ml/min)
[1346] Example 222: (R) and
(S)-3-{3-f(4-Carbamimidoylphenvlammo)-(5-fluoro-8-methoxychroman-6-yl)methyl]-5-oxo-4.5-dihydro[1.2.4]triazol-l-yl}thiophene-2-carboxyli c acid

To 1 ml of a DMF solution containing 100 mg of
[2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester
(Example (33d)), 35 mg of 3-hydrazinothiophene-2-carboxylic acid
methyl ester and 0.028 ml of triethylamine were added. The resulting
mixture was stirred at 85°C for 12 hours under a nitrogen atmosphere and
then concentrated. The residue was dissolved in 1.5 ml of methanol, 1.5
ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium
cyanotrihydroborate was further added thereto. The mixture was stirred
at room temperature for 3 hours, and 1 ml of a 5 N sodium hydroxide
aqueous solution was added thereto. The mixture was stirred at room
temperature overnight. Acetic acid (0.3 ml) was added to the reaction
mixture, and the resulting mixture was crudely purified by reverse-phase
high performance liquid chromatography (acetonitrile-water, 0.1% acetic
acid) to give a crude product of
3-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yI)thiophe ne-2-carboxylic acid.
Iron powder (100 mg) was added to 3 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent solution containing this crude product. The resulting mixture was stirred at 60°C overnight under a nitrogen

atmosphere. The reaction mixture was filtered and purified by
reverse-phase high performance liquid chromatography
(acetonitrile-water, 0.1% trifluoroacetic acid) to give
3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl)
methyl]-5-oxo-4,5-dihydro[l,2,4]triazol-l-yl)thiophene-2-carboxylic
acid trifluoroacetate.
'H-NMR (CD3OD) 8 1.85-2.05 (m, 2H) 2.60-2.85 (m,2H) 3.73 (s, 3H)
4.05-4.25 (m, 2H) 5.89 (s, 1H) 6.78-6.90 (m, 3H) 7.17 (d, J=5.2Hz, 1H)
7.61 (d, J=8.8Hz, 2H) 7.71 (d, J=5.2Hz, 1H)
Mass spectrum (ESI) m/z: 539 (M+H)+
This compound was optically resolved using a SUMICHIRAL OA-2500
column, and the first eluting enantiomer (19.16 mg) of the title
compound was obtained as a white solid.
HPLC retention time: 19 min (Column name: SUMICHIRAL OA-2500,
30 mm Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1348] Example 223j (R) and
(S)-4-{[[4-r2-Fluoroethvn-8-methoxv-3-oxo-3.4-dihvdro-2H-benzo[1.41o
xazin-6-yl]-f5-oxo-l-pvrimidin-2-vl-4,5-dihydro-lH-ri.2.41triazol-3-yl)
methyl"|amino}benzamidine acetate
(223a)
4-(2-Fluoroethyl)-8-methoxy-3 -oxo-3,4-dihydro-2H-benzo[l,4]oxazine-6
-carboaldehyde
[1349] [Chemical Formula 563]

To 3 ml of a DMF solution containing 233 mg of 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine-6-carboaldehyde [CAS No. 711021-34-0], 312 mg of potassium carbonate and 236 mg of 1 -fluoro-2-iodoethane were added. The resulting mixture was stirred at

room temperature for one day, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give
4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[ 1,4]oxazine-6-carboaldehyde (151 mg) as a white solid. [1350] (223b)
[4-(2-Fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6 -yl]-[4-(5-methyl[l,2,4]oxadiazol-3-yl)phenylamino]acetonitrile [1351] [Chemical Formula 564]

The same procedure was carried out as in Example (la), except that
4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine-6-
carboaldehyde was used instead of 2-fluoro-4,5-dimethoxybenzaldehyde,
to give the title compound.
'H-NMR (CDC13) S 2.64 (s, 3H) 3.94 (s, 3H) 4.17-4.30 (m,2H) 4.72
(s,2H) 4.72 (dt, J=47.6,4.8Hz, 2H) 5.46 (br.d, J=7.2Hz, 1H) 6.84 (d,
J=8.8Hz, 2H) 6.92 (d, J=2.0Hz, 1H) 7.03 (d, J=2.0Hz, 1H) 7.99 (d,
J=8.8Hz, 2H)
[1352] (223c) (R) and
(S)-4-{[[4-(2-Fluoroethyl)~8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]o
xazin-6-yl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l,2,4]triazol-3-yl)
methyl]amino}benzamidine acetate
[1353] [Chemical Formula 565]


The same procedure was carried out as in Examples (10c) to (lOe),
except that
[4-(2-fluoroethyI)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-
yl]-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylamino]acetonitrile was
used instead of
(3-methoxy-5-methoxymethylphenyl)-[4-(5-methyl-[l,2,4]oxadiazol-3-yl )phenylamino]acetonitrile in Example (10c), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.78 (s, 3H) 4.08-4.32 (m,2H) 4.40-4.65 (m,4H) 5.67 (s, 1H) 6.88 (d, J=9.2Hz, 2H) 7.01 (d, J=1.6Hz, 1H) 7.04 (d, J=1.6Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.78 (d, J=4.8Hz, 2H) HPLC retention time: 18 min
[1354] Example 224:
4-(rf2-Fluoro-3-hydroxy-5-methoxvphenvO-(5-oxo-l-pyrimidin-2-yl-4.5 -dihydro-lH-[1.2.4]triazol-3-vl)methynaminolbenzamidine acetate [1355] [Chemical Formula 566]

The same procedure was carried out as in Example (lOd), except that
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl
ester (Example (3d)) was used instead of

{2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol -3-yl)phenylimino]-l -methylsulfanylethylidene}carbamic acid methyl ester, to give the title compound.
'H-NMR (CD3OD) 8 1.94 (s, 3H) 3.68 (s, 3H) 5.95 (s, 1H) 6.40-6.58 (m,2H) 6.87 (d, J=8.8Hz, 2H) 7.34 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
[1356] Example 225: (R) and
rS^^-dfS.S-Dimethoxvphenvn-fl-fS-methvlpvridin^-vn-S-oxo^.S-dih vdro-lH-[1.2.4]triazol-3-vl]methvUamino')benzamidine acetate (225a)
{2-(3,5-Dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazoI-3-yl)phenyIi mino]-l-methylsulfanylethylidene}carbamic acid methyl ester [1357] [Chemical Formula 567]

The same procedure was carried out as in Examples (2Id) to (21h),
except that 3,5-dimethoxybenzaldehyde was used instead of
8-methoxy-4H-benzo[l,3]dioxine-6-carboaldehyde in Example (21 d), to
give the first eluting enantiomer of the title compound.
[1358] (225b) (R) and
(S)-4-({(3,5-Dimethoxyphenyl)-[l-(3-methylpyridin-2-yl)-5-oxo-4,5-dih ydro-lH-[l,2,4]triazol-3-yl]methyl}amino)benzamidine acetate [1359] [Chemical Formula 568]

The same procedure was carried out as in Examples (lOd) to (lOe),
except that

{2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli
mino]-l-methylsulfanylethylidene}carbamic acid methyl ester and
(6-methylpyridin-2-yI)hydrazine [CAS No. 5315-24-2] were used instead
of respectively
{2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methy]-[l,2,4]oxadiazol -3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester and 2-hydrazinopyrimidine in Example (lOd), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.90 (s, 3H) 2.26 (s,3H) 3.76 (s, 6H) 5.57 (s, 1H) 6.42 (t, J=2.4Hz, 1H) 6.71 (d, J=2.4Hz, 2H) 6.85 (d, J=8.8Hz, 2H) 7.40 (dd, J=4.8,7.6Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 7.84 (dd, J=1.2,7.6Hz, 1H) 8.35 (dd, J=1.2,4.8Hz, 1H)
HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1360] Example 226j 3-13-rfR) and
(S)-(4-Carbamimidovlphenylamino>-('8-methoxv-4H-benzon.31dioxin-6-yl)methyl]-5-oxo-4.5-dihydro-[1.2,4]triazol-1-yl}thiophene-2-carboxylic acid

The same procedure was carried out as in Example (155), except that
(2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz
ol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl
ester (Example (21h)) was used instead of
{2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to give

the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 3.84 (s, 3H) 4.83-4.93 (m, 2H) 5.24 (s, 2H) 5.54 (s, 1H) 6.80 (d, J=1.6Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.04 (d, J=1.6Hz, 1H) 7.08 (d, J=5.2Hz, 1H) 7.44 (d, J=5.2Hz, 1H) 7.61 (d, J=8.8Hz, 2H) HPLC retention time: 15 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1362] Example 227j 3-(3-r(R1 and
(S)-(4-Carbamimidoylphenylamino)-(3.4.5-trimethoxyphenyl)methvl]-5-oxo-4.5-dihydro-[1.2.4]triazol-l-vl}thiophene-2-carboxylic acid (227a)
[2-[4-(5-Methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanyl-2-(3,4,5-trimethoxyphenyI)ethylidene]carbamic acid methyl ester [1363] [Chemical Formula 570]

The same procedure was carried out as in Examples (la) to (Id), except that 3,4,5-trimethoxybenzaldehyde was used instead of 2-fluoro-4,5-dimethoxybenzaldehyde in Example (la), to give the title compound.
[1364] (227b) 3-{3-[(R) and
(S)-(4-Carbamimidoylphenylamino)-(3,4,5-trimethoxyphenyl)methyl]-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl}thiophene-2-carboxylic acid [1365] [Chemical Formula 571]


[1366] The same procedure was carried out as in Example (155), except that
[2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanyl-2-(
3,4,5-trimethoxyphenyl)ethylidene]carbamic acid methyl ester was used
instead of
{2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli mino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to give the first eluting enantiomer of the title compound. Mass spectrum (ESI) m/z: 525 (M+H)+ (data for racemic mixture) HPLC retention time: 17 min (Column name: SUMICHIRAL OA-2500, 30 mmiji x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1367] Example 228: (R) and
(S)-3-(3-((4-Carbamimidovlphenvlamino)-[2-fluoro-3-(2-hvdroxvethoxv
)-5-methoxvphenvl1methvU-5-oxo-4.5-dihydro[1.2.4]triazol-l-vl)thiophe
ne-2-carboxvlic acid
[1368] [Chemical Formula 572]

The same procedure was carried out as in Example 167, except that 3-hydrazinothiophene-2-carboxylic acid methyl ester was used instead of 4-hydrazinothiazole-5-carboxylic acid methyl ester, to give the first

eluting enantiomer of the title compound.
Mass spectrum (ESI) m/z: 543 (M+H)+ (data for racemic mixture) HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1369] Example 229j (R) and
(S)-4-{[[2-Fluoro-3-f3-hvdroxypropoxy)-5-methoxyphenyl]-f5-oxo-l-pyr
imidin-2-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-vOmethvl]amino}benzamidi
ne acetate
[1370] [Chemical Formula 573]

The same procedure was carried out as in Examples (153a) to (153b), except that (3-bromopropoxy)-t-butyldimethylsilane was used instead of 2-(2-bromoethoxy)tetrahydro-2H-pyran in Example (153a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.86-2.10 (m, 5H) 3.69 (s, 3H) 3.73 (t, J=6.0Hz, 2H) 4.02-4.18 (m, 2H) 5.96 (br.s, 1H) 6.50-6.70 (m, 2H) 6.84 (d, J=8.4Hz, 2H) 7.31 (br.s, 1H) 7.60 (d, J=8.4Hz, 2H) 8.76 (br.s, 2H) HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1371] Example 230; (R) and
(S)-3-f3-{(4-Carbamimidovlphenvlamino)-[3-(2-hvdroxvethoxy)-4,5-dim
ethoxvphenvl]methvl}-5-oxo-4.5-dihydro-ri.2.4]triazol-l-vOthiophene-2
-carboxvlic acid
[1372] [Chemical Formula 574]


The same procedure was carried out as in Example 167, except that
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (159a)) and 3-hydrazinothiophene-2-carboxylic acid methyl
ester were used instead of respectively the
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester and 4-hydrazinothiazole-5-carboxylic acid methyl ester, to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 3.78 (s, 3H) 3.82-3.90 (m, 5H) 4.03-4.15 (m, 2H) 5.56 (s, 1H) 6.82-6.92 (m, 4H) 7.08 (d, J=5.6Hz, 1H) 7.43 (d, J=5.6Hz, 1H) 7.60 (d, J=9.2Hz, 2H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1373] Example 23Jj (R) and
(S)-3-(3-[(4-Carbamimidovl-3-fluorophenylamino)-(5-fluoro-8-methoxv-2.3-dihvdrobenzo[1.41dioxin-6-vnmethvl1-5-oxo-4.5-dihvdro-[1.2,4]triaz ol-l-vl}thiophene-2-carboxylic acid [1374] [Chemical Formula 575]


The same procedure was carried out as in Examples (168a) to (168d), except that 2-fluoro-4-aminobenzonitrile [CAS No. 53312-80-4] was used instead of 4-aminobenzonitrile in Example (168a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 8 3.76 (s, 3H) 4.29 (s, 4H) 5.86 (s, 1H) 6.57 (dd, J=14.0,2.4Hz, 1H) 6.65 (d, J=6.4Hz, 1H) 6.67 (dd, J=8.8, 2.4Hz, 1H) 7.09 (d, J=^5.2Hz, 1H) 7.42 (d, J=5.2Hz, 1H) 7.47 (t, J=8.8Hz, 1H) HPLC retention time: 19 min (Column name: SUMICHIRAL OA-2500, 30 mm(|> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1375] Example 232: (R) and
(S)-4-{3-ff4-Carbamimidoylphenylamino)-(3.5-dimethoxyphenvl)methvl ]-5-oxo-4.5-dihvdro-ri.2.4]triazol-l-vlUhiazole-5-carboxylic acid [1376] [Chemical Formula 576]

The same procedure was carried out as in Examples (166a) to (166c),
except that
{2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenyli
mino]-l-methylsulfanylethylidene}carbamic acid methyl ester (Example
(225a)) was used instead of
[2-(8-methoxy-4H-benzo[l,3]dioxin-6-yl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester in Example (166a), to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 6 3.77 (s, 6H) 5.57 (s, 1H) 6.45 (t, J=2.0Hz, 1H) 6.71 (d, J=2.0Hz, 2H) 6.85 (d, J=8.8Hz, 2H) 7.60 (d, J=8.8Hz, 2H) 8.92 (s, 1H)

HPLC retention time: 18 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1377] Example 233: (R) and
fS)-4-n-U4-CarbamimidovlphenvlaminoV[3-(2-hvdroxvethoxv')-4.5-dim
ethoxvphenvnmethvU-5-oxo-4.5-dihvdro-fl.2.41triazol-l-vnthiazole-5-c
arboxylic acid
[1378] [Chemical Formula 577]

The same procedure was carried out as in Example 167, except that
{2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (159a)) was used instead of
[2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[l,2,4]oxadiaz ol-3-yl)phenylimino]-l-methylsulfanylethylidene]carbamic acid methyl ester, to give the first eluting enantiomer of the title compound. 'H-NMR (CD3OD) 5 3.80 (s, 3H) 3.82-3.92 (m, 5H) 4.04-4.16 (m, 2H) 5.63 (s, 1H) 6.80-6.94 (m, 4H) 7.63 (d, J=8.8Hz, 2H) 9.03 (s, 1H) HPLC retention time: 19 min (Column name: SUMICHIRAL OA-2500, 30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 25 ml/min)
[1379] Example 234j (R) and
(S)-4-(r(5.6-Dimethoxvpvridin-3-ylV(5-oxo-l-pvrimidin-2-vl-4.5-dihvdr o-lH-n.2.41triazol-3-vl)methvnaminolbenzamidine acetate [1380] [Chemical Formula 578]


The same procedure was carried out as in Example (160b), except that
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph
enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (169a)) was used instead of
{2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-
yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester,
to give the first eluting enantiomer of the title compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.82 (s, 3H) 3.92 (s, 3H) 5.67 (s, 1H)
6.88 (d, J=9.2Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.41 (d, J=2.0Hz, 1H) 7.61
(d, J=9.2Hz, 2H) 7.85 (d, J=2.0Hz, 1H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 13 min (Column name: SUMICHIRAL OA-2500,
30 mm Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1381] Example 235; (R) and
(S)-3-{3-[(4-CarbamimidovlphenvlaminoW5-ethoxv-6-methoxvpvridin-3
-vnmethvll-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vUthiophene-2-carboxyli
c acid
[1382] [Chemical Formula 579]

The same procedure was carried out as in Example (169b), except that {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-

yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester
(Example (160a)) was used instead of
{2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)ph enylimino]-l-methylsulfanylethylidene}carbamic acid methyl ester, to give the first eluting enantiomer of the title compound. 'H-NMR (CD3OD) 5 1.36 (t, J=7.2Hz, 3H) 3.92 (s, 3H) 3.97-4.13 (m, 2H) 5.65 (s, 1H) 6.87 (d, J=9.2Hz, 2H) 7.07 (d, J=5.2Hz, 1H) 7.37 (d, J=2.0Hz, 1H) 7.43 (d, J=5.2Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 7.81 (d, J=2.0Hz, 1H)
HPLC retention time: 14 min (Column name: SUMICHIRAL OA-2500, 30 mm [1383] Example 236; 3-Fluoro-4-(r(R) and
fS)-(2-fluoro-4.5-dimethoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro
-lH-[1.2.4")triazol-3-vl)methyl]amino)benzamidine acetate
(236a)
4-{[Cyano-(2-fluoro-4,5-dimethoxyphenyl)methyl]amino}-3-fluorobenzo
nitrile

To 20 ml of a THF solution containing 1.9 g of
2-fluoro-4,5-dimethoxybenzaldehyde, 1.47 g of
4-amino-3-fluoro.benzonitrile [CAS No. 63069-50-1], 6 g of MS3A, 640 mg of Yb(OTf)3, and 4 ml of trimethylsilyl cyanide were added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then filtered through celite. The filtrate was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over

anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) and then filtered through NH silica gel to give the title compound (1.0 g) as a light yellow solid.
'H-NMR (CDCI3) 8 3.91 (s, 3H) 3.93 (s, 3H) 4.71-4.74 (m, 1H) 5.61 (d, J=7.2Hz, 1H) 6.74 (d, J=11.2Hz, 1H) 6.95 (t, J=8.4Hz, 1H) 7.04 (d, J=6.8Hz, 1H) 7.33 (dd, J=2.0, 11.2Hz, 1H) 7.44-7.47 (m, 1H) [1385] (236b)
[2-(4-Cyano-2-fluorophenylimino)-2-(2-fluoro-4,5-dimethoxyphenyl)-l-methylsulfanylethylidene]carbamic acid methyl ester [1386] [Chemical Formula 581]

To 100 ml of an ethanol:THF = 2:1 mixed solvent solution containing 1.0
g of
4-{[cyano-(2-fluoro-4,5-dimethoxyphenyl)methyl]amino}-3-fluorobenzo nitrile, 5.5 ml of a 20% ammonium sulfide aqueous solution was added. The resulting mixture was stirred at room temperature for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure.
To 20 ml of an acetonitrile solution containing the residue obtained, 500 mg of Me30+BF4_ was added. The resulting mixture was stirred at room temperature for 50 minutes, and then a saturated sodium hydrogen carbonate aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The

desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure.
To 20 ml of an ethyl acetate solution containing the residue obtained, 4.8
g of manganese dioxide was added, and the resulting mixture was stirred
at room temperature for 19 hours. The reaction mixture was filtered
through celite, and the filtrate was concentrated under reduced pressure.
To 30 ml of a toluene solution containing the residue obtained, 1.48 ml
of 2,4,6-collidine and 0.74 ml of methyl chloroformate were added.
The resulting mixture was stirred at 85°C for 7 hours under a nitrogen
atmosphere. The reaction mixture was cooled, and then 0.1 N
hydrochloric acid was added thereto. The mixture was extracted with
ethyl acetate. The organic layer was washed with a saturated sodium
hydrogen carbonate aqueous solution, water, and saturated brine and then
dried over anhydrous magnesium sulfate. The desiccating agent was
removed by filtration, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate-heptane) to give the title compound. Mass spectrum (ESI) m/z: 456 (M+Na)+
[1387] (236c) 3-Fluoro-4-{[(R) and
(S)-(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro -lH-[l,2,4]triazol-3-yI)methyl]amino}benzamidine acetate [1388] [Chemical Formula 582]
To 3 ml of a DMF solution containing 503 mg of [2-(4-cyano-2-fluorophenylimino)-2-(2-fluoro-4,5-dimethoxyphenyl)-l-methylsulfanylethylidene]carbamic acid methyl ester, 79 mg of 2-hydrazinopyrimidine and 0.15 ml of triethylamine were added. The resulting mixture was stirred at room temperature for 1 hour under a

nitrogen atmosphere and then at 85°C for 14 hours and 45 minutes. Then, the reaction mixture was concentrated.
The residue obtained was dissolved in 6.2 ml of a methanol:THF:acetic acid = 20:10:1 mixed solvent, and 220 mg of sodium cyanotrihydroborate was added thereto. The resulting mixture was stirred at room temperature for 4 hours. Then, 200 mg of sodium cyanotrihydroborate, 1 ml of methanol, 1 ml of THF, and 0.2 ml of acetic acid were further added to the reaction mixture. The mixture was stirred at the same temperature for 16 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The insoluble matter was removed by filtration, and the filtrate was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give a crude product of
3-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzonitrile.
To 2 ml of a pyridine solution containing this crude product, 0.255 ml of
triethylamine and 1.57 ml of a 20% ammonium sulfide aqueous solution
were added. The resulting mixture was stirred at 70°C for 5 hours
under a nitrogen atmosphere. The reaction mixture was made acidic
with acetic acid, and water was added thereto. The mixture was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
3-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4, 5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}thiobenzamide. Mass spectrum (ESI) m/z: 500 (M+H)+
This compound (40 mg) was suspended in 15 ml of acetonitrile, and 16 mg of Me30+BF4" was added thereto. The resulting mixture was stirred at room temperature for 1 hour and a quarter and then concentrated. To the residue obtained, 1.5 ml of acetonitrile, 1.5 ml of isopropanol, and

0.021 ml of 1,1,3,3-tetramethyldisilazane were added. The resulting
mixture was stirred at 70°C for 28 and a quarter hours and then
concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)
to give
3-fluoro-4-{[(2-fluoro-4,5-dimethoxyphenyl)-(5-oxo-l-pyrimidin-2-yl-4,
5-dihydro-lH-[l,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
Mass spectrum (ESI) m/z: 483 (M+H)+
This compound (13.7 g) was optically resolved using a SUMICHIRAL
OA-2500 column, and the first eluting enantiomer (5.67 mg) of the title
compound was obtained as a white solid.
'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.76 (s, 3H) 3.81 (s, 3H) 5.99 (s, 1H)
6.82 (d, J=11.6Hz, 1H) 6.93 (t, J=8.4Hz, 1H) 7.13 (d, J=6.8Hz, 1H) 7.29
(t, J=4.8Hz, 1H) 7.48-7.54 (m, 2H), 8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500,
30 mm(f> x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 40 ml/min)
[1389] Example 237: 3-f3-(fR) and
(S)-f4-Carbamimidovlphenvlamino)-r2-fluoro-4-(2-hvdroxvethoxv)-5-me
thoxvphenvllmethvl}-5-oxo-4.5-dihvdro-fl.2.41triazol-l-vnthiophene-2-
carboxvlic acid
[1390] [Chemical Formula 583]

To 3 ml of a DMF solution containing 308 mg of (2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy lidene)carbamic acid methyl ester (Example (178c)), 86 mg of

3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.104 ml of
triethylamine were added. The resulting mixture was stirred at 85°C for
13 and a half hours under a nitrogen atmosphere and then concentrated.
The residue obtained was dissolved in 3 ml of methanol, 1 ml of THF,
and 0.3 ml of acetic acid, and then 200 mg of sodium
cyanotrihydroborate was added thereto. The mixture was stirred at
room temperature for 2 hours and 20 minutes, and then 100 mg of
sodium cyanotrihydroborate was further added thereto. The mixture
was stirred at room temperature for 1 hour and 40 minutes. Water and
ethyl acetate were added to the reaction mixture. The resulting mixture
was extracted with ethyl acetate twice. The organic layers were
combined, washed with saturated brine, and dried over anhydrous
magnesium sulfate. The desiccating agent was removed by filtration,
and the filtrate was concentrated under reduced pressure.
To 5 ml of a methanol solution containing the residue obtained, 3 ml of a
5 N sodium hydroxide aqueous solution was added. The mixture was
stirred at room temperature for 11 hours. The pH of the reaction
mixture was adjusted to approximately 3 with 5 N hydrochloric acid.
The mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The desiccating agent was removed by filtration, and the
filtrate was concentrated under reduced pressure. The residue was
crudely purified by reverse-phase high performance liquid
chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give a
crude product of
3-(3-{[2-fluoro-4-(2-hydroxyethoxy)-5-methoxyphenyl]-4-(5-methyl-[l,2 ,4]oxadiazol-3-yl)phenylamino}methyl)-5-oxo-4,5-dihydro-[l,2,4]triazol -1 -yl)thiophene-2-carboxylic acid.
Iron powder (150 mg) was added to 4.5 ml of a methanol:water:acetic acid = 1:1:1 mixed solvent solution containing the crude product obtained. The mixture was stirred at 70°C for 4 hours under a nitrogen atmosphere. After the addition of 1 ml of acetic acid, the mixture was further stirred at the same temperature for 1 hour. The reaction mixture

was filtered and then crudely purified by reverse-phase high performance
liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to
give
3-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-4-(2-hydroxyethoxy)-5-
methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[l,2,4]triazol-l-yl)thiophene
-2-carboxylic acid.
Mass spectrum (ESI) m/z: 543 (M+H)+
The crude product obtained was optically resolved using a
SUMICHIRAL OA-2500 column, and the first eluting enantiomer (9.22
mg) of the title compound was obtained as a white solid.
'H-NMR (CD3OD) 8 3.77-3.80 (m, 2H) 3.83 (s, 3H) 3.94-4.06 (m, 2H)
5.87 (s, 1H) 6.82 (d, J=5.6Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.07 (d,
J=5.6Hz, 1H) 7.12 (d, J=7.2Hz, 1H) 7.43 (d, J=5.6Hz, 1H) 7.59 (d,
J=8.8Hz, 2H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500,
30 mm x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1391] Example 238: 4-ffflO and
fS)-f2-Fluoro-4-f2-hydroxvethoxv)-5-methoxyphenyl]-(5-oxo-l-pvrimidi n-2-vl-4.5-dihvdro-1 H-[ 1.2.4]triazol-3-vl)methvl]amino > benzamidine acetate

The same procedure was carried out as in Examples (3f) to (3h), except that
(2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[l,2,4]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethy

lidene)carbamic acid methyl ester (Example (178c)) was used instead of
{2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[l,2,4
]oxadiazol-3-yl)phenylimino]-l-methylsulfanylethylidene}carbamic acid
methyl ester in Example (3f), to give the first eluting enantiomer of the
title compound.
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.76-3.79 (m, 2H) 3.82 (s, 3H)
3.93-3.96 (m, 2H) 5.91 (s, 1H) 6.83 (d, J=11.6Hz, 1H) 6.85 (d, J=8.8Hz,
2H) 7.12 (d, J=7.2Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H)
8.75 (d, J=4.8Hz, 2H)
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500,
30 mmij) x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1393] The following compounds were produced by the general
production processes for the compounds of this invention and by similar
processes as in the examples described above. Unless otherwise
specified, the data for the following example compounds having two
optical isomers listed are the data for the first eluting enantiomer.
[1394] Example X-l:
2-f4-[(4-carbamimidovlphenylaminoW5-oxo-l-pvrimidin-2-vl-4.5-dihyd
ro-lH-[1.2.41triazol-3-vnmethvl]-2-ethoxvphenoxy}-N,N-dimethvlaceta
mide acetate
[1395] [Chemical Formula 585]

'H-NMR (CD3OD) 5 1.36 (t, J=6.8Hz, 3H) 1.94 (s, 3H) 2.94 (s, 3H) 3.08 (s, 3H) 4.04 (q, J=6.8Hz, 2H) 4.79 (s, 2H) 5.64 (s, 1H) 6.86 (d, J=8.4Hz, 2H) 6.92 (d, J=8.0Hz, 1H) 7.05 (d, J=8.0Hz, 1H) 7.17 (s, 1H) 7.35 (t,

J=4.8Hz, 1H) 7.61 (d, J=8.4Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 532 (M+H)+
[1396] Example X-2:
2-(4-{(4-carbamimidoylphenvlamino')-ri-(2-methoxvDhenvn-5-oxo-4.5-d ihvdro-lH-fl.2.41triazol-3-vnmethvll-2.6-dimethoxvphenoxvVN.N-dime thylacetamide acetate

'H-NMR (CD3OD) 8 1.93 (s, 3H) 2.96 (s, 3H) 3.14 (s, 3H) 3.80 (s, 3H) 3.83 (s, 6H) 4.59 (s, 2H) 5.63 (s, 1H) 6.84-6.91 (m, 4H) 7.03 (ddd, J=1.2, 7.6, 7.6Hz, 1H) 7.15 (dd, J=1.2, 8.4Hz, 1H) 7.31 (dd, J=1.6, 7.6Hz, 1H) 7.44 (ddd, J=1.6, 7.6, 8.4Hz, 1H) 7.64 (d, J=8.8Hz, 2H)
[1398] Example X^ 4-(rrRt and
fS)-f3-cvanomethoxv-5-ethvlphenvB-(5-oxo-1-pvrimidin-2-vl-4.5-dihvdr o-lH-[1.2.41triazol-3-vl)methvl]amino)benzamidine acetate

'H-NMR (CD3OD) 8 1.21 (t, J=7.6Hz, 3H) 1.93 (s, 3H) 2.65 (q, J=7.6Hz,
2H) 4.96 (s, 2H) 5.64 (s, 1H) 6.82-6.92 (m, 3H) 7.07 (s, 1H) 7.13 (s, 1H)
7.31 (br.s, 1H) 7.60 (d, J=9.2Hz, 2H) 8.78 (br.s, 2H)
HPLC retention time: 11 min
[1400] Example X=4j 4-ff(R) and

(SV(3-allvloxvphenvn-f5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-n.2.4]tr iazol-3-vnmethvl]amino}benzamidine acetate [1401] [Chemical Formula 588]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 4.53 (ddd, J=1.6, 1.6, 5.2Hz, 2H) 5.20 (tdd, J=1.6, 1.6, 10.8Hz, 1H) 5.36 (tdd, J=1.6, 1.6, 17.2Hz, 1H) 6.01 (tdd, J=5.2, 10.8, 17.2Hz, 1H) 6.81-6.91 (m, 3H) 7.08-7.18 (m, 2H) 7.28 (t, J=8.0Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 11 min
[1402] Example X^5j 4-frOQ and
(S)-(3-fluoromethvl-5-methoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihv dro-lH-[1.2.4]triazol-3-vOrnethvl]amino}benzamidine trifluoroacetate [1403] [Chemical Formula 589]

'H-NMR (CD3OD) 8 3.82 (s, 3H) 5.36 (d, J=47.6Hz, 2H) 5.74 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.96 (s, 1H) 7.13 (s, 1H) 7.16 (s, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H) HPLC retention time: 13 min
[1404] Example X-6:
4-{f(3-ethoxv-5-hvdroxvmethvlphenvlH5-oxo-l-pvrimidin-2-vl-4.5-dihv dro-1H- [ 1.2.4]triazol-3 -vDmethyl] am ino} benzam idine trifluoroacetate [1405] [Chemical Formula 590]


'H-NMR (CD3OD) 8 1.37 (t, J=7.2Hz, 3H) 4.05 (q, J=7.2Hz, 2H) 4.59 (s, 2H) 5.70 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.92 (s, 1H) 7.01 (br.s, 1H) 7.11 (s,lH) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H) HPLC retention time: 11 min
[1406] Example X£7j 4-([(R) and
fSH3.5-diethoxv-2-fluorophenvlV(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-l H-f 1.2.4]triazol-3-vnmethvllamino) benzamidine trifluoroacetate [1407] [Chemical Formula 591]

5H-NMR (CD3OD) 5 1.31 (t, J=6.8Hz, 3H) 1.40 (t, J=6.8Hz, 3H) 3.86-4.01 (m, 2H) 4.06 (q, J=6.8Hz, 2H) 6.00 (s, 1H) 6.52-6.63 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.36 (t, J=4.8Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1408] Example M 4-1 TOO and
(S)-(3-ethoxv-5-fluoromethvlphenvl)-r5-oxo-l-pyrimidin-2-vl-4.5-dihvdr o-lH-n.2.41triazol-3-vDmethvnaminoibenzamidine trifluoroacetate [1409] [Chemical Formula 592]


'H-NMR (CD3OD) 8 1.38 (t, J=6.8Hz, 3H) 4.06 (q, J=6.8Hz, 2H) 5.35 (d, J=47.6Hz, 2H) 5.73 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.94 (s, 1H) 7.10 (s, 1H) 7.15 (s, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1410] Example X-9:
4-{[[4-(2-dimethylaminoethoxv)-3.5-dimethoxvphenvl1-(5-oxo-l-pvrimid
in-2-vl-4.5-dihvdro-lH-ri.2.41triazol-3-vDmethvl]amino}benzamidine
diacetate
[1411] [Chemical Formula 593]

'H-NMR (CD3OD) 5 1.98 (br.s, 6H) 2.75 (br.s, 6H) 3.14 (br.s, 2H) 3.84 (br.s, 6H) 4.09 (br.s, 2H) 5.53 (br.s, 1H) 6.86 (br.s, 2H) 6.93 (br.s, 2H) 7.26 (br.s, 1H) 7.60 (br.s, 2H) 8.74 (br.s, 2H) Mass spectrum (ESI)m/z: 534 (M+H)+
[1412] Example X-10: 4-UflO and
fSy(3-ethoxv-5-methoxvmethvlphenvlW5-oxo-l-pvrimidin-2-vl-4.5-dih vdro-lH-[1.2.4]triazol-3-vnmethvl]amino>benzamidine trifluoroacetate [1413] [Chemical Formula 594]


'H-NMR (CD3OD) 8 1.37 (t, J=6.8Hz, 3H) 3.37 (s, 3H) 4.04 (q, J=6.8Hz,
2H) 4.43 (s, 2H) 5.70 (s, 1H) 6.83-6.96 (m, 3H) 7.01-7.08 (m, 1H) 7.10
(s, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 8.80 (d, J=4.8Hz,
2H)
HPLC retention time: 12 min
[1414] Example X-ll: 4-([(R) and
(SH3-ethoxvphenylW5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH-n.2.4]tria zol-3-vOmethvl]amino\benzamidine acetate [1415] [Chemical Formula 595]

!H-NMR (CD3OD) 8 1.34 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 4.01 (q, J=7.2Hz,
2H) 5.64 (s, 1H) 6.80-6.92 (m, 3H) 7.05-7.14 (m, 2H) 7.27 (dd, J=8.0,
8.4Hz, 1H) 7.32 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.77 (d, J=4.8Hz,
2H)
HPLC retention time: 11 min
[1416] Example X-12: 4-U(R) and
(S)-[3-ethoxv-5-(2-methoxvethoxv')phenvll-f5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-fl.2.41triazol-3-vnmethvnamino>benzamidine acetate [1417] [Chemical Formula 596]

'H-NMR (CD3OD) 5 1.32 (q, J=6.8Hz, 3H) 1.91 (s, 3H) 3.37 (s, 3H) 3.62-3.74 (m, 2H) 3.97 (q, J=6.8Hz, 2H) 4.00-4.10 (m, 2H) 5.56 (s, 1H) 6.41 (dd, J=2.0, 2.4Hz, 1H) 6.65-6.78 (m, 2H) 6.85 (d, J=8.8Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 13 min
Example X-13: 4-{\(K) and
fSVrS-oxo-l-pvrimidin^-vl^.S-dihvdro-lH-n^^ltriazol-S-vn-fS^.S-tr imethoxvphenyPmethynaminolbenzamidine acetate [1418] [Chemical Formula 597]

'H-NMR (CD3OD) 8 1.95 (br.s, 3H) 3.74 (br.s, 3H) 3.83 (br.s, 6H) 5.63 (br.s, 1H) 6.75-7.00 (m, 4H) 7.35 (br.s, 1H) 7.62 (br.d, J=8.0Hz, 2H) 8.79 (br.s, 2H) HPLC retention time: 13 min
[1419] Example X-14: 4-(\(K) and
(SW3-0-fluoropropoxy)-5-methoxvphenvl]-(5-oxo-l-pvrimidin-2-yl-4.5 -dihydro-lH-[1.2.41triazol-3-vnmethvnaminolbenzamidine acetate [1420] [Chemical Formula 598]


'H-NMR (CD3OD) 8 1.91 (s, 3H) 2.09 (quint.d, J=6.0, 25.6Hz, 2H) 3.75 (s, 3H) 4.05 (t, J=6.0Hz, 2H) 4.57 (td, J=6.0, 47.6Hz, 2H) 5.57 (s, 1H) 6.42 (t, J=2.0Hz, 1H) 6.74 (br.s, 2H) 6.86 (d, J=8.8Hz, 2H) 7.30 (br.s, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (br.d, J=4.0Hz, 2H) HPLC retention time: 13 min
[1421] Example X-15:
4-frO-ethoxv-2-fluoro-5-methoxvphenvlW5-oxo-l-pvrimidin-2-vl-4.5-d ihvdro-lH-[1.2.41triazol-3-vnmethyllamino)benzamidine acetate [1422] [Chemical Formula 599]

'H-NMR (CD3OD) 8 1.40 (t, J=6.8Hz, 3H) 1.92 (s, 3H) 3.71 (s, 3H) 4.07 (q, J=6.8Hz, 2H) 5.96 (s, 1H) 6.53-6.67 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.31 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 479 (M+H)+
[1423] Example X-16:
4-f[(3-ethvl-4.5-dimethoxvphenvn-(5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH41.2.4]triazol-3-vDmethvl]amino}benzamidine acetate [1424] [Chemical Formula 600]


'H-NMR (CD3OD) 8 1.16 (t, J=7.6Hz, 3H) 1.93 (s, 3H) 2.62 (q, J=7.6Hz, 2H) 3.76 (s, 3H) 3.83 (s, 3H) 5.61 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.99 (d, J=2.0Hz, 1H) 7.07 (d, J=2.0Hz, 1H) 7.33 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 475 (M+H)+
[1425] Example X-17: 4-{f(R1 and
(SW3-methoxv-5-(2-methoxvethvOphenvO-f5-oxo-1-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vDmethvl]amino)benzamidine acetate [1426] [Chemical Formula 601]

'H-NMR (CD3OD) 5 1.91 (s, 3H) 2.82 (t, J=6.8Hz, 2H) 3.29 (s, 3H) 3.59 (t, J=6.8Hz, 2H) 3.76 (s, 3H) 5.59 (s, 1H) 6.76 (s, 1H) 6.86 (d J=8.8Hz, 2H) 6.94-7.00 (m, 1H) 7.02 (s,lH) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1427] Example X-18: 4-I1YR) and
rS)-f8-methoxv-4-methvl-3-oxo-3.4-dihvdro-2H-benzo[1.41oxazin-6-vn-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvl]amin olbenzamidine acetate [1428] [Chemical Formula 602]


]H-NMR (CD3OD) 8 1.92 (s, 3H) 3.27 (s, 3H) 3.79 (s, 3H) 4.56 (s, 2H) 5.67 (s, 1H) 6.89 (d J=8.8Hz, 2H) 6.99 (d, J=2.0Hz, 1H) 7.01 (d, J=2.0Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) HPLC retention time: 21 min
[1429] Example X-19:
2-(rn-r2-methoxvphenvn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vll-f3.4 ,5-trimethoxyphenvl')methvl')amino}benzamidine acetate [1430] [Chemical Formula 603]

'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.76 (s, 3H) 3.81 (s, 3H) 3.84 (s, 6H) 5.62 (s, 1H) 6.86 (s, 2H) 6.87 (d, J=8.8Hz, 2H) 7.03 (ddd, J=1.2, 7.6, 7.6Hz, 1H) 7.14 (dd, J=1.2, 8.4Hz, 1H) 7.31 (dd, J=1.6, 7.6Hz, 1H) 7.44 (ddd, J=1.6, 7.6, 8.4Hz, 1H) 7.64 (d, J=8.8Hz, 2H) Mass spectrum (ESI)m/z: 505 (M+H)+
[1431] Example X-20:
4-([[3-('2-fluoroethoxv>)-4.5-dimethoxvphenvl1-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vnmethyl]aminolbenzamidine acetate [1432] [Chemical Formula 604]


'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.76 (s, 3H) 3.80 (s, 3H) 4.10-4.30 (m,2H) 4.67 (td, J=4.0, 48.0Hz, 2H) 5.65 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.90 (s, 1H) 6.92 (s, 1H) 7.33 (t, J=4.4Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=4.4Hz, 2H) Mass spectrum (ESI)m/z: 509 (M+H)+
[1433] Example X-21:
4-{[(3-cvanomethoxy-2-fluoro-5-methoxvphenvlW5-oxo-l-pyrimidin-2-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vDmethyl]amino}benzamidine acetate [1434] [Chemical Formula 605]

1 H-NMR (CD3OD) 5 1.92 (s, 3H) 3.74 (s, 3H) 5.05 (s, 2H) 5.95 (s, 1H) 6.72-6.83 (m, 2H) 6.85 (d, J=8.4Hz, 2H) 7.29 (t, J=4.4Hz, 1H) 7.61 (d, J=8.4Hz, 2H) 8.76 (d, J=4.4Hz, 2H) Mass spectrum (ESI)m/z: 490 (M+H)+
[1435] Example X-22:
4- {[r3-cvanomethoxv-5-methoxvphenvlW 5-oxo-l -pvrimidin-2-vl-4.5-dih ydro-lH-[1.2.4]triazol-3-vl)methyl]amino)benzamidine acetate [1436] [Chemical Formula 606]


'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.78 (s, 3H) 4.96 (s, 2H) 5.62 (s, 1H) 6.56 (dd, J=2.0,2.4Hz, 1H) 6.80-6.93 (m, 4H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 472 (M+H)+
[1437] Example X-23:
4-{[[3-ethoxy-4-f2-fluoroethoxv)phenvl]-f 5-oxo-l -pvrimidin-2-yl-4,5-di hvdro-lH-n.2.4]triazol-3-vDmethyl]amino}benzamidine acetate [1438] [Chemical Formula 607]
'H-NMR (CD3OD) 5 1.36 (t, J=6.8Hz, 3H) 1.95 (s, 3H) 4.05 (q, J=6.8Hz, 2H) 4.14-4.30 (m, 2H) 4.60-4.80 (m, 2H) 5.65 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.97 (d, J=8.0Hz, 1H) 7.07 (dd, J=2.0, 8.0Hz, 1H) 7.17 (d, J=2.0Hz, 1H) 7.34 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 493 (M+H)+
[1439] Example X-24:
4-ir(3-allvloxv-5-hvdroxvmethvlphenvl)-r5-oxo-l-pvrimidin-2-vl-4.5-di hvdro-lH-[1.2.4]triazol-3-vnmethvllamino)benzamidine acetate [1440] [Chemical Formula 608]


'H-NMR (CD3OD) 8 1.92 (s, 3H) 4.51 (ddd, J=1.6, 1.6, 5.2Hz, 2H) 4.55 (s, 2H) 5.19 (tdd, J=1.6, 1.6, 10.4Hz, 1H) 5.34 (tdd, J=1.6, 1.6, 17.2Hz, 1H) 5.66 (s, 1H) 6.00 (tdd, J=5.2, 10.4, 17.2Hz, 1H) 6.86 (d, J=9.2Hz, 2H) 6.89 (br.s, 1H) 7.04 (t, J=2.0Hz, 1H) 7.13 (br.s, 1H) 7.31 (t, J=4.8Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 473 (M+H)+
[1441] Example X-25:
4-([(3-ethoxv-5-methoxvphenvlW5-oxo-l-pvrimidin-2-vl-4.5-dihydro-l H-fl.2.4]triazol-3-vl)methvl]amino}benzamidine acetate [1442] [Chemical Formula 609]

'H-NMR (CD3OD) 5 1.33 (t, J=6.8Hz, 3H) 1.92 (s, 3H) 3.75 (s, 3H) 3.99 (q, J=6.8Hz, 2H) 5.59 (s, 1H) 6.41 (dd, J=1.6, 2.4Hz, 1H) 6.71 (br.s, 2H) 6.86 (d, J=8.8Hz, 2H) 7.33 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 461 (M+H)+
[1443] Example X-26:
4-{[(3-ethvl-5-methoxvmethylphenvl')-f 5-oxo-l-pvrimidin-2-vl-4.5-dihvd ro-lH-[1.2.4]triazol-3-yOmethvl]amino}benzamidine acetate [1444] [Chemical Formula 610]


'H-NMR (CD3OD) 8 1.22 (t, J=7.6Hz, 3H) 1.95 (s, 3H) 2.66 (q, J=7.6Hz, 2H) 3.36 (s, 3H) 4.43 (s, 2H) 5.69 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.14 (s, 1H) 7.34 (br.s, 3H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=5.2Hz, 2H) Mass spectrum (ESI)m/z: 459 (M+H)+
[1445] Example X-27:
4-{[[4-f2-dimethvlaminoethoxy)-2-fluoro-5-methoxvphenvl1-(5-oxo-l-pv
rimidin-2-yl-4,5-dihvdro-lH-[1.2.41triazol-3-vnmethvllamino)benzamidi
ne diacetate
[ 1446] [Chemical Formula 611]

'H-NMR (CD3OD) 5 1.93 (br.s, 6H) 2.76 (br.s, 6H) 3.25 (br.s, 2H) 3.84 (br.s, 3H) 4.18 (br.s, 2H) 5.91 (br.s, 1H) 6.70-7.00 (m, 3H) 7.20 (br.s, 1H) 7.32 (br.s, 1H) 7.61 (br.s, 2H) 8.77 (br.s, 2H) Mass spectrum (ESI)m/z: 522 (M+H)+
[1447] Example X-28:
4-{[[2-fluoro-3-(2-fluoroethoxv>)-4.5-dimethoxvphenvn-(5-oxo-l-pvrimi
din-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvl)amino}benzamidine
acetate
[1448] [Chemical Formula 612]


'H-NMR (CD3OD) 8 1.94 (s, 3H) 3.74 (s, 3H) 3.83 (s, 3H) 4.25-4.39 (m,2H) 4.56-4.76 (m, 2H) 5.97 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.92 (d, J=6.4Hz, 1H) 7.33 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 527 (M+H)+
[1449] Example X-29:
4-(r[5-ethoxv-2-fluoro-3-(3-fluoropropoxv')phenvn-(5-oxo-l-pvrimidin-2
-vl-4.5-dihvdro-lH-[1.2,41triazol-3-vl)methvnaminoVbenzamidine
acetate
[1450] [Chemical Formula 613]

'H-NMR (CD3OD) 8 1.30 (t, J=6.8Hz, 3H) 1.94 (s, 3H) 2.16 (quint.d, J=6.0, 25.2Hz, 2H) 3.93 (q, J=6.8Hz, 2H) 4.14 (t, J=6.0Hz, 2H) 4.62 (td, J=6.0, 47.2Hz, 2H) 5.97 (s, 1H) 6.55-6.69 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.33 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 525 (M+H)+
[451] Example X-30:
4-{[(3-ethoxv-4.5-dimethoxvphenvlH5-oxo-l-pvrimidin-2-vl-4.5-dihydr o-lH-[1.2.41triazol-3-vDmethvl]amino}benzamidine acetate [1452] [Chemical Formula 614]


'H-NMR (CD3OD) 8 1.35 (t, J=6.8Hz, 3H) 1.93 (s, 3H) 3.74 (s, 3H) 3.81 (s, 3H) 3.94-4.12 (m, 2H) 5.61 (s, 1H) 6.78-6.98 (m, 4H) 7.33 (t, J=4.8Hz, 1H) 7.61 (d, J=8.4Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 491 (M+H)+
[1453] Example X-31:
4-{[[2-fluoro-4-(2-fluoroethoxvV5-methoxvphenyl1-(5-oxo-l-pvrimidin-
2-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vnmethvl]aminolbenzamidine
acetate
[1454] [Chemical Formula 615]

'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.83 (s, 3H) 4.03-4.24 (m, 2H) 4.63 (td, J=4.0, 47.6Hz, 2H) 5.94 (s, 1H) 6.78-6.94 (m, 3H) 7.12 (d, J=7.2Hz, 1H) 7.34 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 497 (M+H)+
[1455] Example X-32:
4-([[2-fluoro-5-methoxv-3-fl-methylpvrrolidin-3-vloxv')phenvl]-(5-oxo-
l-pyridin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvl]amino>benzami
dine acetate
[1456] [Chemical Formula 616]


Mass spectrum (ESI)m/z: 533 (M+H)+
[1457] Example X-33:
2-(3-{(4-carbamimidoylphenylamino')-[l-(2-fluorophenvl)-5-oxo-4.5-dih ydro-lH-fl.2,41triazol-3-vnmethvU-2-fluoro-5-methoxvphenoxy)-N.N-d imethvlacetamide trifluoroacetate [1458] [Chemical Formula 617]

'H-NMR (CD3OD) 5 2.96 (s, 3H) 3.08 (s, 3H) 3.72 (s, 3H) 4.90 (s, 2H) 6.00 (s, 1H) 6.60-6.63 (m, 2H) 6.86 (d, J=8.4Hz, 2H) 7.27 (t, J=8.0Hz, 2H) 7.42-7.48 (m, 2H) 7.63 (d, J=8.4Hz, 2H) Mass spectrum (ESI)m/z: 552 (M+H)+
[1459] Example X-34:
2-{3-[f4-carbamimidoylphenylaminoV( 5-oxo-l -pyridin-2-yl-4,5-dihvdro-lH-n.2.4]triazol-3-vl')methvl]-2-fluoro-5-methoxvphenoxv>-N.N-dimeth vlacetamide trifluoroacetate [1460] [Chemical Formula 618]

'H-NMR (CD3OD) 5 2.97 (s, 3H) 3.08 (s, 3H) 3.70 (s, 3H) 4.90 (s, 2H)

6.03 (s, 1H) 6.58-6.64 (m, 2H) 6.86 (d, J=8.4Hz, 2H) 7.35 (dd, J=6.0, 6.4Hz, 1H) 7.63 (d, J=8.4Hz, 2H) 8.02 (dt, J=1.6, 8.0Hz, 1H) 8.13 (d, J=8.0Hz, 1H) 8.43 (d, J=4.8Hz, 1H) Mass spectrum (ESI)m/z: 535 (M+H)+
[1461] Example X-35: 2-D-UR) and
(S)-(4-carbamimidoviphenvlamino)-ri-(2-methoxyphenyO-5-oxo-4.5-dih ydro-lH-[1.2.4]triazol-3-yl]methvl)-2-fluoro-5-methoxyphenoxv)-N.N-d imethylacetamide acetate [1462] [Chemical Formula 619]

'H-NMR (CD3OD) 5 1.90 (s, 3H) 2.97 (s, 3H) 3.09 (s, 3H) 3.71 (s, 3H) 3.80 (s, 3H) 5.94 (s, 1H) 6.60 (dd, J=2.8, 6.8Hz, 1H) 6.66 (dd, J=2.8, 4.4Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.01 (dt, J=1.2, 7.6Hz, 1H) 7.12 (dd, J=0.8, 8.4Hz, 1H) 7.29 (dd, J-1.6, 7.6Hz, 1H) 7.39-7.43 (m, 1H) 7.62 (d, J=8.8Hz, 2H) HPLC retention time: 7 min
[1463] Example X-36:
4-({(3-ethoxv-2-fluoro-5-methylphenylV[1-(2-methoxvphenylV5-oxo-4.5
-dihvdro- 1H-T1.2,4]tr iazol-3-vnmethvl} amino)benzamidine
trifluoroacetate
[1464] [Chemical Formula 620]

'H-NMR (CD3OD) 8 1.41 (t, J=6.8Hz, 3H) 2.29 (s, 3H) 3.81 (s, 3H) 4.09 (q, J=6.8Hz, 2H) 5.95 (s, 1H) 6.83-6.87 (m, 3H) 6.91 (dd, J=1.6, 8.0Hz,

1H) 7.02 (dt, J=1.2, 7.6Hz, 1H) 7.13 (dd, J=1.2, 8.4Hz, 1H) 7.30 (dd, J=1.6, 7.6Hz, 1H) 7.43 (ddd, J=1.6, 7.6, 8.4Hz, 1H) 7.62-7.65 (m, 2H) Mass spectrum (ESI)m/z: 491 (M+H)+
[1465] Example X-37:
4-{[n-ethoxv-2-fluoro-5-methvlphenvlW5-oxo-l-pvrimidin-2-vl-4.5-dih vdro-lH-[1.2.4]triazol-3-vOmethvriamino}benzamidine trifluoroacetate [1466] [Chemical Formula 621]

'H-NMR (CD3OD) 8 1.39 (t, J=6.8Hz, 3H) 2.25 (s, 3H) 4.06 (q, J=6.8Hz, 2H) 5.98 (s, 1H) 6.81-6.88 (m, 4H) 7.35 (br.s, 1H) 7.62 (d, J=8.4Hz, 2H) 8.76 (br.s, 2H) Mass spectrum (ESI)m/z: 463 (M+H)+
[1467] Example X-38: A-i\(K) and
(S)-[2-fluoro-3-('2-fluoroethoxv)-5-methvlphenvn-('5-oxo-l-pvrimidin-2-yl-4.5-dihydro-lH-ri.2.4]triazol-3-yl)methvl]amino)benzarmdine acetate [1468] [Chemical Formula 622]
'H-NMR (CD3OD) 8 1.92 (s, 3H) 2.25 (s, 3H) 4.21-4.31 (m, 2H) 4.64-4.79 (m, 2H) 5.94 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.88-6.93 (m, 2H) 7.29 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1469] Example X-39:
4-{[[2-fluoro-5-f2-fluoroethoxvV3-f2-methoxvethoxy")phenyl]-(5-oxo-l-pvrimidin-2-vl-4,5-dihvdro-lH-[1.2.4]triazoI-3-vOmethyl]aminolbenzam idine acetate

[1470] [Chemical Formula 623]

:H-NMR (CD3OD) 8 1.97 (s, 3H) 3.42 (s, 3H) 3.74-3.76 (m, 2H) 4.09-4.18 (m, 4H) 4.57-4.73 (m, 2H) 6.01 (s, 1H) 6.64-6.72 (m, 2H) 6.87 (d, J=8.0Hz, 2H) 7.36 (t, J=4.8Hz, 1H) 7.63 (d, J=8.0Hz, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 541 (M+H)+
[1471] Example X-40: 4-fffR) and
(SVfS-ethoxv-S-methvlphenvn-rS-oxo-l-pvrimidin^-vl^.S-dihvdro-lH-[1.2,4]triazol-3-yDmethyl]amino}benzamidine acetate [1472] [Chemical Formula 624]
'H-NMR (CD3OD) 8 1.33 (t, J=6.8Hz, 3H) 1.91 (s, 3H) 2.29 (s, 3H) 3.99 (q, J=6.8Hz, 2H) 5.55 (s, 1H) 6.67 (s, 1H) 6.85 (d, J=9.2Hz, 2H) 6.90 (s, 1H) 6.94 (s, 1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1473] Example X-41: 4-U(R) and
(S')-[3-(2-fluoroethoxv')-5-methvlphenvl]-f 5-oxo-l-pvrimidin-2-vl-4.5-di hvdro-lH-[1.2,4]triazol-3-vnmethvl]amino}benzamidine acetate [1474] [Chemical Formula 625]


'H-NMR (CD3OD) 5 1.91 (s, 3H) 2.29 (s, 3H) 4.11-4.21 (m, 2H) 4.59-4.73 (m, 2H) 5.57 (s, 1H) 6.72 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.95 (s, 1H) 6.98 (s, 1H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1475] Example X-42: 4-fffRl and
(S')-[2-fluoro-5-f2-fluoroethoxv')phenvl1-r5-oxo-l-pvrimidin-2-vl-4.5-dih vdro-lH-[1.2.4]triazol-3-vDmethvl]amino}benzamidine acetate [1476] [Chemical Formula 626]

'H-NMR (CD3OD) 8 1.93 (s, 3H) 4.10-4.20 (m, 2H) 4.57-4.72 (m, 2H) 5.95 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.91-6.95 (td, J=3.6, 9.2Hz, 1H) 7.07 (t, J=5.2Hz, 1H) 7.14 (dd, J=2.8, 5.6Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 13 min
[1477] Example X-43: 4-iUR) and
(S)-[3-ethoxy-2-fluoro-5-f2-fluoroethoxy)phenyl]-(5-oxo-l-pvrimidin-2-yl-4.5-dihvdro-lH-[1.2.4]triazol-3-v0methvnamino}benzamidine acetate [1478] [Chemical Formula 627]


]H-NMR (CD3OD) 8 1.40 (t, J=6.8Hz, 3H) 1.91 (s, 3H) 4.05-4.16 (m, 4H) 4.56-4.71 (m, 2H) 5.94 (s, 1H) 6.63-6.66 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 13 min
[1479] Example X-44:
4-{[[2-fluoro-3-(2-fluoroethoxv)-5-methoxyphenyl1-(l-(3-fluoropvridin-
2-vlV5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvl1amino}benzarnidi
ne acetate
[1480] [Chemical Formula 628]

'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.73 (s, 3H) 4.23-4.32 (m, 2H) 4.65-4.80 (m, 2H) 6.01 (s, 1H) 6.63-6.69 (m, 2H) 6.87 (d, J=8.8Hz, 2H) 7.56 (quintet, J=4.4Hz, 1H) 7.64 (d, J=8.8Hz, 2H) 7.83 (t, J=8.4Hz, 1H) 8.37 (d, J=4.4Hz, 1H) Mass spectrum (ESI)m/z: 514 (M+H)+
[1481] Example X-45: 4-i\(K) and
(SH2-fluoro-3-methoxy-5-methvlphenvlV(5-oxo-l-pyrimidin-2-vl-4,5-di hydro-lH-[1.2.41triazol-3-yOmethvl]amino}benzamidine acetate [1482] [Chemical Formula 629]


'H-NMR (CD3OD) 8 1.91 (s, 3H) 2.21 (s, 3H) 3.80 (s, 3H) 5.93 (s, 1H) 6.81-6.86 (m, 2H) 6.82 (d, J=9.2Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.59 (d, J=9.2Hz, 2H) 8.72 (d, J=4.8Hz, 2H) HPLC retention time: 12 min
[1483] Example X-46: 4-(f(Rl and
fSW3-ethoxy-4-methoxvphenvD-(5-oxo-l-pyrazin-2-yl-4.5-dihvdro-lH-[ l,2.4]triazol-3-yOmethvI]amino)benzamidine acetate [1484] [Chemical Formula 630]

'H-NMR (CD3OD) 8 1.36 (t, J=6.8Hz, 3H) 1.92 (s, 3H) 3.81 (s, 3H) 4.04 (q, J=6.8Hz, 2H) 5.58 (s, 1H) 6.83-6.87 (m, 2H) 6.94 (d, J=8.4Hz, 1H) 7.08 (dd, J=1.6, 8.0Hz, 1H) 7.14 (d, J=2.4Hz, 1H) 7.57-7.61 (m, 2H) 8.40 (d, J=2.4Hz, 1H) 8.47 (br.s, 1H) 9.42 (d, J=1.2Hz, 1H) HPLC retention time: 13 min
[1485] Example X-47: 4-frfR) and
(SV(8-fluoromethoxv-4H-benzo[1.3]dioxin-6-yl)-(5-oxo-l-pvrimidin-2-y l-4.5-dihvdro-lH-n.2.4]triazol-3-vnmethvnamino)benzamidine acetate [1486] [Chemical Formula 631]


'H-NMR (CD3OD) 5 1.91 (s, 3H) 4.87 (s, 2H) 5.24 (s, 2H) 5.59 (s, 1H) 5.68 (d, J=54.0Hz, 2H) 6.85 (d, J=8.8Hz, 2H) 7.01 (d, J=1.2Hz, 1H) 7.23 (d, J=1.2Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 16 min
[1487] Example X-48:
2-f4-[(4-carbamimidovlphenvlaminoW5-oxo-l-pyrimidin-2-vl-4.5-dihvd
ro-lH-[1.2.4]triazol-3-vDmethvl1-2-methoxyphenoxy}-N.N-dimethvlacet
amide trifluoroacetate
[1488] [Chemical Formula 632]

'H-NMR (CD3OD) 5 2.96 (s, 3H) 3.08 (s, 3H) 3.86 (s, 3H) 4.81 (s, 2H) 5.67 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.93 (d, J=8.4Hz, 1H) 7.06 (dd, J=8.4, 2.0Hz, 1H) 7.19 (d, J=2.0Hz, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 518 (M+H)+
[1489] Example X-49:
2-(3-((4-carbamimidovlphenvlaminoV[3-(3-dimethvlamino-2.2-dimethvl propoxy")-5-ethvl-2-fluorophenvl]methvU-5-0X0-4.5-dihvdro-lH-f 1.2.4]t riazol-1 -vDbenzamide bistrifluoroacetate [1490] [Chemical Formula 633]


Mass spectrum (ESI)m/z: 603 (M+H)+
[1491] Example X-50: (R) and
fSV2-{34(4-carbamimidovlphenvlaminoW3-ethoxv-4-methoxyphenvOm ethvl1-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vUbenzoic acid acetate [1492] [Chemical Formula 634]

'H-NMR (d6-DMSO) 8 1.31 (br.s, 3H) 3.74 (s, 3H) 4.01 (br.s, 2H) 5.36 (s, 1H) 6.84 (br.d, J=6.0Hz, 2H) 6.95 (br.d, J=8.4Hz, 1H) 7.05 (br.d, J=6.4Hz, 1H) 7.21-7.33 (m, 3H) 7.52 (br.d, J=7.6Hz, 2H) 7.68 (br.d, J=6.4Hz, 1H) 8.36 (br.s, 1H) (data for racemic mixture) Mass spectrum (ESI)m/z: 503 (M+H)+(data for racemic mixture) HPLC retention time: 12 min
[1493] Example X-51:
4-(([3-methoxv-4-(2-methoxv-l-methylethoxv)phenvl1-[l-(2-methoxvph
envl)-5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvUamino)benzamidi
ne trifluoroacetate
[1494] [Chemical Formula 635]



3H) 7.65 (d, J=8.8Hz, 2H) 7.96 (dd, J=7.6, 1.2Hz, 1H) Mass spectrum (ESI)m/z: 477 (M+H)+
[1499] Example X-54:
2-f3-{(4-carbamimidoylphenvlaminoV[3-methoxy-4-(tetrahydrofuran-3-v
loxy)phenvl]methvU-5-oxo-4,5-dihvdro-n.2.4]triazol-l-vnbenzamide
trifluoroacetate
[1500] [Chemical Formula 638]

Mass spectrum (ESI)m/z: 544 (M+H)+
[1501] Example X-55: (R) and
(S")-4-{[(4-cvanomethoxv-3-fluoro-5-methoxvphenYl)-(5-oxo-l-pvrimidi
n-2-yl-4,5-dihvdro-lH-[1.2.41triazol-3-yl)methyl]amino}benzamidine
acetate
[1502] [Chemical Formula 639]

Mass spectrum (ESI)m/z: 490 (M+H)+(data for racemic mixture) HPLC retention time: 13 min
[1503] Example X-56:
2-(3-[f4-carbamimidoylphenvlamino)-f2-fluoro-4-methoxvphenvl)methyl ]-5-oxo-4,5-dihvdro-n.2.4]triazol-l-vl>benzoic acid trifluoroacetate [1504] [Chemical Formula 640]


'H-NMR (CD3OD) 5 3.81 (s, 3H) 5.92 (s, 1H) 6.80 (m, 2H) 6.86 (d, J=8.8Hz, 2H) 7.38-7.66 (m, 4H) 7.63 (d, J=8.8Hz, 2H) 7.96 (dd, J=7.2, 1.6Hz, 1H) Mass spectrum (ESI)m/z: 477 (M+H)+
[1505] Example X-57:
2-(3-[(4-carbamimidoylphenylaminoV(2-fluoro-4.5-dimethoxyphenynme thvl]-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vUphenvOcarbamic acid methyl ester trifluoroacetate [1506] [Chemical Formula 641]

'H-NMR (CD3OD) 8 3.67 (s, 3H) 3.77 (s, 3H) 3.84 (s, 3H) 5.98 (s, 1H)
6.86 (m, 1H) 6.88 (d, J=8.8Hz, 2H) 7.05 (d, J=7.2Hz, 1H) 7.02 (m, 1H)
7.03 (m, 1H) 7.44 (dd, J=8.0, 1.6Hz, 1H) 7.64 (d, J=8.8Hz, 2H) 8.80 (m,
1H)
Mass spectrum (ESf)m/z: 536 (M+H)+
[1507] Example X-58:
4-{[[3-methoxv-4-(2-methoxvethoxv)phenvn-(5-oxo-l-pvrimidin-2-vl-4,
5-dihvdro-lH-[1.2.4]triazol-3-vDmethyl]amino}benzamidine
trifluoroacetate
[1508] [Chemical Formula 642]


1 H-NMR (CD3OD) 8 3.41 (s, 3H) 3.73 (m, 2H) 3.84 (s, 3H) 4.12 (m, 2H) 5.67 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 6.99 (d, J=8.0Hz, 1H) 7.08 (dd, J=8.0, 2.0Hz, 1H) 7.16 (d, J=2.0Hz, 1H) 7.38 (t, J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.79 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 491 (M+H)+
[1509] Example X-59:
4-{[["3-allvloxv-2-fluoro-5-methoxvphenvlV(5-oxo-l-pvrimidin-2-vl-4.5-dihydro-lH-fl,2.4]triazol-3-vDmethvl]amino)benzamidine acetate [1510] [Chemical Formula 643]

'H-NMR (CD3OD) 5 1.94 (br.s, 3H) 3.76 (br.s, 3H) 4.60 (br.s, 2H) 5.24
(br.d, J=10Hz, 1H) 5.45 (br.d, J=17Hz, 1H) 5.97 (br.s, 1H) 6.03 (m, 1H)
6.62 (br.s, 2H) 6.84 (br.s, 2H) 7.35 (br.s, 1H) 7.61 (br.s, 2H) 8.81 (br.s,
2H)
Mass spectrum (ESI)m/z: 491 (M+H)+
[1511] Example X-60: (R) and
(SV4-{[[3-fluoromethoxv-4-methoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4. 5-dihvdro-lH-[1.2.4]triazol-3-vnmethvl]amino>benzamidine acetate [1512] [Chemical Formula 644]


'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.83 (s, 3H) 5.64 (s, 1H) 5.66 (d, J=54Hz, 2H) 6.87 (d, J=8.8Hz, 2H) 7.04 (d, J=8.4Hz, 1H) 7.28 (br.d, J=8.4Hz, 1H) 7.32 (m, 2H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) (data for racemic mixture)
Mass spectrum (ESI)m/z: 465 (M+H)+(data for racemic mixture) HPLC retention time: 13 min
[1513] Example X-61:
4-(r('3-ethoxv-5-fluoro-4-methoxvphenvn-(5-oxo-l-pvrimidin-2-vl-4.5-d ihvdro-1 H-[ 1.2.41triazol-3-vl)methvl]amino)benzamidine acetate [1514] [Chemical Formula 645]

1 H-NMR (CD3OD) 6 1.36 (t, J=7.2Hz, 3H) 1.93 (s, 3H) 3.82 (s, 3H) 4.04 (q, J=7.2Hz, 2H) 5.64 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.95 (dd, J=10.8, 1.6Hz, 1H) 7.03 (br.s, 1H) 7.32 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 479 (M+H)+
[1515] Example X-62: (R) and
rS)-4-([[3.4-dimethoxv-5-f2-methoxvethvl)phenyl]-(5-oxo-l-pvridazin-3
-yl-4.5-dihydro-lH-fl.2.4]triazol-3-yDmethyllamino}benzamidine
acetate
[1516] [Chemical Formula 646]


'H-NMR (CD3OD) 8 1.94 (s, 3H) 2.84 (t, J=6.8Hz, 2H) 3.54 (t, J=6.8Hz, 2H) 3.77 (s, 3H) 3.82 (s, 3H) 5.64 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.03 (d, J=2.0Hz, 1H) 7.13 (d, J=2.0Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 7.77 (dd, J=8.8, 4.8Hz, 1H) 8.50 (dd, J=8.8, 1.2Hz, 1H) 9.03 (dd, J=4.8, 1.2Hz, 1H) (data for racemic mixture)
Mass spectrum (ESI)m/z: 505 (M+H)+(data for racemic mixture) HPLC retention time: 9 min
[1517] Example X-63:
2-f3-((4-carbamimidovlphenvlamino')-['3-f2-dimethvlaminopropoxvV5-et hvl-2-fluorophenvnmethvU-5-0X0-4.5-dihvdro-rK2.41triazol-l-vnbenza mide bistrifluoroacetate [1518] [Chemical Formula 647]

Mass spectrum (ESI)m/z: 575 (M+H)+
[1519] Example X-64:
2-(3-{(4-carbamimidovlphenvlamino)-[3-(2-dimethvlamino-l-methyletho xv)-5-ethvl-2-fluorophenvllmethvl>-5-oxo-4.5-dihvdro-[l,2.4]triazol-l-v Hbenzamide bistrifluoroacetate [1520] [Chemical Formula 648]


Mass spectrum (ESI)m/z: 575 (M+H)+
[1521] Example X-65: (R) and
(S)-4-{fr4-fluoro-3-f2-fluoroethoxv)-5-methoxvphenvll-f5-oxo-l-pvrimi
din-2-yl-4,5-dihvdro-lH-n.2.4]triazol-3-vnmethvnaminolbenzamidine
acetate
[1522] [Chemical Formula 649]

Mass spectrum (ESI)m/z: 497 (M+H)+(data for racemic mixture) HPLC retention time: 13 min
[1523] Example X-66:
4-([f4-methoxv-3.5-dimethylphenvn-('5-oxo-l-pvrimidin-2-vl-4,5-dihydr o-lH-[l .2.4]triazol-3-vOmethvl1amino} benzamidine acetate [1524] [Chemical Formula 650]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 2.25 (s, 6H) 3.68 (s, 3H) 5.55 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.02 (s, 2H) 7.32 (t, J=4.4Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.78 (d, J=4.4Hz, 2H)

Mass spectrum (ESI)m/z: 445 (M+H)+
[1525] Example X-67:
4-ir(,4-methoxv-3-methvlphenvn-fl-f2-methoxvphenvl)-5-oxo-4.5-dihvd ro-lH-[1.2.4]triazol-3-yl)methyllamino}benzamidine acetate [1526] [Chemical Formula 651]

'H-NMR (CD3OD) 5 1.93 (s, 3H) 2.21 (s, 3H) 3.81 (s, 3H) 3.83 (s, 3H) 5.57 (s, 1H) 6.85 (d, J=8.4Hz, 2H) 6.94 (d, J=8.0Hz, 1H) 7.03 (t, J=7.6Hz, 1H) 7.14 (d, J=8.4Hz, 1H) 7.30 (m, 3H) 7.44 (t, J=8.0Hz, 1H) 7.62 (d, J=8.4Hz, 2H) Mass spectrum (ESI)m/z: 459 (M+H)+
[1527] Example X-68:
4-(fr4-difluoromethoxv-3-methoxvphenvn-(5-oxo-l-pyrimidiii-2-vl-4.5-
dihvdro-lH41.2.4]triazol-3-yQmethvl]amino}benzamidine
trifluoroacetate
[1528] [Chemical Formula 652]

'H-NMR (CD3OD) 8 3.88 (s, 3H) 5.76 (s, 1H) 6.70 (t, J=75.2Hz, 1H)
6.88 (d, J=8.8Hz, 2H) 7.15 (m, 2H) 7.32 (s, 1H) 7.38 (br.s, 1H) 7.62 (d,
J=8.8Hz, 2H) 8.80 (br.s, 2H)
Mass spectrum (ESI)m/z: 483 (M+H)+
[1529] Example X-69:

4-(((2-fluoro-4.5-dimethoxvphenvn-ri-r2-hvdroxvinethvlDhenvn-5-oxo-
4.5-dihvdro-lH-n.2.41triazol-3-vnmethvl1aminolbenzamidine
trifluoroacetate
[1530] [Chemical Formula 653]

JH-NMR (d6-DMSO) 5 3.77 (s, 3H) 3.82 (s, 3H) 4.54 (d, J=3.2Hz, 2H) 5.96 (s, 1H) 6.85 (d, J=11.6Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.02 (d, J=6.8Hz, 1H) 7.34-7.64 (m, 4H) 7.64 (d, J=8.8Hz, 2H) Mass spectrum (ESI)m/z: 493 (M+H)+
[1531] Example X-70:
4-(r('4-fluoro-3.5-dimethoxvphenvI'>-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro -lH-fl.2.41triazol-3-vl)methvl1amino}benzamidine acetate r 15321 [Chemical Formula 654]
Mass spectrum (ESI)m/z: 465 (M+H)+
[1533] Example X-71:
4-([f3-cvanomethoxv-4-methoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dih ydro-lH-n.2.4]triazol-3-vnmethvllamino)benzamidine trifluoroacetate [1534] [Chemical Formula 655]


'H-NMR (CD3OD) 8 3.75 (s, 3H) 4.85 (s, 2H) 5.96 (s, 1H) 6.70 (d, J=8.8Hz, 2H) 6.97 (d, J=8.4Hz, 1H) 7.17 (m, 2H) 7.26 (t, J=4.8Hz, 1H) 7.50 (d, J=8.8Hz, 2H) 8.68 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 472 (M+H)+
[1535] Example X-72: (R) and
(SM-{[Q.4-dimethoxy-5-methoxymethylphenvlW5-oxo-l-pyridazin-3-v l-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvnamino>benzamidine acetate [1536] [Chemical Formula 656]

!H-NMR (CD3OD) 8 1.94 (s, 3H) 3.35 (s, 3H) 3.77 (s, 3H) 3.84 (s, 3H)
4.44 (s, 2H) 5.67 (s, 1H) 6.87 (d, J=9.2Hz, 2H) 7.18 (d, J=2.0Hz, 1H)
7.21 (d, J=2.0Hz, 1H) 7.60 (d, J=9.2Hz, 2H) 7.77 (dd, J=9.2,4.8Hz, 1H)
8.50 (dd, J=8.8, 1.2Hz, 1H) 9.03 (dd, J=4.8, 1.2Hz, 1H) (data for racemic
mixture)
HPLC retention time: 9 min
[1537] Example X-73: (R) and
(SM-(((2-fluoro-4.5-dimethoxvphenvlWl-(3-hydroxvpyridin-2-vD-5-ox o-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvnamino}benzamidine acetate [1538] [Chemical Formula 657]

'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.74 (s, 3H) 3.81 (s, 3H) 5.92 (s, 1H) 6.83 (d, J=l 1.6Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.09 (d, J=7.2Hz, 1H) 7.28 (dd, .N8.4, 4.8Hz, 1H) 7.40 (dd, J=8.0, 1.2Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 7.99 (dd, J=4.8, 1.2Hz, 1H) (data for racemic mixture) Mass spectrum (ESI)m/z: 480 (M+H)+(data for racemic mixture) HPLC retention time: 12 min
[1539] Example X-74: (R) and
fS)-4-{[(2-methoxv-6-methvlpvridin-4-vl)-(5-oxo-l-pvridazin-3-vl-4.5-d ihydro-lH-[1.2.4]triazol-3-vl)methvl1aminolbenzamidine acetate [1540] [Chemical Formula 658]

1H-NMR (CD3OD) 5 1.95 (s, 3H) 2.39 (s, 3H) 3.85 (s, 3H) 5.67 (s, 1H) 6.78 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.99 (s, 1H) 7.60 (d, J=8.8Hz, 2H) 7.77 (dd, J=9.2, 4.4Hz, 1H) 8.50 (d, J=9.2Hz, 1H) 9.03 (dd, J=4.8, 1.2Hz, 1H) (data for racemic mixture)
Mass spectrum (ESI)m/z: 432 (M+H)+(data for racemic mixture) HPLC retention time: 12 min
[1541] Example X-75: (R) and
rS>-4-([(2.6-dimethoxvpvridin-4-vl')-(5-oxo-l-pyridazin-3-yl-4.5-dihvdro -lH-[l,2,41triazol-3-vDmethvl]amino}benzamidine acetate [1542] [Chemical Formula 659]


'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.86 (s, 6H) 5.59 (s, 1H) 6.52 (s, 2H) 6.85 (d, J=9.2Hz, 2H) 7.61 (d, J=9.2Hz, 2H) 7.75 (dd, J=9.2, 4.8Hz, 1H) 8.56 (d, J=9.2Hz, 1.2Hz, 1H) 9.00 (dd, J=4.8, 1.2Hz, 1H) (data for racemic mixture)
Mass spectrum (ESI)m/z: 448 (M+H)+(data for racemic mixture) HPLC retention time: 14 min
[1543] Example X-76:
4-{f(2.6-dimethoxvpvridin-4-vl)-f5-oxo-l-pyrazin-2-vl-4.5-dihvdro-lH-[ 1.2.4]triazol-3-yl)methyl]amino)benzamidine acetate [1544] [Chemical Formula 660]

'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.87 (s, 6H) 5.60 (s, 1H) 6.50 (s, 2H) 6.84 (d, J=8.4Hz, 2H) 7.60 (d, J=8.4Hz, 2H) 8.41 (br.s, 1H) 8.48 (br.s, 1H) 9.42 (br.s, 1H) Mass spectrum (ESI)m/z: 448 (M+H)+
[1545] Example X-77: (RJ and
(S)-4-({[3-ethoxv-4-(2-methoxvethoxy)phenvl]-[l-(3-methoxvpvridin-2-
vl')-5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-3-yl]methyl}amino')benzamidine
acetate
[1546] [Chemical Formula 661]


'H-NMR (CD3OD) 8 1.38 (t, J=7.2Hz, 3H) 1.91 (s, 3H) 3.42 (s, 3H)
3.72-3.75 (m, 2H) 3.87 (s, 3H) 4.03-4.12 (m, 2H) 4.13-4.14 (m, 2H) 5.60
(s, 1H) 6.86 (d, J=9.2Hz, 2H) 7.00 (d, J=8.0Hz, 1H) 7.06 (dd, J=2.0,
8.4Hz, 1H) 7.13 (d, J=2.4Hz, 1H) 7.52 (dd, J=4.4, 8.4Hz, 1H) 7.62 (d,
J=9.2Hz, 2H) 7.67 (dd, J=1.6, 8.4Hz, 1H) 8.10 (dd, J=1.2, 4.8Hz, 1H)
(data for racemic mixture)
Mass spectrum (ESI)m/z: 534 (M+H)+
HPLC retention time: 10 min (column: CHIRALPAK™ AD, 2 cmcp * 25
cmL, Manufacturer: Daicel Chemical Industries, Ltd., Mobile phase:
2-propanol/hexane=l/2, 0.1 % trifluoroacetic acid, Elution rate; 9 ml/min)
[1547] Example X-78: (R) and
(S>-4-({[3-methoxv-4-('2-methoxvethoxv')phenvl'|-n-('2-methoxvphenvl')-
5-0X0-4.5-dihvdro-lH-fl .2.41triazol-3-vl]methvl}amino)benzamidine
acetate
[1548] [Chemical Formula 662]
!H-NMR (CD3OD) 8 1.91 (s, 3H) 3.41 (s, 3H) 3.72-3.75 (m, 2H) 3.80 (s, 3H) 3.84 (s, 3H) 4.12-4.14 (m, 2H) 5.61 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.00 (d, J=8.4Hz, 1H) 7.03 (dd, J=1.6, 4.0Hz, 1H) 7.05 (dd, J=2.4, 5.2Hz, 1H) 7.13-7.15 (m, 2H) 7.31 (dd, J=2.0, 7.6Hz, 1H) 7.43 (ddd, J=1.6, 7.6, 9.2Hz, 2H) 7.63 (d, J=8.8Hz, 1H) Mass spectrum (ESI)m/z: 519 (M+H)+

HPLC retention time: 12 min (Column: CHIRALPAK™ AD, 2 cm(p x 25 cmL, Manufacturer: Daicel Chemical Industries, Ltd., Mobile phase: 2-propanol/hexane=2/3, 0.1% trifluoroacetic acid, Elution rate: 9 ml/min)
[1549] Example X-79: (R) and
(S)-3-f3-r(4-carbamimidovl-3-fluorophenylaminoV(3.4-dimethoxvphenyl
)methyl]-5-oxo-4.5-dihydro[1.2.4]triazol-l-yl}thiophene-2-carboxvlic
acid acetate
[1550] [Chemical Formula 663]

'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.82 (s, 3H) 3.84 (s, 3H) 5.56 (s, 1H) 6.60 (dd, J=14.4, 2.0Hz, 1H) 6.69 (dd, J=8.8, 2.0Hz, 1H) 6.97 (d, J=8.8Hz, 1H) 7.06-7.09 (m, 2H) 7.13 (d, J=2.0Hz, 1H) 7.43 (d, J=5.6Hz, 1H) 7.47 (t, J=8.8Hz, 1H)
HPLC retention time: 16 min (Column name: SUM1CHIRAL OA-2500, 30 mmcp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 25 ml/min)
[1551] Example X-80: (R) and
fSV4-(r(5-methoxvchroman-7-vn-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-l H-[l.2,41triazol-3-vnmethvnamino|benzamidine acetate [1552] [Chemical Formula 664]

*H-NMR (CD3OD) 5 1.87-1.94 (m, 5H) 2.58 (t, J=6.4Hz, 2H) 3.78 (s,

3H) 4.06 (t, J=4.8Hz, 2H) 5.52 (s, 1H) 6.58 (d, J=1.2Hz, 1H) 6.66 (d, J=1.2Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 473 (M+H)+(data for racemic mixture) HPLC retention time: 12 min
[1553] Example X-81:
4-({(2-fluoro-4.5-dimethoxvphenvl)41-f3-methvlpvridin-2-yQ-5-oxo-4.5 -dihydro-lH-[1.2.4]triazol-3-vl]methvUamino)benzamidine acetate [1554] [Chemical Formula 665]

'H-NMR (CD3OD) 5 1.97 (s, 3H) 2.27 (s, 3H) 3.77 (s, 3H) 3.83 (s, 3H) 5.96 (s, 1H) 6.86 (d, J=5.6Hz, 1H) 6.87 (d, J=8.8Hz, 2H) 7.05 (d, J=6.8Hz, 1H) 7.44 (dd, J=4.8, 8.0Hz, 1H) 7.64 (d, J=8.8Hz, 2H) 7.86 (dd, J=1.2, 7.6Hz, 1H) 8.37 (d, J=4.0Hz, 1H) Mass spectrum (ESI)m/z: 478 (M+H)+(data for racemic mixture)
[1555] Example X-82: (R) and
(,S)-4-{rf9-methoxv-2.3-dihvdro-5H-benzolein.41dioxepin-7-vn-f5-oxo-
l-pvrimidin-2-vl-4.5-dihvdro-lH-fl.2.4]triazol-3-vl)methvl]amino)benza
midine acetate
[1556] [Chemical Formula 666]

'H-NMR (CD3OD) 8 1.93 (s, 3H) 3.83 (s, 3H) 3.96-4.05 (m, 4H) 4.64 (s, 2H) 5.62 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.02 (d, J=2.4Hz, 1H) 7.19 (d,

J=2.4Hz, 1H) 7.32 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.78 (d,
J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 489 (M+H)+(data for racemic mixture)
[1557] Example X-83: (R) and
(S)-4-{f (8-fluoromethvl-4H-benzo[1.3]dioxin-6-vn-f 5-oxo-l-pyrimidin-2
-vl-4.,5-dmydro-lH-n.2.41triazol-3-vDmethvl]ammo}benzamidine
acetate
[1558] [Chemical Formula 667]

^-NMR (CD3OD) 8 1.92 (s, 3H) 4.88 (m, 2H) 5.26 (s, 2H) 5.30 (s, 1H) 5.42 (s, 1H) 5.58 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.24 (br.s, 1H) 7.28 (t, J=4.8Hz, 1H) 7.45 (br.s, 1H) 7.59 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 477 (M+H)+(data for racemic mixture) HPLC retention time: 14 min
[1559] Example X-84:
2-(4-[(4-carbamimidovlphenvlamino>-('5-oxo-l-o-tolvl-4.5-dihvdro-lH-r 1.2.4]triazol-3-vBmethvl]-2-ethoxvphenoxvl-N-methvlacetamide acetate [1560] [Chemical Formula 668]

'H-NMR (CD3OD) 8 1.41 (t, J=6.8Hz, 3H) 1.96 (s, 3H) 2.19 (s, 3H) 2.81 (s, 3H) 4.11 (q, J=6.8Hz, 2H) 4.51 (s, 2H) 5.68 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.03 (d, J=8.4Hz, 1H) 7.07 (dd, J=2.0, 8.4Hz, 1H) 7.19 (d, J=1.6Hz, 1H) 7.26-7.28 (m, 2H) 7.32-7.35 (m, 2H) 7.63 (d, J=8.8Hz, 2H)

Mass spectrum (ESI)m/z: 530 (M+H)+
[1561] Example X-85: (R) and
(SM-{rr8-f2-fluoroethoxy)-4H-benzo[l,3]dioxin-6-yll-f5-oxo-l-pvrimid
in-2-yl-4.5-dihydro-lH-[1.2.4]triazol-3-vDmethvl]amino}benzamidine
acetate
[1562] [Chemical Formula 669]

'H-NMR (CD3OD) 5 1.92 (s, 3H) 4.20 (q, J=4.0Hz, 1H) 4.27 (q, J=4.0Hz, 1H) 4.62 (t, J=7.6Hz, 1H) 4.74 (t, J=4.4Hz, 1H) 4.86 (m, 2H) 5.24 (s, 2H) 5.52 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.85-6.88 (m, 1H) 7.07 (d, J=1.6Hz, 1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 507 (M+H)+(data for racemic mixture) HPLC retention time: 17 min
[1563] Example X-86: (R) and
fS)-4-([f4-fluoro-3-methoxy-5-methoxvmethylphenvD-f5-oxo-l-pvrimidi
n-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vl)methvl"|amino>benzamidine
acetate
[1564] [Chemical Formula 670]

'H-NMR (CD3OD) 5 1.91 (s, 3H) 3.34 (s, 3H) 3.86 (s, 3H) 4.47 (s, 2H) 5.60 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.18 (d, J=5.6Hz, 1H) 7.26-7.29 (m, 2H) 7.59 (d, J=8.8Hz, 2H) 8.75 (d, J=5.2Hz, 2H)

Mass spectrum (ESI)m/z: 479 (M+H)+(data for racemic mixture) HPLC retention time: 12 min
[1565] Example X-87: (R) and
(S)-4-{[f8-aIlvloxv-4H-benzo[l J]dioxin-6-yO-f5-oxo-l-pyrimidin-2-vl-4,5-dihydro-lH-^.2,4]triazol-3-yl)methvl]aminolbenzamidine acetate [1566] [Chemical Formula 671]

'H-NMR (CD3OD) 5 1.93 (s, 3H) 4.52 (d, J=4.4Hz, 2H) 4.83 (m, 2H) 5.16 (d, J=10.4Hz, 1H) 5.22 (s, 2H) 5.33 (d, J=16.8Hz, 1H) 5.56 (s, 1H) 5.94-6.03 (m, 1H) 6.78-6.90 (m, 3H) 7.03 (s, 1H) 7.31 (br.s, 1H) 7.59 (d, J=7.6Hz, 2H) 8.76 (d, J=4.4Hz, 2H) (data for racemic mixture) Mass spectrum (ESI)m/z: 501 (M+H)+(data for racemic mixture) HPLC retention time: 17 min
[1567] Example X-88: (R) and
(S>-4-{[(3-acetvl-4.5-dimethoxvphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dih vdro-lH-[1.2,4]triazol-3-vDmethyl1amino|benzamidine acetate [1568] [Chemical Formula 672]

'Pi-NMR (CD3OD) 8 1.91 (s, 3H) 2.56 (s, 3H) 3.86 (s, 3H) 3.88 (s, 3H) 5.62 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.27 (t, J=4.8Hz, 1H) 7.38 (d, J=2.0Hz, 1H) 7.42 (d, J=2.0Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.75 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 489 (M+H)+(data for racemic mixture)

HPLC retention time: 13 min
[1569] Example X-89: (R) and
(S)-4-{ff8-methoxy-4-methvl-4H-benzori.31dioxin-6-yQ-f5-oxo-l-pvrim
idin-2-vl-4.5-dihvdro-1 H-[ 1.2.4]triazol-3-v0methvllamino} benzamidine
acetate
[1570] [Chemical Formula 673]

'H-NMR (CD3OD) 8 1.47, 1.52 (each d, J=6.8Hz, total 3H) 1.92 (s, 3H) 3.81, 3.82 (each s, total 3H) 5.03 (q, J=6.4Hz, 1H) 5.15 (d, J=6.0Hz, 1H) 5.29 (d, J=5.6Hz, 1H) 5.57 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.92 (s, 1H) 7.07 (s, 1H) 7.32 (t, J=4.8Hz, 1H) 7.61 (d, J=9.2Hz, 2H) 8.78 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 489 (M+H)+(data for racemic mixture) HPLC retention time: 15 min
[1571] Example X-90:
2-{4-r(4-carbamimidovlphenvlamino)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvd ro-lH-[1.2.41triazol-3-vnmethyl]-2-ethoxvphenoxv)-N-methvlacetamide

'H-NMR (CD3OD) 5 1.40 (t, J=6.8Hz, 3H) 1.97 (s, 3H) 2.81 (s, 3H) 4.06-4.14 (m, 2H) 4.50 (s, 2H) 5.67 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.02 (d, J=8.4Hz, 1H) 7.10 (br.d, J=8.4Hz, 1H) 7.22 (br.s, 1H) 7.37 (t,

J=4.8Hz, 1H) 7.62 (d, J=8.8Hz, 2H) 8.80 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 518 (M+H)+
[1573] Example X-91:
4-([f3-fluoromethyl-4.5-dimethoxyphenvl)-(5-oxo-l-pyrimidin-2-vl-4.5-dihvdro-lH-[1.2,4]triazol-3-vl)methvl]amino}benzamidine acetate [1574] [Chemical Formula 675]

' H-NMR (CD3OD) 8 1.92 (s, 3H) 3.80 (s, 3H) 3.86 (s, 3H) 5.31 (s, 1H) 5.43 (s, 1H) 5.61 (s, 1H) 6.86 (d, J=8.0Hz, 2H) 7.19 (s, 1H) 7.28 (s, 2H) 7.60 (d, J=8.0Hz, 2H) 8.77 (br.s, 2H) Mass spectrum (ESI)m/z: 479 (M+H)+
[1575] Example X-92: (R) and
fS)-4-( [(8-acetoxv-4H-benzon.31dioxin-6-vn-f 5-oxo-l -pyrimidin-2-yl-4 .5-dihvdro-lH-[1.2.41triazol-3-vl)methvl]amino}benzamidine acetate [1576] [Chemical Formula 676]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 2.58 (s, 3H) 4.93 (m, 2H) 5.34 (s, 2H) 5.62 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.41 (br.s, 1H) 7.59 (d, J=8.8Hz, 2H) 7.79 (br.s, 1H) 8.75 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 487 (M+H)+(data for racemic mixture) HPLC retention time: 16 min
[1577] Example X-93:
2-(3-[C4-carbamimidovlphenvlamino)-(3-ethoxv-4-methvlcarbamovlmeth

oxvphenvlWthvl]-5-oxo-4J-dihvdro-lH-[1.2.41triazol-l-vl}benzarnidin
e acetate
[1578] [Chemical Formula 677]

'H-NMR (CD3OD) 8 1.41 (t, J=7.2Hz, 3H) 1.93 (s, 3H) 2.82 (s, 3H) 4.10-4.15 (m, 2H) 4.50 (s, 2H) 5.63 (s, 1H) 6.87 (d, J=8.8Hz, 2H) 7.03 (d, J=8.4Hz, 1H) 7.08 (dd, J=1.6, 8.0Hz, 1H) 7.19 (d, J=2.0Hz, 1H) 7.46 (dt, J=1.6, 7.2Hz, 2H) 7.52 (dd, J=1.2, 8.0Hz, 1H) 7.57 (ddd, J=1.6, 7.2, 8.0Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 7.66 (dd, J=1.6, 8.0Hz, 1H) Mass spectrum (ESI)m/z: 559 (M+H)+
[1579] Example X-94:
4-{r(8-bromo-2.3-dihvdrobenzon.4]dioxin-6-vl)-r5-oxo-l-pvrimidin-2-v l-4.5-dihvdro-lH-ri.2.41triazol-3-vnmethyl"|aminolbenzamidine acetate [1580] [Chemical Formula 678]

'H-NMR (CD3OD+CD3C02D) 5 4.26 (t, J=2.8Hz, 2H) 4.34 (t, J=3.6Hz, 2H) 5.67 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 7.06 (d, J=2.0Hz, 1H) 7.32 (d, J=2.0Hz, 1H) 7.40 (t, J=4.4Hz, 1H) 7.65 (d, J=8.8Hz, 2H) 8.82 (d, J=4.4Hz, 2H) Mass spectrum (ESI)m/z: 523 (M+H)+
[1581] Example X-95:
4-({(2-fluoro-4.5-dimethoxyphenvl')-r5-oxo-l-(3-trifluoromethvlpvridin-2-vn-4,5-dihvdro-lH-[1.2,41triazol-3-vnmethvUamino')benzamidine

acetate
[1582] [Chemical Formula 679]

'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.75 (s, 3H) 3.82 (s, 3H) 5.90 (s, 1H) 6.84 (d, J=12.0Hz, 1H) 6.85 (d, J=9.2Hz, 2H) 7.05 (d, J=7.2Hz, 1H) 7.62 (d, J=9.2Hz, 2H) 7.72 (ddd, J=0.4, 4.4, 8.0Hz, 1H) 8.34 (dd, J=1.2, 8.0Hz, 1H) 8.79 (dd, J=1.6, 5.2Hz, 1H) Mass spectrum (ESI)m/z: 532 (M+H)+
[1583] Example X-96:
4-f[(8-methoxymethyl-2,3-dihydrobenzofl.4]dioxin-6-vlW5-oxo-1-pvri
midin-2-vl-4.5-dihvdro-lH-ri.2.41triazol-3-vl)methyl1amino}benzamidin
e acetate
[1584] [Chemical Formula 680]

'H-NMR (CD3C02D) 5 3.41 (s, 3H) 4.22-4.32 (m, 4H) 4.51 (s, 2H) 5.77 (s, 1H) 6.92 (d, J=8.8Hz, 2H) 7.06 (d, J=2.0Hz, 1H) 7.18 (d, J=2.0Hz, 1H) 7.42 (t, J=4.8Hz, 1H) 7.71 (d, J=8.8Hz, 2H) 8.92 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 489 (M+H)+
[1585] Example X-97:
4-{[(2-fluoro-4.5-dimethoxvphenyl')-(5-oxo-l-thiazol-2-vl-4.5-dihvdro-l H-ri.2.4]triazol-3-vnmethvl1amino>benzamidine acetate [1586] [Chemical Formula 681]
631


1 H-NMR (CD3OD) 8 1.93 (s, 3H) 3.72 (s, 3H) 3.79 (s, 3H) 5.89 (s, 1H) 6.79 (d, J=l0.4Hz, 1H) 6.84 (d, J=8.8Hz, 2H) 7.10 (d, J=6.8Hz, 1H) 7.23 (d, J=3.6Hz, 1H) 7.49 (d, J=3.6Hz, 1H) 7.58 (d, J=8.8Hz, 2H) Mass spectrum (ESI)m/z: 470 (M+H)+
[1587] Example X-98:
4-{fr7-methoxvbenzo[1.31dioxol-5-yn-f 5-oxo-l-pvrimidin-2-vl-4.5-dihy dro- 1H-T1.2.41triazol-3-vnmethvllaminolbenzamidine acetate [1588] [Chemical Formula 682]

1 H-NMR (CD3OD) 8 1.94 (s, 3H) 3.86 (s, 3H) 5.58 (br.s, 1H) 5.92 (s, 2H) 6.73 (br.s, 1H) 6.78-6.82 (m, 3H) 7.34 (br.s, 1H) 7.62 (br.s, 2H) 8.78 (br.s, 2H) Mass spectrum (ESI)m/z: 461 (M+H)+
[1589] Example X-99:
5-ff4-carbamimidovlphenvlaminoVf5-oxo-l-l-pvrimidin-2-yl-4.5-dihvdr o-lH-n.2.41triazol-3-yDmethyl]-7-methoxvbenzofuran-2-carboxvlic acid amide acetate [1590] [Chemical Formula 683]


'H-NMR (CD3OD) 5 1.89 (s, 3H) 3.98 (s, 3H) 5.65 (s, 1H) 6.86 (d, J=9.2Hz, 2H) 7.23 (t, J=4.8Hz, IH) 7.27 (d, J=1.2Hz, 1H) 7.43 (s, 1H) 7.47 (br.s, IH) 7.57 (d, J=8.8Hz, 2H) 8.74 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 500 (M+H)+
[1591] Example X-100:
4-{[f7-methoxv-2-methoxvmethvlbenzofuran-5-vn-(5-oxo-l-pvrimidin-2
-vl-4.5-dihvdro-lH-[1.2.41triazol-3-vnmethvl]amino}benzamidine
acetate
[1592] [Chemical Formula 684]

'H-NMR (CD3OD) 8 1.90 (s, 3H) 3.36 (s, 3H) 3.91 (s, 3H) 4.49 (s, 2H) 5.67 (s, IH) 6.68 (s, IH) 6.84 (d, J=8.8Hz, 2H) 7.09 (s, IH) 7.23 (br.s, IH) 7.33 (s, IH) 7.55 (d, J=8.8Hz, 2H) 8.73 (d, J=4.0Hz, 2H) Mass spectrum (ESI)m/z: 501 (M+H)+
[1593] Example X-101: methanesulfonic acid 6-[(R) and (S)-(4-carbamimidoylphenvlamino)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro -lH-fl.2.4]triazol-3-yl)methvl]-4H-benzo[1.3]dioxin-8-vl ester acetate [1594] [Chemical Formula 685]


'H-NMR (CD3OD) 5 1.93 (s, 3H) 3.23 (s, 3H) 4.91 (m, 2H) 5.30 (s, 2H) 5.60 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 7.23 (d, J=1.6Hz, 1H) 7.29 (d, J=4.4Hz, 1H) 7.39 (d, J=2.4Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 539 (M+H)+(data for racemic mixture) HPLC retention time: 16 min
[1595] Example X-102:
4-(r(7-methoxv-3-oxo-2.3-dihvdrobenzofuran-5-yQ-(5-oxo-l-pyrimidin-
2-vl-4,5-dihydro-lH-[1.2.4]triazol-3-v0methvl]aminolbenzamidine
acetate
[1596] [Chemical Formula 686]

1 H-NMR (CD3OD) 8 1.91 (s, 3H) 3.92 (s, 3H) 4.73 (s, 2H) 5.66 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 7.28 (t, J=4.8Hz, 1H) 7.39 (s, 1H) 7.49 (s, 1H) 7.60 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 473 (M+H)+
[1597] Example X-103: (R) and
(S)-44K8-difluoromethoxv-4H4>enzo[1.3]dioxin-6-ylW5-oxo-l-pvrimid
in-2-yl-4,5-dihvdro-lH41.2.4]triazol-3-yOmethyl]amino)benzamidine
acetate
[1598] [Chemical Formula 687]


'H-NMR (CD3OD) 8 1.92 (s, 3H) 4.59 (br.s, 2H) 5.27 (s, 2H) 5.55 (s, 1H) 6.74 (t, J=74.8Hz, 1H) 6.83 (d, J=8.8Hz, 2H) 7.13 (s, 1H) 7.24 (s, 1H) 7.26 (t, J=5.2Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.75-8.78 (m, 2H) Mass spectrum (ESI)m/z: 511 (M+H)+(data for racemic mixture) HPLC retention time: 13 min
[1599] Example X-104:
4-{[f8-ethvl-2.3-dihvdro-benzori,41dioxin-6-vlVf5-oxo-l-pvrimidin-2-vl -4.5-dihvdro-lH-fl.2.4]triazol-3-vnmethyl]amino>benzamidine acetate [1600] [Chemical Formula 688]

1 H-NMR (CD3OD) 8 1.13 (t, J=7.6Hz, 3H) 1.93 (s, 3H) 2.56 (q, J=7.6Hz, 2H) 4.16-4.25 (m, 4H) 5.55 (s, 1H) 6.80-6.91 (m, 4H) 7.33 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8z, 2H) 8.77 (d, J=4.8Hz, 2H) Mass spectrum (ESI)m/z: 473 (M+H)+
[1601] Example X-105:
4-{[(7-methoxvbenzofuran-5-vlV(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-l H-fl.2.4]triazol-3-vnmethvl]amino>benzamidine acetate [1602] [Chemical Formula 689]

'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.93 (s, 3H) 5.72 (s, 1H) 6.77 (s, 1H) 6.86 (br.d, J=6.4Hz, 2H) 7.08 (br.s, 1H) 7.28 (br.s, 1H) 7.38 (br.s, 1H) 7.57 (br.d, J=6.4Hz, 2H) 7.71 (s, 1H) 8.75 (br.s, 2H) Mass spectrum (ESI)m/z: 457 (M+H)+
[1603] Example X-106: (R) and
rSV4-(r(9-fluoromethvl-3.4-dihvdro-2H-benzorbl[1.41dioxepin-7-vn-r5-oxo-1-pvrimidin^-vl^.S-dihvdro-lH-n^^ltriazol-S-vllmethvllamino^b enzamidine acetate [1604] [Chemical Formula 690]

1 H-NMR (CD3OD) 5 1.92 (s, 3H) 2.17 (quint, J=5.6Hz, 2H) 4.19 (m, 4H) 5.31 (s, 1H) 5.43 (s, 1H) 5.57 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.18 (br.s, 1H) 7.25 (br.s, 1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
Mass spectrum (ESI)m/z: 491 (M+H)+(data for racemic mixture) HPLC retention time: 13 min
[1605] Example X-107:
4-([f2-chloro-4.5-dimethoxvphenvn-f 5-oxo-l-pyrimidin-2-vl-4.5-dihvdr o-lH-[1.2,4]triazol-3-vOmethvl]amino}benzamidine acetate [1606] [Chemical Formula 691 ]


'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.74 (s, 3H) 3.82 (s, 3H) 6.00 (s, 1H) 6.82 (d, J=8.8Hz, 2H) 7.03 (s, 1H) 7.16 (s, 1H) 7.31 (br.s, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (br.s, 2H) Mass spectrum (ESI)m/z: 481 (M+H)+
[1607] Example X-108:
2-{3-[(4-carbamimidoylphenylamino)-(5-oxo-l-pvrimidin-2-vl-4.5-dihyd ro-lH-ri.2.4]triazol-3-vnmethvl]-5-ethvl-2-fluorophenoxv>-N.N-dimeth ylacetamide trifluoroacetate [1608] [Chemical Formula 692]

'H-NMR (CD3OD) 8 1.17 (t, J=7.7Hz, 3H) 2.50 (q, J=7.7H, 2H) 2.91 (s, 3H) 3.04 (s, 3H) 4.90 (s, 2H) 6.00 (s, 1H) 6.82-6.95 (m, 4H) 7.41 (br.s, 1H) 7.59 (d, J=8.8Hz, 2H) 8.77 (br.s, 2H) Mass spectrum (ESI)m/z: 534 (M+H)+
[1609] Example X-109:
4-{[n-f2-aminophenvn-5-oxo-4.5-dihvdro-lH-ri.2.41triazol-3-vn-f2-flu oro-3, 5-dimethoxvphenvDmethvDamino}benzamidine trifluoroacetate [1610] [Chemical Formula 693]


'H-NMR (CD3OD) 8 3.64 (s, 3H) 3.77 (s, 3H) 6.04 (s, 1H) 6.60 (dd, J=5.2, 2.6Hz, 1H) 6.67 (dd, J=7.3, 2.6, 1H) 6.88 (d, J=8.7Hz, 2H) 7.10 (t, J=7.6Hz, 1H) 7.16 (d, J=7.6Hz, 1H) 7.30 (t, J=7.6Hz, 1H) 7.44 (d, J=7.6Hz, 1H) 7.65 (d, J=8.7Hz, 2H)
[1611] Example X-110:
3-amino-2-G-((4-carbamimidovlphenylaminoV[2-fluoro-3-(2-fluoroetho xvV5-methoxvphenvl1methvU-5-oxo-4.5-dihvdro-lH-[1.2.41triazol-l-vn -1 -methvlpvridinium bistrifluoroacetate [1612] [Chemical Formula 694]

Two isomers:
'H-NMR (CD3OD) 8 3.73 (s, 3H) 4.03 and 4.08 (s, 3H) 4.24 (m, 1H) 4.31 (m, 1H) 4.66 (m,lH) 4.79 (m,lH) 6.09 and 6.10 (m, 1H) 6.62 and 6.65 (m, 1H) 6.66-6.71 (m, 1H) 6.90 (d, J=8.9Hz, 2H) 7.65 (d, J=8.9Hz, 2H) 7.72 and 7.74 (dd, J=8.1,5.3Hz, 1H) 7.90 (d, J=8.1Hz, 1H) 8.17 and 8.20 (d, J=5.3Hz, 1H)
[1613] Example X-lll:
4-{[[3-(2-dimethvlaminopropoxvV5-ethvl-2-fluorophenvl]-('5-oxo-l-pvri
din-2-vl-4.5-dihydro-lH-[1.2.4]triazol-3-ynmethvl]amino>benzamidine
bistrifluoroacetate
[1614] [Chemical Formula 695]


Two isomers:
'H-NMR (CD3OD) 5 1.20 (t, J=7.8Hz, 3H) 1.45 and 1.47 (d, J=6.9Hz, 3H) 2.62 (q, J=7.8Hz, 2H) 2.95 (s, 6H) 3.83-3.93 (m, 1H) 4.30 (dd, J=11.7, 7.3Hz, 1H) 4.39 (ddd, J=11.7, 3.9, 2.4Hz, 1H) 6.03 (s, 1H) 6.89 (d, J=8.7Hz, 2H) 7.06 (dd, J=5.9, 0.9Hz, 1H) 7.09 (dd, J=7.3, 0.9Hz, 1H) 7.32 (dd, J=7.5, 4.6Hz, 1H) 7.65 (d, J=8.7Hz, 2H) 7.96 (t, J=7.5Hz, 1H) 8.06 (d, J=7.5Hz, 1H) 8.44 (d, J=4.6Hz, 1H)
[1615] Example X-112:
4-r(ri-(2-aminophenvn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vn-[5-eth
vl-2-fluoro-3-(2-fluoroethoxv')phenvl1methvUamino)benzamidine
trifluoroacetate
[1616] [Chemical Formula 696]

1 H-NMR (CD3OD) 8 1.19 (t, J=7.7Hz, 3H) 2.60 (q, J=7.7Hz, 2H) 4.25 (m, 1H) 4.33 (m, 1H) 4.67 (m, 1H) 4.80 (m, 1H) 6.03 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.93 (dd, J=5.2, 2.2Hz, 1H) 6.98 (t, J=7.6Hz, 1H) 6.99 (d, J=6.6, 2.2Hz, 1H) 7.06 (d, J=7.6Hz, 1H) 7.25 (d, J=7.6Hz, 1H) 7.35 (d, J=7.6Hz, 1H) 7.65 (d, J=8.8Hz, 2H)
[1617] Example X-113:
N-[2-(3-{(4-carbamimidovlphenylamino)-[3-(2-dimethvlaminoethoxv>-5-ethvl-2-fluorophenvl]methvU-5-0X0-4.5-dihvdro-lH-[1.2.4]triazol-l-vl')p henvl]acetamide bistrifluoroacetate [1618] [Chemical Formula 697]


'H-NMR (CD3OD) 8 1.20 (t, J=7.8Hz, 3H) 1.97 (s, 3H) 2.63 (q, J=7.8Hz, 2H) 3.00 (s, 6H) 3.64 (t, J=5.5Hz, 2H) 4.44 (t, J=5.5Hz, 2H) 6.04 (s, 1H)
6.87 (d, J=8.7Hz, 2H) 7.03 (dd, J=6.0, 1.4Hz, 1H) 7.07 (dd, J=8.5, 1.4Hz,
1H) 7.26 (t, J=7.5Hz, 1H) 7.37 (t, J=7.5Hz, 1H) 7.45 (d, J=7.5Hz, 1H)
7.65 (d, J=8.7Hz, 2H) 7.73 (d, J=7.5Hz, 1H)
[1619] Example X-114:
[2-(3-((4-fcarbamimidovlphenvlamino)-[3-('2-dimethvlaminoethoxv)-5-et hvl^-fluorophenvllmethvll-S-oxo^.S-dihvdro-lH-ri^^ltriazol-l-vDph envljcarbamic acid methyl ester bistrifluoroacetate [1620] [Chemical Formula 698]

1 H-NMR (CD3OD) 5 1.20 (t, J=7.7Hz, 3H) 2.64 (q, J=7.7Hz, 2H) 3.00 (s, 6H) 3.63 (t, J=5.2Hz, 2H) 3.68 (s, 3H) 4.44 (t, J=5.2Hz, 2H) 6.04 (s, 1H)
6.88 (d, J=8.8Hz, 2H) 7.04 (dd, J=5.6, 1.7Hz, 1H) 7.08 (d, J=7.8, 1.7Hz,
1H) 7.20 (td, J=7.7, 1.5Hz, 1H) 7.35-7.45 (m, 3H) 7.65 (d, J=8.8Hz, 2H)
[1621] Example : X-115:
4-([[3-(2-dimethvlaminoethoxy')-5-ethyl-2-fluorophenvl]-f5-oxo-l-pvrim
idin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethyl]aminolbenzamidine
bistrifluoroacetate
[1622] [Chemical Formula 699]

'H-NMR (CD3OD) 5 1.12 (t, J=7.7Hz, 3H) 2.57 (q, J=7.7Hz, 2H) 2.95 (s, 6H) 3.55 (m, 2H) 4.38 (m, 2H) 6.05 (br.s, 1H) 6.78-7.04 (m, 4H) 7.41 (br.s, 1H) 7.58 (d, J=8.8Hz, 2H) 8.71 (br.s, 2H) Mass spectrum (ESI)m/z: 520 (M+H)+
[1623] Example X-116:
4-{[[5-ethvl-2-fluoro-3-f2-fluofoethoxv')phenyl1-f 5-oxo-l-pvrimidin-2-yl
-4.5-dihvdro-lH-n.2.4]triazol-3-vnmethvl]amino)benzamidine
trifluoroacetate
[1624] [Chemical Formula 700]

1 H-NMR (CD3OD) 8 1.19 (t, J=7.8Hz, 3H) 2.60 (q, J=7.8Hz, 2H) 4.26 (m, 1H) 4,34 (m, 1H) 4.68 (m, 1H) 4.80 (m, 1H) 6.02 (s, 1H) 6.88 (d, J=8.8Hz, 2H) 6.94 (dd, J=5.4, MHz, 1H) 6.99 (dd, J=7.5, 1.4Hz, 1H) 7.37 (t, J=5.1Hz, 1H) 7.65 (d, J=8.8Hz, 2H) 8.80 (d, J=5.1Hz, 2H)
[1625] Example X-117:
2-f3{f4-carbamimidovlphenylaminoV[3-r3-dimethvlamino-2.2-dimethylp ropoxv)-5-ethvlphenvl]methvU-5-oxo-4.5-dihvdro-[1.2,4")triazol-l-vllbe nzoic acid trifluoroacetate [1626] [Chemical Formula 701]


'H-NMR (CD3OD) 8 1.23 (s, 6H) 1.25 (t, J=7.9Hz, 3H) 2.68 (q, J=7.9Hz, 2H) 2.95 (s, 6H) 3.31 (s, 2H) 3.92 (s, 2H) 5.68 (s, 1H) 6.89 (s, 1H) 6.90 (d, J=8.8Hz, 2H) 6.99 (s, 1H) 7.07 (s, 1H) 7.49-7.53 (m, 2H) 7.64-7.67 (m, 3H) 7.94 (dd, J=8.4, 1.4Hz, 1H)
[1627] Example X-118:
4-{rri-r3-aminopvridin-l-vn-5-oxo-4.5-dihvdro-lH-|"L2.41triazol-3-vn-r 8-methoxvchroman-6-vDmethvl]amino}benzamidine trifluoroacetate [1628] [Chemical Formula 702]

1 H-NMR (CD3OD) 5 1.95 (m, 2H) 2.75 (m, 2H) 3.78 (s, 3H) 4.15 (m, 2H) 5.57 (s, 1H) 6.75-6.83 (m, 2H) 6.84 (d, J=8.7Hz, 2H) 7.16-7.42 (br.s, 3H) 7.60 (d, J=8.7Hz, 2H)
[1629] Example X-119:
4-("(("5-difluoromethoxv-2-fluorophenvn-|"l-f2-methoxvphenvn-5-oxo-4.
5-dmvdro-lH-[1.2.4]triazol-3-yl]methvOamino}benzamidine
trifluoroacetate
[1630] [Chemical Formula 703]

t I
'H-NMR (CD3OD) S 3.81 (s, 3H) 6.03 (s, 1H) 6.74 (t, J=73.9Hz, 1H) 6.86 (d, J=8.7Hz, 2H) 7.02 (td, J=5.6, 0.9Hz, 1H) 7.13 (dd, J=5.6, 0.9Hz, 1H) 7.17 (m, 1H) 7.22 (d, J=8.4Hz, 1H) 7.27-7.29 (m, 2H) 7.43 (td, J=8.4, 1.2Hz, 1H) 7.65 (d, J=8.7Hz, 2H)
[1631] Example X-120:
4-([ri-(,3-aminopvridin-2-vlV5-oxo-4.5-dihvdro-lH-|"1.2.4]triazol-3-vn-r 4-ethoxv-3-methoxvphenvl)methvllamino} benzamidine trifluoroacetate [1632] [Chemical Formula 704]

'H-NMR (CD3OD) 8 1.39 (t, J=7.5Hz, 3H) 3.75 (s, 3H) 4.05 (q, J=7.5Hz, 2H) 5.68 (s, 1H) 6.88 (d, J=8.6Hz, 2H) 6.97 (d, J=8.2Hz, 1H) 7.07 (dd, J=8.2, 2.2Hz, 1H) 7.15 (d, J=2.2Hz, 1H) 7.28 (dd, J=8.4, 4.3Hz, 1H) 7.40 (dd, J=4.3, 1.0Hz, 1H) 7.63 (d, J=8.6Hz, 2H) 7.84 (dd, J=4.3,1.0Hz, 1H)
[1633] Example X-121:
4-{[(3-allyloxy-5-fluoromethvlphenvI>-(5-oxo-l-pyrimidin-2-vl-4.5-dihy dro-lH-[1.2.4]triazol-3-yOmethyl]amino}benzamidine acetate [1634] [Chemical Formula 705]


[1635] Example ; X-122:
4-{[[4-(2-fluoroethvl)-8-methoxv-3-oxo-3.4-dihvdro-2H-benzo|'1.4]oxazi n-6-yl1-(5-oxo-l-pvrimidin-2-yl-4J-dihydro-lH4U2,4]triazol-3-vOmeth vl] amino Ibenzamidine acetate [1636] [Chemical Formula 706]

[1637] Example X-123:
4-{[(3-methoxyphenvlW5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[l-2.41t riazol-S-vDmethynaminolbenzamidine acetate [1638] [Chemical Formula 707]

[1639] Example X-124:
4-([[3-r2-fluoroethoxy)phenyl]-('5-oxo-l-pyrimidin-2-yl-4.5-dihydro-lH-fl.2.4]triazoI-3-vOmethvl]amino}benzamidine acetate [1640] [Chemical Formula 708]


[1641] Example X-125:
4-([[3-(2-fluoroethoxv)-5-vinvlphenvll-('5-oxo-l-pvrimidin-2-vl-4.5-dihv dro-lH-n.2.41triazol-3-vDmethvnamino}benzamidine acetate [1642] [Chemical Formula 709]

[1643] Example X-126:
4-(r(3-methoxv-5-vinvlphenvl)-(5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-lH-[1.2,4]triazol-3-yI)methyl]amino}benzamidine acetate [1644] [Chemical Formula 710]

[1645] Example X-127:
2-f3-^4-carbamimidovlphenvlamino)-[2-fluoro-5-methoxy-3-n-methvlp vrrolidin-3-vloxv)phenvl]methyU-5-oxo-4,5-dihvdro-n.2,4]triazol-l-vl) benzoic acid bistrifluoroacetate [1646] [Chemical Formula 711]


[1647] Example X-128:
2-r3-{f4-carbamimidovlphenvlamino)-[4-f2-dimethvlamino-l-methvletho
xv)-3-ethoxvphenvl]methyU-5-oxo-4.5-dihydro-[1.2,4]triazol-l-vl)benzo
ic acid diacetate
[1648] [Chemical Formula 712]

[1649] Example X-129:
4-({[4-f2-dimethylamino-l-methylethoxy)-3-ethoxvphenyl]-[W2-methox
vphenvlV5-oxo-4J-dihvdro-lH4h2,4]triazol-3-yl]methvUamino)benza
midine diacetate
[1650] [Chemical Formula 713]
[1651] Example X-130:
2-(3-{(4-carbamimidovlphenvlamino)-[4-(l-dimethvlcarbamovlethoxv')-3 -ethoxyphenvl]methvU-5-oxo-4,5-dihvdro-[1.2,4]triazol-l-vObenzoic acid acetate



4-{[[3-ethoxy-4-(l-methvlpvrrolidin-3-vloxv)phenvl]-r5-oxo-l-pyridin-2
-vl-4.5-dihvdro-lH-("1.2,41triazol-3-vl)methvl]amino}benzamidine
diacetate
[1658] [Chemical Formula 717]

[1659] Example X-134:
4-({[3-ethoxv-4-(l-methvlpvrrolidin-3-vloxv)phenvn-[l-(2-methoxvphen
vlV5-oxo-4.5-dihydro-lH-[l,2,4]triazol-3-vl]methvUamino)benzamidine
diacetate
[1660] [Chemical Formula 718]

[1661] Example X-135:
2-(4-|(4-carbamimidovlphenvlamino)-[l-('2-fluorophenvl)-5-oxo-4.5-dih
ydro-lH-[1.2.4]triazol-3-vl]methvl}-2-ethoxyphenoxy)-N,N-dimethylpro
pionamide acetate
[1662] [Chemical Formula 719]



















ihydro-lH-[1.2.4]triazol-3-vl]methyl|-2-ethoxvphenoxy)-N.N-dimethvla cetamide trifluoroacetate [1716] [Chemical Formula 746]

[1719] Example X-164:
2-G-((4-carbamimidovlphenvlaminoM4-n-dimethylcarbamovlethoxy)-3
-methoxyphenvl]methvU-5-oxo-4.5-dihvdro-[1.2.41triazol-l-vObenzoic
acid trifluoroacetate
[1720] [Chemical Formula 748]



oxv)-3-methoxvphenyl1methvl}-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vnbe nzamide trifluoroacetate [1726] [Chemical Formula 751]

[1729] Example X-169:
3-(4-{(4-carbamimidovlphenvlamino)-[^^-methoxvphenvl)-5-oxo-4,5-d ihvdro-lH-ri.2.41triazol-3-vllmethvU-2-ethoxvphenoxvV2.2.N.N-tetram ethylpropionamide trifluoroacetate [1730] [Chemical Formula 753]


[1735] Example X-172:
2-(4-{("4-carbamimidovlphenvlaminoV[l-f2-methoxvphenvn-5-oxo-4.5-d ihvdro-lH-[1.2.41triazol-3-vllmethvll-2-methoxvphenoxv')-N,N-dimethvl











2-(3-((4-carbamimidovlphenylamino)-[3-f2-dimethvlamino-l-methvletho xy)-5-ethyl-2-fluorophenvl]methvU-5-oxo-4.5-dihvdro-fl.2.41triazol-l-v 1}benzoic acid bistrifluoroacetate [1766] [Chemical Formula 771]

[1767] Example X-188:
4-{[[3-(3-dimethvlamino-2.2-dimethvlpropoxv')-5-ethvl-2-fluorophenvl]-(5xo-l-pvridin-2-vl-4.5-dihvdro-lH-n.2,4]triazol-3-vOmethvl1aminol benzamidine bistrifluoroacetate [1768] [Chemical Formula 772]

[1769] Example X-189:
2-B-((4-carbamimidovlphenylaminoM3-f2-dimethylaminoethoxv)-5-eth vl-2-fluorophenyl]methvl>-5-oxo-4.5-dihydro-[1.2.4]triazol-l-vU benzoic acid bistrifluoroacetate [1770] [Chemical Formula 773]


[1771] Example ; X-190:
2-f3-[fl-f2-acetvlaminophenyl)-5-oxo-4.5-dihydro-lH-[l,2,4]triazol-3-vl 1-f4-carbamimidovlphenvlamino)methyl]-5-ethvl-2-fluorophenoxy)-N.N-dimethylacetamide trifluoroacetate [1772] [Chemical Formula 774]

'H-NMR (CD3OD) 8 1.17 (t, J=7.8Hz, 3H) 1.90 (s, 3H) 2.58 (q, J=7.8Hz, 2H) 2.98 (s, 3H) 3.10 (s, 3H) 4.92 (s, 2H) 6.04 (s, 1H) 6.88 (d, J=8.6Hz, 2H) 6.90-6.95 (m, 2H) 7.25 (t, J=7.4Hz, 1H) 7.37 (t, J=7.4Hz, 1H) 7.48 (d, J=7.4Hz, 1H) 7.65 (d, J=8.6Hz, 2H) 7.75 (d, J=7.4Hz, 1H)
[1773] Example X-191: 4-{3-rOO and
(SH4-Carbamimidoylphenvlamino)-(5.6-dimethoxvpvridin-3-vDrnethvl] -5-0X0-4.5-dihvdro-n.2.4]triazol-l-vnUhiazole-5-carboxvlic acid [1774] [Chemical Formula 775]

[1775] Example X-192: (R) and
(S)-4-f3-{f4-Carbamimidovlphenvlamino)-[3-(2-hvdroxvethoxvV5-meth
oxvphenvnmethvU-5-oxo-4.5-dihvdro[1.2.41triazol-l-vl)thiazole-5-carb
oxvlic acid
[1776] [Chemical Formula 776]

'H-NMR (CD3OD) 8 3.78 (s, 3H) 3.84 (t, J=4.7Hz, 2H) 4.18 (m, 2H) 5.67 (s, 1H) 6.50 (t, J=1.8Hz, 1H) 6.73 (t, J=1.8Hz, 1H) 6.75 (t, J=1.8Hz, 1H) 6.86 (d, J=9.0Hz, 2H) 7.61 (d, J=9.0Hz, 2H) 8.89 (s, 1H) HPLC retention time: 17 min (Column name: SUMICHIRAL OA-2500, 30 mm 9 x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1777] Example X-193:
5-(34(^-Carbamimidovlphenvlamino)-(3,4-dimethoxyphenvOmethyl]-5-oxo-4,5-dihvdro-fl.2.41triazol-l-yU-lH-pyrazole-4-carboxvlic acid [1778] [Chemical Formula 777]

'H-NMR (CD3OD) 5 3.82 (s, 3H) 3.84 (s, 3H) 5.56 (s, 1H) 6.86 (d, J=9.1Hz, 2H) 6.97 (d, J=7.9Hz, 1H) 7.09 (d, J=7.9, 2.0Hz, 1H) 7.15 (d, J=2.0Hz, 1H) 7.61 (d, J=9.1Hz, 2H) 8.01 (s, 1H)
[1779] Example X-194:
5-{3-[(4-Carbamimidoylphenvlamino)-(5-fluoro-8-methoxvchroman-6-vl )methvl]-5-oxo-4.5-dihvdro-ri.2.41triazol-l-vi}-lH-pyrazole-4-carboxvli c acid ethyl ester acetate [1780] [Chemical Formula 778]


1 H-NMR (CD3OD) 5 1.18 (t, J=7.3Hz, 3H) 1.95 (s, 3H) 2.00 (tt, J=6.4, 5.5Hz, 2H) 2.77 (t, J=6.4Hz, 2H) 3.78 (s, 3H) 4.15 (m, 2H) 4.21 (t, J=5.5Hz, 2H) 5.91 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 6.92 (d, J=6.8Hz, 1H) 7.64 (d, J=8.8Hz, 2H) 8.26 (s, 1H)
[1781] Example X-195: (R) and
fS)-4-(((2-Fluoro-4.5-dimethoxvphenvl)-r5-oxo-l-(3-oxo-3,4-dihvdropvr azin-2-vO-4.5-dihydro-lH-[1.2.4]triazol-3-vl1methvUamino')benzamidine acetate
'H-NMR (CD3OD) 5 1.95 (s, 3H) 3.76 (s, 3H) 3.82 (s, 3H) 5.89 (s, 1H) 6.83 (d, J=11.0Hz, 1H) 6.84 (d, J=8.7Hz, 2H) 7.10 (d, J=6.0Hz, 1H) 7.49 (br.s, 1H) 7.60 (d, J=8.7Hz, 2H) 7.68 (br.s, 1H)
HPLC retention time: 15 min (Column name: SUMICHIRAL OA-2500, 20 mm q> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 10 ml/min)
[1783] Example X-196: (R) and
fSV4-(rri-f2-Aminopvridin-3-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-
vll-f8-methoxv-4H-benzo[1.3]dioxin-6-vnmethvl]aminolbenzamidine
acetate


'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.83 (s, 3H) 4.86 (s, 2H) 5.24 (s, 2H) 5.57 (s, 1H) 6.75 (dd, J=7.4, 5.2Hz, 1H) 6.79 (d, J=1.5Hz, 1H) 6.85 (d, J=8.9Hz, 2H) 7.04 (d, J=1.5Hz, 1H) 7.62 (d, J=8.9Hz, 2H) 7.66 (dd, J=7.4, 2.2Hz, 1H) 7.94 (dd, J=5.2, 2.2Hz, 1H) HPLC retention time: 10 min
[1785] Example X-197: (R) and
(SM4[[5-Ethyl-2-fluoro-3-(2-hydroxvethoxv)phenvl]-(5-oxo-l-pvrimidi n-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-vDmethvl]amino}benzamidine

'H-NMR (CD3OD) 8 1.16 (t, J=7.2Hz, 3H) 1.95 (s, 3H) 2.57 (q, J=7.2Hz, 2H) 3.88 (t, J=4.3Hz, 2H) 4.11 (t, J=4.3Hz, 2H) 5.99 (s, 1H) 6.85 (d, J=8.9Hz, 2H) 6.92-6.96 (m, 2H) 7.35 (t, J=4.3Hz, 1H) 7.61 (d, J=8.9Hz, 2H) 8.77 (t, J=4.3Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30 mm q> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1787] Example X-198: (R) and
(S)-5-(3-{(4-CarbamimidovlphenylaminoV[2-fluoro-3-(3-hvdroxvpropox v)-5-methoxyphenyi]methyl|-5-oxo-4.5-dihydro-[1.2.4]triazol-l-yO-3H-i

midazole-4-carboxylic acid acetate [1788] [Chemical Formula 782]

'H-NMR (CD3OD) 8 1.95 (s, 3H) 2.01 (quint, J=6.3Hz, 2H) 3.73 (s, 3H) 3.75 (t, J=6.3Hz, 2H) 4.13 (t, J=6.3Hz, 2H) 5.91 (s, 1H) 6.61 (dd, J=4.9, 2.8Hz, 1H) 6.64 (dd, J=7.0, 2.8Hz, 1H) 6.83 (d, J=9.3Hz, 2H) 7.58 (s, 1H)7.61 (d, J=9.3Hz, 2H)
[1789] Example X-199: (R) and
(SV4-{["[5-Ethvl-2-fluoro-3-f3-hvdroxvpropoxy')phenvl]-(5-oxo-l-Dvrimi
din-2-yl-4.5-dihydro-lH-[l,2.4]triazol-3-ynmethvl]amino)benzamidine
acetate

'H-NMR (CD3OD) 5 1.16 (t, J=7.4Hz, 3H) 1.95 (s, 3H) 2.00 (quint, J=6.3Hz, 2H) 2.57 (q, J=7.4Hz, 2H) 3.74 (t, J=6.3Hz, 2H) 4.14 (t, J=6.3Hz, 2H) 5.98 (s, 1H) 6.86 (d, J=8.5Hz, 2H) 6.88-6.94 (m, 2H) 7.34 (t, J=4.3Hz, 1H) 7.61 (d, J=8.5Hz, 2H) 8.76 (t, J=4.3Hz, 2H) HPLC retention time: 7 min (Column name: SUM1CHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1791] Example X-200: (R) and
fSV4-an-f3-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-(2-fluoro-4.5-dimethoxvphenyOmethvUamino')benzamidine acetate


'H-NMR (CD3OD) 8 1.95 (s, 3H) 3.75 (s, 3H) 3.82 (s, 3H) 5.95 (s, 1H) 6.83 (d, J=11.4Hz, 1H) 6.85 (d, J=8.6Hz, 2H) 7.07 (d, J=7.7Hz, 1H) 7.20 (br.s, 1H) 7.33 (br.s, 1H) 7.62 (d, J=8.6Hz, 2H) 7.81 (br.s, 1H) HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1793] Example X-201:
^({ri-a-Aminopvridin-S-vn-S-oxo^.S-dihvdro-lH-n^^ltriazol-S-vn-f 2-fluoro-4.5-dimethoxyphen vOmethyl} amino)benzamidine trifluoroacetate

'H-NMR (CD3OD) 8 3.76 (s, 3H) 3.83 (s, 3H) 6.01 (s, 1H) 6.87 (d, J=11.4Hz, 1H) 6.88 (d, J=8.7Hz, 2H) 7.00 (dd, J=6.9, 5.5Hz, 1H) 7.04 (d, J=7.3Hz, 1H) 7.65 (d, J=8.7Hz, 2H) 7.92 (dd, J=5.5, 1.4Hz, 1H) 8.21 (dd, J=6.9, 1.4Hz, 1H)
[1795] Example X-202: (R) and
rS)-4-((ri-f2-Aminopvridin-3-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vl]-(2-fluoro-3.5-dimethoxvphenvnmethvllamino)benzamidine acetate [1796] [Chemical Formula 786]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.71 (s, 3H) 3.85 (s, 3H) 5.98 (s, 1H) 6.59 (dd, J=5.1, 2.6Hz, 1H) 6.63 (dd, J=7.1, 2.6Hz, 1H) 6.74 (dd, J=7.5, 5.3Hz, 1H) 6.85 (d, J=8.9Hz, 2H) 7.62 (d, J=8.9Hz, 2H) 7.66 (dd, J=7.5, 1.6Hz, 1H) 7.94 (dd, J=5.3, 1.6Hz, 1H)
HPLC retention time: 12 min (Column name: SUMICHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1797] Example X-203: (R) and
fS)-4-((|-l-(2-Aminophenvn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-vll-( 2-fluoro-3.5-dimethoxvphenvl)methvnamino)benzamidine acetate [1798] [Chemical Formula 787]

'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.72 (s, 3H) 3.86 (s, 3H) 5.98 (s, 1H) 6.59 (dd, J=5.1, 2.6Hz, 1H) 6.64 (dd, J=7.1, 2.6Hz, 1H) 6.75 (td, J=7.8, 1.3Hz, 1H) 6.85 (d, J=9.1Hz, 2H) 6.88 (dd, J=7.8, 1.3Hz, 1H) 7.11 (td, J=7.8, 1.3Hz, 1H) 7.22 (dd, J=7.8, 1.3Hz, 1H) 7.63 (d, J=9.1Hz, 2H) HPLC retention time: 7 min
[1799] Example X-204:
4-([ri-(3-Aminopvridin-2-vlV5-oxo-4.5-dihvdro-n.2.41triazol-3-vn-f3-r
4-fluoro-7-methoxy-2.3-dihvdrobenzofuran-5-vl)methvl]amino)benzamid
ine trifluoroacetate
[1800] [Chemical Formula 788]


'H-NMR (CD3OD) 8 3.28 (t, J=8.9Hz, 2H) 3.77 (s, 3H) 4.26 (t, J=8.9Hz, 2H) 5.93 (s, 1H) 6.86 (d, J=8.7Hz, 2H) 6.94 (d, J=5.4Hz, 1H) 7.23 (dd, J=7.5, 4.1Hz, 1H) 7.33 (d, J=7.5Hz, 1H) 7.63 (d, J=8.7Hz, 2H) 7.81 (d, J=4.1Hz, 1H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 20 mm 9 x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 10 ml/min)
[1801] Example X-205:
4-f{[1-f3-Aminopvridin-2-yl)-5-oxo-4.5-dihvdro-[1.2.4]triazol-3-vl1-[5-e
thvl-2-fluoro-3-(2-hvdroxvethoxv)phenvnmethvl}amino")benzamidine
acetate
[1802] [Chemical Formula 789]

'H-NMR (CD3OD) 8 1.17 (t, J=7.4Hz, 3H) 1.94 (s, 3H) 2.57 (q, J=7.4Hz, 2H) 3.88 (t, J=4.4Hz, 2H) 4.11 (t, J=4.4Hz, 2H) 6.01 (s, 1H) 6.85 (d, J=9.1Hz, 2H) 6.91 (d, J=6.2Hz, 1H) 6.97 (d, J=7.6Hz, 1H) 7.22 (dd, J=8.3, 4.5Hz, 1H) 7.33 (dd, J=8.3, 1.5Hz, 1H) 7.61 (d, J=9.1Hz, 2H) 7.81 (dd, J=4.5, 1.5Hz, 1H)
[1803] Example X-206: 4-(UK) and
rSV[l-G-Aminopvridin-2-vn-5-oxo-4.5-dihvdro-n.2.41triazol-3-vll-r5-e
thvl-2-fluoro-3-(2-hvdroxvethoxv')phenvl"|methvUamino")benzamidine
acetate

[1804] [Chemical Formula 790]

'H-NMR (CD3OD) 8 1.17 (t, J=7.4Hz, 3H) 1.95 (s, 3H) 2.57 (q, J=7.4Hz, 2H) 3.88 (t, J=4.4Hz, 2H) 4.11 (t, J=4.4Hz, 2H) 5.98 (s, 1H) 6.85 (d, J=9.1Hz, 2H) 6.93-6.96 (m, 2H) 7.20 (dd, J=8.3,4.5Hz, 1H) 7.32 (dd, J=8.3, 1.5Hz, 1H) 7.61 (d, J=9.1Hz, 2H) 7.80 (dd, J=4.5, 1.5Hz, 1H) HPLC retention time: 12 min (Column name: SUMICHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1805] Example X-207: 4-({(R) and
rSt-n-O-Aminopvridin^-vn-S-oxo^.S-dihvdro-n^^ltriazol-S-vn-rS-f 2-hydroxvethoxvV5-methoxvphenvl1methvUamino')benzamidine acetate [1806] [Chemical Formula 791]

'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.76 (s, 3H) 3.84 (t, J=4.9Hz, 2H) 4.12 (t, J=4.9Hz, 2H) 5.60 (s, 1H) 6.48 (t, J=1.7Hz, 1H) 6.62-6.65 (m, 2H) 6.85 (d, J=9.1Hz, 2H) 7.21 (dd, J=7.6, 4.7Hz, 1H) 7.34 (dd, J=7.6, 1.7Hz, 1H) 7.60 (d, J=9.1Hz, 2H) 7.83 (dd, J=4.7, 1.7Hz, 1H) HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mm 9 x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 15 ml/min)
[1807] Example X-208: (R) and
(S)-2-{3-[(4-Carbamimidoyl-3-fluorophenvlaminoV('3-ethoxv-4-methoxy

phenyOmethyl]-5-oxo-4.5-dihvdro-[1.2.4]triazol-l-vl}benzoic acid [1808] [Chemical Formula 792]

'H-NMR (CD3OD) 8 1.37 (t, J=7.2Hz, 3H) 3.82 (s, 1H) 4.06 (q, J=7.2Hz,
2H) 5.55 (s,lH) 6.55 (dd, J=14.4, 2.4Hz, 1H) 6.68 (dd, J=8.8, 2.4Hz, 1H)
6.97 (d, J=8.4Hz, 1H) 7.05-7.11 (m, 2H) 7.34-7.48 (m, 4H) 7.70 (dd,
J=7.6, 1.6Hz, 1H)
Mass spectrum (ESI) m/z: 521 (M+H)+
HPLC retention time: 12 min
[1809] Example X-209: (R) and
fS)-f3-[f4-CarbamimidovlphenylaminoH5-oxo-l-pvrimidin-2-yl-4.5-dih vdro-lH-[l .2.4]triazol-3-yDmethvll2-fluoro-5-methoxyphenoxv) acetic acid methyl ester acetate [1810] [Chemical Formula 793]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.70 (s, 3H) 3.77 (s, 3H) 4.78 (s, 2H) 5.95 (s, 1H) 6.56 (dd, J=7.2, 3.2Hz, 1H) 6.70 (m, 1H) 6.86 (d, J=8.8Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) Mass spectrum (ESI) m/z: 523 (M+H)+
HPLC retention time: 16 min (Column name: SUMICHIRAL OA-2500, 30 mm q> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 25 ml/min)

[1811] Example X-210:
4-r3-{(4-Carbamimidovlphenvlamino)-[2-fluoro-3-r2-fluoroethoxv')-5-me
thoxvphenvlJmethvU-S-oxo^.S-dihydro-lH-n^^ltriazol-l-vO-thiazole-
5-carboxvlic acid
[1812] [Chemical Formula 794]

^-NMR (CD3OD) 5 3.74 (s, 3H) 4.23 (m, 1H) 4.31 (m, 1H) 4.67 (m,
1H) 4.78 (m, 1H) 5.96 (s, 1H) 6.66 (m, 2H) 6.86 (d, J=9.2Hz, 2H) 7.63
(d, J=9.2Hz, 2H) 8.88 (s, 1H)
Mass spectrum (ESI) m/z: 546 (M+H)+
HPLC retention time: 20 min (Column name: SUMICHIRAL OA-2500,
30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 30 ml/min)
[1813] Example X-211: (R) and
(S)-{3-[f4-Carbamimidovlphenvlamino)-(5-oxo-l-pvridin-2-vl-4.5-dihvd ro-lH-[l. 2.4]triazol-3-vDmethvl]-2-fIuoro-5-methoxvphenoxv) acetic acid methyl ester acetate [1814] [Chemical Formula 795]

[1815] Example X-212: (R) and
(S)-4-{[(3-Ethynyl-5-methoxvphenvn-f5-oxo-l-pvrimidin-2-vl-4.5-dihvd ro-lH-[1.2.41triazol-3-yl)methvl]amino)benzamidine acetate

[1816] [Chemical Formula 796]

[1817] Example X-213: (R) and
(S)-4-([[3-(2-HvdroxvethoxvV5-methoxvphenvl]-f5-oxo-l-pvrimidin-2-y l-4.5-dihvdro-lH41.2.41triazol-3-vnmethvnamino)benzamidine acetate [1818] [Chemical Formula 797]

[1819] Example X-214: (R) and
(S)-4-(rr8-Ethvnvl-4H-benzori.3]dioxin-6-vn-(5-oxo-l-pvrimidin-2-vl-4 ,5-dihvdro-lH-n.2.41triazol-3-vl)methvl]amino>benzamidine acetate [1820] [Chemical Formula 798]

[1821] Example X-215: [R) and
fS^^-fffS-Ethvnvlchroman^-vlVCS-oxo-l-pvrimidin^-vl^.S-dihvdro-l H-[l,2.4]triazol-3-vnmethvl]amino>benzamidine acetate [1822] [Chemical Formula 799]


[1823] Example X-216:
243-[(4-CarbamimidoylphenvlaminoW5.6-dimethoxypyridin-3-vOmethy ll-5-oxo-4.5-dihvdro-ri.2.4]triazol-l-vUbenzoic acid acetate [1824] [Chemical Formula 800]

[1825] Example X-217:
2-{3-[("4-Carbamimidovlphenvl-3-fluorophenylamino)-(5,6-dimethoxvpvr
idin-3-vnmethvll-5-oxo-4.5-dihvdro-[l .2.4]triazol-l -vU benzoic acid
acetate
[1826] [Chemical Formula 801]

[1827] Example X-218: CE) and
(SV4-([[l-f2-Aminopvridin-3-vn-5-oxo-4.5-dihvdro-lH-n.2.41triazol-3-
yl]-(5-fluoro-8-methoxychroman-6-vDmethvl]amino}benzamidine
acetate
[1828] [Chemical Formula 802]


[1829] Example X-219: (R) and
fS)-2-Fluoro-4-fff5-fluoro-8-methoxychroman-6-ylW5xo-l-pyrimidin-
2-yl-4.5-dihvdro-lH-[1.2.41triazol-3-yl)methyl]amino)benzamidine
acetate
[1830] [Chemical Formula 803]

[1831] Example X-220:
4-("{[2-Fluoro-5-methoxv-3-(2-methoxvethoxv)phenvll-[l-(3-hvdroxvpyr
azin-2-vl)-5-oxo-4.5-dihvdro-lH-[1.2.4")tna2ol-3-vnmethvl|amino)benza
mi dine acetate
[1832] [Chemical Formula 804]

[1833] Example X-221:
5-(3-{(4-CarbamimidovlphenvlaminoV[2-fluoro-5-methoxv-3-f2-methox vethoxv)phenvl]methyl)-5-oxo-4,5-dihvdro-[1.2.4]triazol-l-vO-lH-pyraz ole-4-carboxvlic acid ethyl ester acetate [1834] [Chemical Formula 805]


[1835] Example X-222:
4-({n-G-Aminopvridin-2-vlV5-oxo-4.5-dihvdro-lH-[1.2.4]triazol-3-vl]-
[2-fluoro-3-(3-hvdroxypropoxv)-5-niethoxyphenvllmethvUamino')benza
midine acetate
[1836] [Chemical Formula 806]

[1837] Example X-223:
5-(3-U4-Carbamimidovlphenvlamino)-[2-fluoro-3-("2-hvdroxvethoxvV5-methoxvphenvljmethvl 1-5-0X0-4.5-dihvdro-[1.2,41triazol-l-yl)-lH-pvraz ole-4-carboxylic acid [1838] [Chemical Formula 807]

[1839] Example X-224: (R) and
(S)-4-{[f2-Fluoro-3-f3-hydroxvpropylV5-methoxvphenvri-(5-oxo-l-pvri
midin-2-yl-4.5-dihydro-lH-[1.2.4]triazol-3-vnmethvllamino}benzamidin
e acetate
[1840] [Chemical Formula 808]


'H-NMR (CD3OD) 8 1.80-1.88 (m, 2H) 1.91 (s, 3H) 2.71 (t, J=6.4Hz, 2H) 3.57 (t, J=6.4Hz, 2H) 3.70 (s, 3H) 5.94 (s, 1H) 6.76-6.82 (m, 1H) 6.85 (d, J=8.8Hz, 2H) 6.90-6.96 (m, 1H) 7.30 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 4.6mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 1 ml/min)
[1841] Example X-225: (R) and
(SV2-{3-[(4-Carbamimidovlphenyl-3-fluorophenylamino)-(8-methoxv-4
H-benzo[1.3]dioxin-6-vDmethyl]-5-oxo-4.5-dihydrori.2.41triazol-l-vnb
enzoic acid
[1842] [Chemical Formula 809]

'H-NMR (CD3OD) 8 3.85 (s, 3H) 4.84-4.92 (m, 2H) 5.24 (s, 2H) 5.56 (s,
1H) 6.59 (d, J=14.4Hz, 1H) 6.70 (d, J=8.8Hz, 1H) 6.81 (s, 1H) 7.03 (s,
1H) 7.35-7.50 (m, 4H) 7.72 (d, J=8.0Hz, 1H)
HPLC retention time: 27 min (Column name: SUMICHIRAL OA-2500,
30 mm 9 x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution,
Elution rate: 20 ml/min)
[1843] Example X-226: (R) and

fSV2-Fluoro-4-(r(9-methoxv-3.4-dihvdro-2H-benzorbiri.41dioxepin-7-vl
)-f5-oxo-l-pvrimidin-2-vl-4.5-dihydro-lH-|"1.2.4]triazol-3-vl)methvllami
nolbenzamidine acetate
[1844] [Chemical Formula 810]
'H-NMR (CD3OD) 8 1.93 (s, 3H) 2.10-2.15 (m, 2H) 3.77 (s, 3H) 4.11 (t, J=4.8Hz, 4H) 5.57 (s, 1H) 6.58 (dd, J=2.0, 14.4Hz, 1H) 6.67 (dd, J=2.0, 8.8Hz, 1H) 6.78 (d, J=2.0Hz, 1H) 6.88 (d, J=2.0Hz, 1H) 7.30 (t, J=4.8Hz, 1H) 7.43 (t, J=8.4Hz, 1H) 8.75 (t, J=4.8Hz, 2H)
HPLC retention time: 26 min (Column name: SUMICHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 20 ml/min)
[1845] Example X-227: (R) and
(S)-4-{[(9-Methoxv-2.3.4.5-tetrahvdro-benzo[b]oxepin-7-vl')-(5-oxo-l-pv
rimidin-2-vl-4.5-dihvdro-lH-n.2.41triazol-3-vl')methvnamino)benzamidi
ne acetate
[1846] [Chemical Formula 811]

'H-NMR (CD3OD) 8 1.62-1.68 (m, 2H) 1.88-1.96 (m, 2H) 1.91 (s, 3H) 2.72-2.78 (m, 2H) 3.76 (s, 3H) 3.90 (t, J=4.8Hz, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.94 (d, J=2.0Hz, 1H) 7.06 (d, J=2.0Hz, 1H) 7.29 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H)

[1847] Example X-228: (R) and
(S)-4-{[[2-Fluoro-3-(YS)-2-hvdroxvpropoxv)-5-methoxvphenvl]-(5-oxo-l
-pvrimidin-2-vl-4.5-dihvdro-lH-fl,2.4]triazol-3-vl')methvl]amino}benza
midine acetate
[1848] [Chemical Formula 812]

JH-NMR (CD3OD) 5 1.25 (d, J=6.8Hz, 3H) 1.92 (s,3H) 3.68 (s, 3H) 3.89 (d, J=5.6Hz, 2H) 4.06-4.14 (m, 1H) 5.96 (s, 1H) 6.57-6.64 (m, 2H) 6.84 (d, J=8.8Hz, 2H) 7.30 (t, J=4.8Hz, 1H) 7.59 (d, J=8.8Hz, 2H) 8.74 (d, J=4.8Hz, 2H)
[1849] Example X-229: (R) and
(S)-2-{3-[(4-CarbamimidovlphenylaminoW5-fluoro-8-methoxvchrornan-6-yPmethvI]-5-oxo-4,,5-dihvdro-|"1.2.4]triazol-l-yl)benzamide acetate [1850] [Chemical Formula 813]

[1851] Example X-230: (R) and
(S>-4-("((,3.4-Dimethoxvphenvl-[l-f3-fluoropvridin-2-vl)-5-oxo-4.5-dihvd ro-lH-[1.2.4]triazol-3-vllmethvl)amino)-2-fluorobenzamidine acetate [1852] [Chemical Formula 814]


[1853] Example X-231: (R) and
(S)-2-Fluoro-4-(rri-f3-fluoropvridin-2-vn-5-oxo-4.5-dihvdro-lH-ri.2.41t
riazol-3-vll-(8-methoxv-4H-benzori.31dioxin-6-vnmethvl1aminolbenza
midine acetate
[1854] [Chemical Formula 815]

[1855] Example X-232:
4-([(3-Ethvnvl-5-methoxvphenvn-C5-oxo-l-pvrimidin-2-vl-4.5-dihvdro-l H-f 1.2.41triazol-3-vnmethvllamino}benzamidine acetate [1856] [Chemical Formula 816]

'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.47 (s, 1H) 3.77 (s, 3H) 5.60 (s, 1H) 6.85 (d, J=8.0Hz, 2H) 6.93 (s, 1H) 7.15 (s, 1H) 7.42-7.63 (m, 2H) 7.60 (d, J=8.0Hz, 2H) 8.76 (d, J=3.6Hz, 2H)
[1857] Example X-233: (R) and
CS'>-4-(rr3-Ethvnvl-5-r2-fluoroethoxv)phenvn-r5-oxo-l-pvrimidin-2-vl-4 .5-dihvdro-lH-n.2.4]triazol-3-vOmethvl]amino}benzamidine acetate [1858] [Chemical Formula 817]


'H-NMR (CD3OD) 8.1.92 (s, 3H) 3.49 (s, 1H) 4.15-4.18 (m, 1H) 4.23-4.25 (m, 1H) 4.62 (t, J=4.0Hz, 1H) 4.74 (t, J=4.0Hz, 1H) 5.61 (s, 1H) 6.85 (d, J=8.8Hz, 2H) 6.98 (q, J=1.2Hz, 1H) 7.19 (t, J=2.0Hz, 1H) 7.27-7.30 (m, 2H) 7.60 (d, J=8.8Hz, 2H) 8.76 (d, J=5.2Hz, 2H) HPLC retention time: 13 min
[1859] Example X-234: (R) and
(S'M-ff [3-(2-Methoxyethoxy)-5-vinvlphenvl]-( 5-oxo-l -pvrimidin-2-vl-4 .5-dihvdro-lH-[1.2.4]triazol-3-vOmethvl]amino}benzamidine acetate [1860] [Chemical Formula 818]

'H-NMR (CD3OD) 8 1.91 (s, 3H) 3.38 (s, 3H) 3.67-3-75 (m, 2H) 4.11 (dd, J=3.2, 6.0Hz, 2H) 5.23 (d, J=10.8Hz, 1H) 5.61 (s, 1H) 5.78 (d, J= 17.6Hz, 1H) 6.68 (dd, J=10.8,17.6Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 6.95 (s, 1H) 7.05 (s, 1H) 7.24 (s, 1H) 7.29 (t, J=4.4Hz, 1H) 7.59 (t, J=8.8Hz, 2H) 8.76 (d, J=4.4Hz, 2H) HPLC retention time: 13 min
[1861] Example X-235: (R) and
(S)-4-([(2-Fluoro-3-hvdroxv-5-methoxvphenvl)-("5-oxo-l-pvrimidin-2-vl -4.5-dihvdro-lH-[1.2.4]triazol-3-vnmethvl]aminolbenzamidine acetate [1862] [Chemical Formula 819]


1 H-NMR (CD3OD) 8 1.92 (s, 3H) 3.67 (s, 3H) 5.93 (s, 1H) 6.45 (dd, J=3.2,7.2Hz, 1H) 6.52 (dd, J=3.2,5.2Hz, 1H) 6.85 (d, J=8.8Hz, 2H) 7.31 (t, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) 8.76 (d, J=4.8Hz, 2H) HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mm q> x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1863] Example X-236: (R) and
(S)-4-{f(8-Ethvnvl-2.3-dihvdrobenzo[1.4]dioxin-6-vl)-(r5-oxo-l-pyrimidi
n-2-vl-4.5-dihvdro-lH-[1.2,4]triazol-3-vDmethvl]amino)benzamidine
acetate
[1864] [Chemical Formula 820]

'H-NMR (CD3OD) 8 1.92 (s, 3H) 3.62 (s, 1H) 4.21-4.24 (m, 2H)
4.26-4.30 (m, 2H) 5.53 (s, 1H) 6.84 (d, J=8.8Hz, 2H) 7.05 (d, J=2.0Hz,
1H) 7.17 (d, J=2.0Hz, 1H) 7.31 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H)
8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 10 min (Column name: SUMICHIRAL OA-2500,
30 mm (p x 25 cm, Manufacturer: Sumika Chemical Analysis Service,
Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution,
Elution rate: 40 ml/min)
[1865] Example X-237: (R) and

fS)-4-{[[3-Ethyl-5-(2-hydroxyethoxy)phenyl]-(5-oxo-l-pvrimidin-2-vl-4. 5-dihydro-lH-[l,2,41triazol-3-vl)methvl]aminolbenzamidine acetate [1866] [Chemical Formula 821]

'H-NMR (CD3OD) 5 1.20 (t, J=7.6Hz, 3H) 1.91 (s, 3H) 2.61 (q, J=7.6Hz, 2H) 3.83 (t, J=4.8Hz, 2H) 4.03 (t, J=4.8Hz, 2H) 5.58 (s, 1H) 6.76 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.97 (d, J=2.0Hz, 1H) 7.00 (s, 1H) 7.30 (t, J=4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H) HPLC retention time: 6 min (Column name: SUMICHIRAL OA-2500, 30 mm (p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1867] Example X-238: (R) and
fS)-4-{[[5-Ethoxy-2-fluoro-3-f3-hydroxvpropoxv)phenyl1-('5-oxo-l-pyri
midin-2-vl-4.5-dihvdro-lH-[1.2.4]triazol-3-yI)methyl1amino}benzamidin
e acetate
[1868] [Chemical Formula 822]
'H-NMR (CD3OD) 8 1.30 (t, J=7.2Hz, 3H) 1.94 (s, 3H) 1.99 (Sept, J=6.0Hz, 2H) 3.74 (t, J=6.0Hz, 2H) 3.90-3.97 (m, 2H) 4.12 (t, J=6.0Hz, 2H) 5.98 (s, 1H) 6.58 (dd, J=2.4, 4.4Hz, 1H) 6.63 (dd, J=2.4, 6.8Hz, 1H) 6.86 (d, J=8.8Hz, 2H) 7.35 (t, J=4.8Hz, 1H) 7.63 (d, J=8.8Hz, 2H) 8.78 (d, J=4.8Hz, 2H)

HPLC retention time: 9 rain (Column name: SUMICHIRAL OA-2500, 30 mm (p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1869] Example X-239: 3-f3-(fR) and
(^W4-Carbamimidoylphenvlamino)-r4-(2-hvdroxyethoxv")-3-rnethoxvphe
nyl1methvU-5-oxo-4,5-dihvdro-n,2.4]triazol-l-vOthiophene-2-carboxvli
c acid
[1870] [Chemical Formula 823]

'H-NMR (CD3OD) 5 3.84-3.89 (m, 5H) 4.02-4.08 (m, 2H) 4.59 (br.s, 1H) 5.56 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.99 (d, J=8.0Hz, 1H) 7.06-7.08 (m, 2H) 7.17 (s, 1H) 7.42 (d, J=4.8Hz, 1H) 7.61 (d, J=8.8Hz, 2H) HPLC retention time: 11 min (Column name: SUMICHIRAL OA-2500, 30 mm cp x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1871] Example X-240: 4-fffR) and
(S>-r4-(2-Hvdroxvethoxv)-3-methoxvphenvl]-(5-oxo-l-pvrimidin-2-vl-4. 5-dihvdro-lH-[1.2,4]triazol-3-vl)methvllamino>benzamidine acetate [1872] [Chemical Formula 824]
'H-NMR (CD3OD) 5 1.92 (s, 3H) 3.84 (s, 3H) 3.85 (t, J=4.8Hz, 2H) 4.03

(t, J=4.8Hz, 2H) 5.62 (s, 1H) 6.86 (d, J=8.4Hz, 2H) 6.96 (d, J=8.4Hz, 1H) 7.09 (d, J=8.4Hz, 1H) 7.19 (s, 1H) 7.32 (t, J=4.8Hz, 1H) 7.60 (d, J=8.4Hz, 2H) 8.78 (d, J==4.8Hz, 2H)
HPLC retention time: 8 min (Column name: SUMICHIRAL OA-2500, 30 mm (p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1873] Example X-241: 4-{[fR) and
fSV[4-f3-HvdroxvpropoxvV3-methoxvphenvl]-(5-oxo-l-pvrimidin-2-yl-4.5-dihydro-lH-[L2.4]triazol-3-yl)methyllamino}benzamidine acetate [1874] [Chemical Formula 825]

'H-NMR (CD3OD) 5 1.91 (s, 3H) 1.94-2.00 (m, 2H) 3.73 (t, J=6.4Hz, 2H) 3.82 (s, 3H) 4.09 (t, J=6.4Hz, 2H) 5.58 (s, 1H) 6.86 (d, J=8.8Hz, 2H) 6.95 (d, J=8.4Hz, 1H) 7.08 (d,J=8.4Hz, 1H) 7.17 (s, 1H) 7.30 (t, 4.8Hz, 1H) 7.60 (d, J=8.8Hz, 2H) 8.77 (d, J=4.8Hz, 2H)
HPLC retention time: 7 min (Column name: SUMICHIRAL OA-2500, 30 mm (p x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.05 M ammonium acetate-methanol solution, Elution rate: 40 ml/min)
[1875] Example X-242: 4-(3-{(IO and
(S)-(4-Carbamimidoylphenvlamino)-[2-fluoro-4-(2-hydroxvethoxvV5-me thoxvphenvllmethvU-5-0X0-4.5-dihvdro-n.2.4]triazol-l-vnthiazole-5-ca rboxylic acid [1876] [Chemical Formula 826]


lH-NMR (CD3OD) 5 3.80-3.84 (m, 2H) 3.84 (s, 3H) 3.96-4.09 (m, 2H) 5.89 (s, 1H) 6.83-6.88 (m, 3H) 7.11 (d, J=7.2Hz, 1H) 7.62 (d, J=8.4Hz, 2H) 8.88 (s, 1H)
HPLC retention time: 17 min (Column name: SUMICHIRAL OA-2500, 30 mm 9 x 25 cm, Manufacturer: Sumika Chemical Analysis Service, Ltd., Mobile phase: 0.5 mM ammonium acetate-methanol solution, Elution rate: 30 ml/min)
[1877] Example X-243: 4-lUK) and
(S)-[3-(2-DimethvlaminoethoxvV5-methylphenvl]-f5-oxo-l-pyrimidin-2-
vl-4.5-dihvdro-lH-n.2,41triazol-3-yI)methvnamino}benzamidine
diacetate


[1881] Example X-245: 4-1 TOO and
CS)-C2-Fluoro-5-methoxv-3-methylphenvl)-(r5-oxo-l-pvrimidin-2-vl-4.5-d ihvdro-lH-n-2,4]triazol-3-vQmethvl]amino}benzamidine acetate [1882] [Chemical Formula 829]


J=6.0Hz, 1H) 6.85 (d, J=8.5Hz, 2H) 7.62 (d, J=8.5Hz, 2H) 8.11 (s, 1H)
[1887] Example X-248: (R) and
('S)-3-{3-[('4-Carbamimidovlphenvlamino)-(2-fluoro-3,5-dimethoxvphenv
Omethyl]-5-oxo-4J-dihvdro-[1.2.4]triazol-l-yl)thiophene-2-carboxylic
acid

[1891] (Pharmacological Test Example 1)
[Inhibitory activity against clotting factor Vila]
[1892] (1) Method
Dimethylsulfoxide (DMSO) solutions were prepared with compounds of
the invention at concentration of 10 mmol/L (10 mmol/L compound
solutions).
One packet of tris-hydroxymethylaminomethane-preset (hereinafter
referred to as "Tris preset") (Product of Sigma Corp., Catalog No.
T8293), 8.8 g of sodium chloride (NaCl) and 1 g of bovine serum
albumin (hereinafter abbreviated as "BSA") were dissolved in 1 L of
water to prepare a Tris-BSA buffer (100 mmol/L Tris, 0.15 mol/L NaCl,
0.1% BSA, pH 7.4).

This Tris-BSA buffer (180 uL) was added to the aforementioned 10 mmol/L compound solution (20 uL). A 10-fold dilution series was prepared for this mixture using the aforementioned Tris-BSA buffer, and solutions with the compound at concentrations of 1.0 mmol/L, 100, 10, 1, 0.1, 0.01 and 0.001 umol/L were prepared (1.0 mmol-0.001 umol/L compound solutions).
As a control, a solution was prepared by 10-fold dilution of DMSO with the Tris-BSA buffer (hereinafter referred to as "control 10% solution"). After dissolving one packet of Tris preset, NaCl (8.8 g) and BSA (1 g) in water (about 900 mL), there were added 1 mol/L aqueous calcium chloride (CaCh) (15 mL) and 1 mg/mL aqueous cephalin (30 mL), and the total volume was brought to 1 L by adding water. To this solution there was added a human tissue factor (hereinafter, "TF") sample (product of Calbiochem, Catalog No. 612151) (450 u,g) to a TF sample concentration of 10 nmol/L, and then a human clotting factor Vila (hereinafter, "Factor Vila") purified sample (product of Enzyme Research Laboratories, Catalog No. HFVIIa) (250 fxg) was added to a Factor Vila purified sample concentration of 5 nmol/L, to prepare an enzyme solution (100 mmol/L Tris-HCl, 0.15 mol/L NaCl, 15 mmol/L CaCb, 30 n.g/mL cephalin, 1 mg/mL BSA, 10 nmol/L TF, 5 nmol/L Factor Vila).
To 110 uL of this enzyme solution there was added 15 uL of each of the 1.0 mmol-0.001 umol/L compound solutions, and then 25 uL of a 1.0 mmol/L synthetic chromogenic substrate solution (Spectrozyme FVIIa, product of American Diagnostica, Catalog No. 217L) was added and the mixture was allowed to stand at room temperature for 40 minutes. Next, the amount of 4-nitroanilide released into the solution was quantitated by spectrophotometry (405 nm).
A control measurement was conducted in the same manner, using the control 10% solution instead of the compound solution. This measurement yielded the enzyme reaction inhibition in the presence of 100 nmol/L to 0.1 nmol/L of each compound of the invention. The enzyme reaction inhibition at each compound concentration was

subjected to non-linear regression analysis, and the IC50 value for
inhibitory activity of each compound against clotting factor Vila was
calculated.
[1893] (2) Results
Tables 1 to 4 show the IC50 values (IC50 FVIIa (uM)) for inhibitory
activity of each compound against clotting factor Vila.



as therapeutic and/or prophylactic agents for diseases associated with thrombus formation.




CLAIMS
1. A compound represented by general formula (1) or a salt thereof: [Chemical Formula 1]

(D
wherein Rla, Rlb, R,c and Rld each independently represent hydrogen, hydroxyl, CI-6 alkyl or halogen;
R2 represents C6-10 aryl optionally having 1-5 substituents selected from Group Al below, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Al below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-5 substituents selected from Group Al below;
R3 represents a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Al below, C6-10 aryl optionally having 1-5 substituents selected from Group Al below or a 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group A1 below; and
Z1 and Z2 represent hydrogen,
wherein Group Al consists of hydroxyl, halogen, cyano, nitro, oxo, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyl optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, C3-8 cycloalkyloxy optionally having 1-5 substituents selected from Group Bl below, C2-6 alkenyloxy, C2-6 alkynyloxy, CI-6 alkylthio, CI-6 alkylsulfinyl, Cl-6 alkylsulfonyl, Cl-6 alkylsulfonyloxy, C6-10 aryl

optionally having 1-5 substituents selected from Group Bl below, C6-10 aryloxy optionally having 1-5 substituents selected from Group Bl below, 5- to 10-membered heteroaryl optionally having 1-5 substituents selected from Group Bl below, 5- to 10-membered heteroaryloxy optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclic group optionally having 1-5 substituents selected from Group Bl below, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-5 substituents selected from Group Bl below, a group represented by the formula -NRU-R2t and a group represented by the formula -CO-R3t,
where Ru and R2t each independently represent hydrogen, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group Bl below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkylsulfonyl optionally having 1-3 substituents selected from Group Bl below, carbamoyl, aminosulfonyl, C6-10 aryl optionally having 1-5 substituents selected from Group Bl below or 5- to 10-membered heteroaryl optionally having 1 -5 substituents selected from Group B1 below, and R3t represents hydroxyl, CI-6 alkyl optionally having 1-3 substituents selected from Group Bl below, CI-6 alkoxy optionally having 1-3 substituents selected from Group Bl below, amino, mono(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below or di(Cl-6 alkyl)amino optionally having 1-3 substituents selected from Group Bl below,
wherein Group Bl consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, C3-8 cycloalkyl, amino, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, carbamoyl, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl, C6-10 aryl optionally having 1-5 substituents selected from Group CI below and 5-to 10-membered heteroaryl optionally having 1-5 substituents selected from Group CI below,
wherein Group CI consists of halogen, CI-6 alkyl and CI-6

alkoxy.
2. A compound represented by general formula (1-1) or a salt
thereof:
[Chemical Formula 2]

(1-1)
wherein Rla, Rlb, Rlc, Rld, R2, R3, Z1 and Z2 have the same definitions as Rla, Rlb, Rlc, Rld, R2, R3, Z1 and Z2 in claim 1.
3. A compound represented by general formula (1-2) or a salt
thereof:
[Chemical Formula 3]

(1-2)
wherein Rla, Rlb, Rlc, Rld, R2, R3, Z1 and Z2 have the same definitions as Rla, Rlb, Rlc, R,d, R2, R3, Z1 and Z2 in claim 1.
4. A compound according to any one of claims 1 to 3 or a salt
thereof, wherein Rla, Rlb, Rlc and Rld are each independently hydrogen,
fluorine or hydroxyl.
5. A compound according to any one of claims 1 to 4, or a salt
thereof, wherein R2 is phenyl optionally having 1-4 substituents selected
from Group Dl below, pyridyl optionally having 1-3 substituents

selected from Group Dl below or a 9- to 12-membered benzene-fused cyclic group optionally having 1-4 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,
wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
6. A compound according to any one of claims 1 to 4 or a salt
thereof, wherein R2 is phenyl optionally having 1-4 substituents selected
from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,
wherein Group D2 consists of hydroxyl, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
7. A compound according to any one of claims 1 to 4 or a salt
thereof, wherein R2 is phenyl optionally having 2 or 3 substituents
selected from Group D3 below,
wherein Group D3 consists of fluorine, chlorine, methyl optionally having 1 substituent selected from Group D4 below, ethyl

optionally having 1 substituent selected from Group D4 below, vinyl, ethynyl, methoxy optionally having 1 or 2 substituents selected from Group D4 below, ethoxy optionally having 1 or 2 substituents selected from Group D4 below, 1-propyloxy optionally having 1 or 2 substituents selected from Group D4 below, 2-propyloxy optionally having 1 or 2 substituents selected from Group D4 below, allyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy and acetyl,
wherein Group D4 consists of hydroxyl, fluorine, cyano, methoxy, methylamino, dimethylamino, methylaminocarbonyl and dimethylaminocarbonyl.
8. A compound according to any one of claims 1 to 4 or a salt thereof, wherein R2 is a group represented by the formula: [Chemical Formula 4]

wherein R21 represents hydrogen, fluorine or chlorine;
R22 represents hydrogen, hydroxyl, methyl optionally having 1 substituent selected from Group D5 below, ethyl optionally having 1 substituent selected from Group D5 below, methoxy optionally having 1 substituent selected from Group D5 below, ethoxy optionally having 1 or 2 substituents selected from Group D5 below, 1-propyloxy optionally having 1 substituent selected from Group D5 below, 2-propyloxy optionally having 1 substituent selected from Group D5 below, allyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy or acetyl;
R23 represents hydrogen, fluorine, hydroxyl, methoxy optionally having 1 substituent selected from Group D6 below, ethoxy optionally having 1 substituent selected from Group D6 below or 2-propyloxy optionally having 1 substituent selected from Group D6 below; and
R24 represents hydrogen, fluorine, hydroxyl, methyl optionally having 1 substituent selected from Group D7 below, ethyl, vinyl, ethynyl,

methoxy optionally having 1 substituent selected from Group D7 below, ethoxy optionally having 1 substituent selected from Group D7 below, 2-propyloxy or allyloxy,
wherein Group D5 consists of hydroxyl, fluorine, cyano, methoxy, dimethylamino, dimethylaminocarbonyl, 2-fluoroethoxy and 2-hydroxyethoxy,
wherein Group D6 consists of fluorine, cyano, methoxy, dimethylamino, methylaminocarbonyl and dimethylaminocarbonyl,
wherein Group D7 consists of hydroxyl, fluorine, cyano and ethoxy having one methoxy.
9. A compound according to claim 8 or a salt thereof, wherein
R21 is hydrogen or fluorine.
10. A compound according to claim 8 or 9 or a salt thereof, wherein R22 is hydrogen, hydroxyl, cyanomethyl, methoxymethyl, methoxy, dimethylaminocarbonylmethoxy, ethoxy, 2-fluoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-(dimethylamino)ethoxy, tetrahydrofuryloxy, tetrahydropyranyloxy, fluoromethoxy, 3-hydroxypropyloxy, 2-fluoroethoxymethyl or 2-hydroxyethoxymethyl.
11. A compound according to any one of claims 8 to 10 or a salt thereof, wherein R23 is hydrogen, fluorine, methoxy, cyanomethoxy, ethoxy, 2-propyloxy or 2-methoxyethoxy.
12. A compound according to any one of claims 8 to 11 or a salt thereof, wherein R24 is hydrogen, hydroxyl, methyl, methoxymethyl, ethyl, vinyl, ethynyl, methoxy, ethoxy or 2-fluoroethoxy.
13. A compound according to any one of claims 1 to 4 or a salt thereof, wherein R2 is pyridyl optionally having 1 -3 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7

alkylcarbonyl,
wherein Group D2 consists of hydroxyi, halogen, cyano, oxo, CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
14. A compound according to any one of claims 1 to 4 or a salt
thereof, wherein R2 is pyridyl having 2 substituents selected from the
group consisting of CI-6 alkyl and CI-6 alkoxy.
15. A compound according to any one of claims 1 to 4 or a salt thereof, wherein R2 is pyridyl having 2 substituents selected from the group consisting of methyl, methoxy and ethoxy.
16. A compound according to any one of claims 1 to 4 or a salt thereof, wherein R2 is a group represented by the formula:
[Chemical Formula 5]

wherein R25 represents methyl or methoxy; and R26 represents methoxy or ethoxy.
17. A compound according to any one of claims 1 to 4 or a salt
thereof, wherein R2 is a 9- to 12-membered benzene-fused cyclic group
optionally having 1-4 substituents selected from Group Dl below,
wherein Group Dl consists of hydroxyi, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D2 below, C2-6 alkenyloxy, CI-6 alkylsulfonyloxy, a 5- or 6-membered non-aromatic heterocyclooxy group optionally having 1-3 substituents selected from Group D2 below and C2-7 alkylcarbonyl,
wherein Group D2 consists of hydroxyi, halogen, cyano, oxo,

CI-6 alkoxy optionally having halogen, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl and di(Cl-6 alkyl)aminocarbonyl.
18. A compound according to any one of claims 1 to 4 or a salt
thereof, wherein R2 is a group represented by the formula:
[Chemical Formula 6]

wherein R represents hydrogen or halogen;
R28 represents hydrogen, hydroxyl, halogen, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or C2-7 alkylcarbonyl;
R29 represents hydrogen, cyano, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or carbamoyl;
X represents carbon optionally having 1 or 2 substituents selected from Group D8 below, nitrogen optionally having 1 substituent selected from Group D8 below or oxygen;
m represents an integer of 0-3 and n represents an integer of 0-2, with the proviso that the sum of m and n is 1-4; and
Rings A and B optionally contain one double bond in the ring and optionally have an oxo group on the ring,
wherein Group D8 consists of hydrogen, hydroxyl, halogen, CI-6 alkoxy, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl and CI-6 alkyl optionally having halogen.
19. A compound according to claim 18 or a salt thereof, wherein


wherein R27 represents hydrogen or halogen;
R"8 represents hydrogen, hydroxyl, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, C2-6 alkenyl, C2-6 alkynyl, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or C2-7 alkylcarbonyl;
R29 represents hydrogen, cyano, CI-6 alkyl optionally having 1-3 substituents selected from Group D8 below, CI-6 alkoxy optionally having 1-3 substituents selected from Group D8 below or aminocarbonyl; and
Ring A optionally has an oxo group on the ring,
wherein Group D8 consists of hydrogen, hydroxyl, halogen, CI-6 alkoxy, mono(Cl-6 alkyl)amino, di(Cl-6 alkyl)amino, mono(Cl-6 alkyl)aminocarbonyl, di(Cl-6 alkyl)aminocarbonyl and CI-6 alkyl optionally having halogen.
20. A compound according to claim 19 or a salt thereof, wherein
R28 is methyl, ethyl, methoxy, ethoxy, vinyl or ethynyl.
21. A compound according to claim 19 or 20 or a salt thereof,
wherein R29 is hydrogen.
22. A compound according to any one of claims 1 to 21 or a salt

thereof, wherein R3 is phenyl optionally having 1-3 substituents selected from Group El below, pyridyl optionally having 1-3 substituents selected from Group El below, N-oxypyridyl optionally having 1-3 substituents selected from Group El below, N-Cl-6 alkylpyridiniurn optionally having 1-3 substituents selected from Group El below, pyrazinyl optionally having 1-3 substituents selected from Group El below, pyridazinyl optionally having 1-3 substituents selected from Group El below, pyrimidinyl optionally having 1-3 substituents selected from Group El below, pyrazolyl optionally having 1 or 2 substituents selected from Group El below, imidazolyl optionally having 1 or 2 substituents selected from Group El below, thiazolyl optionally having 1 or 2 substituents selected from Group El below, thienyl optionally having 1-3 substituents selected from Group El below or dihydropyrazinyl having an oxo group, with the proviso that when R3 is N-Cl-6 alkylpyridinium, R3 forms an ion pair with an anion in the molecule,
wherein Group El consists of hydroxyl, halogen, cyano, CI-6 alkyl, CI-6 alkoxy, a group represented by the formula -NH-R2!t and a group represented by the formula -CO-R3U,
where R21t represents hydrogen, CI-6 alkyl, C2-6 alkenyl, C2-7 alkylcarbonyl optionally having 1-3 substituents selected from Group E2 below, C2-7 alkoxycarbonyl optionally having 1-3 substituents selected from Group E2 below, CI-6 alkylsulfonyl, carbamoyl or aminosulfonyl, and R31t represents hydroxyl, CI-6 alkyl, CI-6 alkoxy, amino, mono(Cl-6 alkyl)amino or di(Cl-6 alkyl)amino),
wherein Group E2 consists of hydroxyl, Cl-6 alkoxy and C3-8 cycloalkyl.
23. A compound according to any one of claims 1 to 21 or a salt thereof, wherein R3 is phenyl optionally having 1 or 2 substituents selected from Group E3 below, pyridyl optionally having 1 or 2 substituents selected from Group E3 below, N-oxypyridyl optionally having 1 or 2 substituents selected from Group E3 below, pyrazinyl optionally having 1 or 2 substituents selected from Group E3 below, pyridazinyl optionally having 1 or 2 substituents selected from Group E3

below, pyrimidinyl optionally having 1 or 2 substituents selected from Group E3 below, pyrazolyl optionally having 1 or 2 substituents selected from Group E3 below, imidazolyl optionally having 1 or 2 substituents selected from Group E3 below, thiazolyl optionally having 1 or 2 substituents selected from Group E3 below, thienyl optionally having 1 or 2 substituents selected from Group E3 below or dihydropyrazinyl having an oxo group,
wherein Group E3 consists of halogen, CI-6 alkyl, CI-6 alkoxy, a group represented by the formula -NH-R22t,
where R22t represents hydrogen or C2-7 alkoxycarbonyl, and a group represented by the formula -CO-R32t,
where R32t represents hydroxyl, CI-6 alkoxy or amino.
24. A compound according to any one of claims 1 to 21 or a salt
thereof, wherein R3 is phenyl optionally having one group selected from
Group E4 below, pyridyl optionally having one group selected from
Group E5 below, N-oxypyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,
pyrazolyl optionally having one group selected from Group E4 below,
imidazolyl optionally having one group selected from Group E4 below,
thiazolyl optionally having one group selected from Group E4 below,
thienyl optionally having one group selected from Group E4 below or
dihydropyrazinyl having an oxo group,
wherein Group E4 consists of methoxy, carboxyl, carbamoyl, methoxycarbonyl and methoxycarbonylamino,
wherein Group E5 consists of fluorine, methyl, methoxy and amino.
25. A medicament comprising a compound according to any one
of claims 1 to 24 or a salt thereof.
26. A therapeutic and/or prophylactic agent for a disease
associated with thrombus formation, comprising a compound according
to any one of claims 1 to 24 or a salt thereof.
27. A therapeutic and/or prophylactic agent for a disease selected
from Group Fl below, comprising a compound according to any one of
claims 1 to 24 or a salt thereof,

wherein Group Fl consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis, disseminated intravascular coagulation syndrome and malignant tumor.
28. A therapeutic and/or prophylactic agent for a disease selected from Group F2 below, comprising a compound according to any one of claims 1 to 24 or a salt thereof,
wherein Group F2 consists of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis and disseminated intravascular coagulation syndrome.
(Example 3)
29. The compound:
4-({[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidin-2-yl-4,5-dihydro-lH-[l, 2,4|triaz,ol-3-yl (methyl }amino)benzamidine

or a pharmaceuiically acceptable salt thereof.
(Example 157)
30.The compound: 5-{3-|(4.carbamimidoylphenylamino)-(2-fluoro-4.5-dimethoxy])henyl)me
lhyll-5-oxo-4.5-dihydro-[1.2.41triazol-l-yl}-lH-pyrazole-4-carboxylic acid



(Example 168)
31. The compound:
3-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2.3-dihydrob cnzo[l,4]dioxin-6-yl)methyl 1-5-0X0-4.5-dihydro-fl,2,4]triazol-1-yUthiop

32. Claim 4x (New)
The compound:
4-{[ ll-(3-Aminopyridin-2-yl)-5-oxo-4,5-dihydro-lH-[1.2.4]triazol-3-yl]


(Example 153)
33. The compound: 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-l-pyrimidi


(Example J67)
35. The compound:
4-(3-{(4-carbamimidoylphcnylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-mcthox yphenyl] methyl}-5-0X0-4.5-dihydrof 1,2.4]triazol-l-yl)tliiazolc-5-

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Patent Number 269490
Indian Patent Application Number 5772/CHENP/2008
PG Journal Number 44/2015
Publication Date 30-Oct-2015
Grant Date 26-Oct-2015
Date of Filing 24-Oct-2008
Name of Patentee EISAI R&D MANAGEMENT CO; LTD.
Applicant Address 6-10, KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO 112-8088
Inventors:
# Inventor's Name Inventor's Address
1 RICHARD CLARK, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
2 FUMIYOSHI MATSUURA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
3 KAZUNOBU KIRA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
4 SHINSUKE HIROTA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
5 HIROSHI AZUMA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
6 TADASHI NAGAKURA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
7 KIMIYO TABATA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
8 TAKAO OMAE C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
9 TATSUO HORIZOE, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
10 KAZUTOMI KUSANO, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
11 RICHARD CLARK, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
12 FUMIYOSHI MATSUURA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
13 KAZUNOBU KIRA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
14 SHINSUKE HIROTA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
15 HIROSHI AZUMA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
16 TADASHI NAGAKURA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
17 KIMIYO TABATA, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
18 TAKAO OMAE C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
19 TATSUO HORIZOE, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
20 KAZUTOMI KUSANO, C/O TSUKUBA RESEARCH LABORATORIES, EISAI CO; LTD, 1-3, TOKODAI 5-CHOME, TSUKUBA-SHI, IBARAKI 300-2635
PCT International Classification Number C07D 249/12
PCT International Application Number PCT/JP07/55813
PCT International Filing date 2007-03-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2006-218819 2006-08-10 Japan
2 2006-162594 2006-06-12 Japan
3 60/804878 2006-06-15 Japan
4 2006-83486 2006-03-24 Japan
5 60/786687 2006-03-29 Japan